<tr><td>Assembly process code</td><td>Comprehensive entropy value</td></tr><tr><td>B1</td><td>3.422</td></tr><tr><td>B2</td><td>3.869</td></tr><tr><td>B3</td><td>3.108</td></tr><tr><td>B4</td><td>3.901</td></tr><tr><td>B5</td><td>4.221</td></tr><tr><td>B6</td><td>4.002</td></tr><tr><td>B7</td><td>4.236</td></tr><tr><td>B8</td><td>3.654</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Comprehensive entropy value of spindle rotating MAU in each assembly procedure \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[122,363,873,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(7) The weight of each assembly process is obtained by AHP and $a = \\\\{0.102, 0.107, 0.121, 0.107, 0.165, 0.115\\\\}$ . Finally, the comprehensive evaluation entropy of spindle rotating MAU is: $E_{A_j} = \\\\sum_{k=1}^{8} E_{B_k} a_k \\\\approx 3.844$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,449,465,463]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.3 Average failure rate prediction for MAUs \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,464,867,479]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The comprehensive evaluation entropy values of other MAUs can be obtained, as shown in Table 3. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[124,499,873,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0023/74f17afffb4001b127289a260ad62249aff5fb14b3dbee38ca6a2fbcbb401e7a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>MAU number</td><td>MAU name</td><td>Entropy value of comprehensive evaluation</td></tr><tr><td>A1</td><td>Spindle rotating MAU</td><td>3.844</td></tr><tr><td>A2</td><td>Active pulley rotating MAU</td><td>3.537</td></tr><tr><td>A3</td><td>Driven pulley rotating MAU</td><td>3.479</td></tr><tr><td>A4</td><td>Pull jaw moving MAU</td><td>4.268</td></tr><tr><td>A5</td><td>Motor coded braking MAU</td><td>5.287</td></tr><tr><td>A6</td><td>Balance cylinder piston moving MAU</td><td>4.892</td></tr><tr><td>A7</td><td>Spindle cone hole blowing MAU</td><td>2.973</td></tr><tr><td>A8</td><td>Spindle inner cooling and blowing MAU</td><td>3.107</td></tr><tr><td>A9</td><td>Spindle central cooling MAU</td><td>3.215</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3. Entropy value of comprehensive evaluation of various MAUs \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[112,66,213,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"QR2MSE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[784,66,880,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,82,438,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Materials Science and Engineering \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[473,82,606,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1043 (2021) 042022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[636,82,880,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi:10.1088/1757-899X/1043/4/042022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[495,939,510,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[121,139,873,189]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The average failure rate of the similar MAU for pull jaw moving MAU is $\\\\overline{\\\\lambda}^{*} = 2.462$ , and the corresponding comprehensive evaluation entropy value is $E_{A}^{*} = 4.268$ . According to equation (8) and (9), the estimated average failure rate of other MAUs are obtained, as showed in Table 4. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[300,209,697,448]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0434/377f6d83db96b10eb75f68ac40657cebd75cd245f16796696725b926247ad94b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>MAU</td><td>Scoring coefficient CJ</td><td>Predicted average failure rate λi</td></tr><tr><td>A1</td><td>0.90</td><td>1.283×10-4</td></tr><tr><td>A2</td><td>0.83</td><td>1.213×10-4</td></tr><tr><td>A3</td><td>0.82</td><td>1.199×10-4</td></tr><tr><td>A4</td><td>1</td><td>1.462×10-4</td></tr><tr><td>A5</td><td>1.24</td><td>1.813×10-4</td></tr><tr><td>A6</td><td>1.15</td><td>1.640×10-4</td></tr><tr><td>A7</td><td>0.70</td><td>0.998×10-4</td></tr><tr><td>A8</td><td>0.73</td><td>1.041×10-4</td></tr><tr><td>A9</td><td>0.75</td><td>1.069×10-4</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 4. Predicted average failure rate of each MAU of spindle box. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[122,461,502,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.4 Average failure rate prediction for spindle box \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[121,476,873,519]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to predict the reliability of complex mechanical products it is necessary to determine the importance degree of the influence of the MAU on the reliability of products. The comparison matrix is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[127,521,235,537]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\tilde {D} = [ D ^ {-}, D ^ {+} ] =\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[127,539,885,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\left[ \\\\begin{array}{c c c c c c c c c} [ 1, 1 ] & [ 1. 2, 1. 5 ] & [ 1. 1, 1. 3 ] & [ 1. 2, 1. 6 ] & [ 1, 1. 3 ] & [ 0. 8, 1. 4 ] & [ 1. 3, 1. 6 ] & [ 1. 2, 1. 4 ] & [ 1. 1, 1. 6 ] \\\\\\\\ [ 0. 6, 0. 8 ] & [ 1, 1 ] & [ 1. 2, 1. 4 ] & [ 1. 1, 1. 2 ] & [ 0. 9, 1. 1 ] & [ 1, 1. 2 ] & [ 1. 3, 1. 4 ] & [ 1. 1, 1. 4 ] & [ 1, 1. 4 ] \\\\\\\\ [ 0. 7, 0. 9 ] & [ 0. 7, 0. 8 ] & [ 1, 1 ] & [ 0. 8, 1 ] & [ 0. 9, 1. 3 ] & [ 0. 7, 1 ] & [ 1. 2, 1. 3 ] & [ 1. 1, 1. 3 ] & [ 1. 2, 1. 3 ] \\\\\\\\ [ 0. 6, 0. 8 ] & [ 0. 8, 0. 9 ] & [ 1, 1. 2 ] & [ 1, 1 ] & [ 1. 1, 1. 3 ] & [ 0. 8, 1. 3 ] & [ 1. 1, 1. 4 ] & [ 1. 2, 1. 5 ] & [ 1. 3, 1. 4 ] \\\\\\\\ [ 0. 7, 1 ] & [ 0. 9, 1. 1 ] & [ 0. 7, 1. 1 ] & [ 0. 7, 0. 9 ] & [ 1, 1 ] & [ 0. 6, 0. 9 ] & [ 1, 1. 2 ] & [ 0. 9, 1. 2 ] & [ 0. 8, 1. 2 ] \\\\\\\\ [ 0. 7, 1. 2 ] & [ 0. 8, 1 ] & [ 1, 1. 4 ] & [ 0. 7, 1. 2 ] & [ 1. 1, 1. 6 ] & [ 1, 1 ] & [ 1. 2, 1. 4 ] & [ 1. 3, 1. 4 ] & [ 1. 2, 1. 3 ] \\\\\\\\ [ 0. 6, 0. 7 ] & [ 0. 7, 0. 7 ] & [ 0. 7, 0. 8 ] & [ 0. 7, 0. 9 ] & [ 0. 8, 1 ] & [ 0. 7, 0. 8 ] & [ 1, 1 ] & [ 0. 9, 1 ] & [ 0. 9, 1. _ {2} ] \\\\\\\\ [ \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\quad \\\\end{array} \\\\right]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[146,703,766,718]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The eigenvectors belonging to $D^{-}$ and $D^{+}$ normalization are obtained by MATLAB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[396,721,695,734]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nx ^ {-} = [ 0. 1 3 8 0, 0. 1 2 4 6, 0. 1 1 1 1, 0. 1 2 1 2, 0. 1 0 1 0,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[396,738,606,753]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n0. 1 2 1 2, 0. 0 9 4 3, 0. 0 9 4 3, 0. 0 9 4 0 ]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[347,756,648,771]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nx ^ {+} = [ 0. 1 4 1 4, 0. 1 2 1 2, 0. 1 0 7 7, 0. 1 1 7 8, 0. 1 0 7 7,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[347,774,559,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n0. 1 2 7 9, 0. 0 8 7 5, 0. 0 9 0 9, 0. 0 9 7 6 ]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[147,791,524,807]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"By equation (16) and (17), $\\\\alpha' = 0.9084, \\\\beta' = 1.1249$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[329,809,665,824]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\tilde {\\\\omega} = \\\\left[ \\\\begin{array}{c} / 0. 1 2 5 4, 0. 1 5 9 1 \\\\end{array} \\\\right], \\\\left[ \\\\begin{array}{c} / 0. 1 1 3 2, 0. 1 3 6 3 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null,\n \"table_footnote\": null,\n \"text\": \"$$\\n[ 0. 1 1 0 1, 0. 1 4 3 9 ], [ 0. 0 8 5 7, 0. 0 9 8 4 ], [ 0. 0 8 5 7,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[329,863,515,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n0. 1 0 2 3 J, \\\\left[ 0. 0 8 5 7, 0. 1 0 9 8 J \\\\right]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,66,213,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n 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Series: Materials Science and Engineering \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[473,82,606,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1043 (2021) 042022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[636,82,880,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi:10.1088/1757-899X/1043/4/042022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,939,510,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,133,870,167]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Take $\\\\gamma = 0.5$ , and calculate the influence weight of the MAUs on the spindle box from equation (18). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[352,168,643,199]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} \\\\omega = [ 0. 1 4 2 3, 0. 1 2 4 8, 0. 1 1 1 1, 0. 1 2 1 3, 0. 1 0 6 5, \\\\\\\\ \\\\left. \\\\left[ 0. 1 2 7 0, 0. 0 9 2 1, 0. 0 9 4, 0. 0 9 7 8 \\\\right] \\\\right. \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[146,202,793,217]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, according to equation (19), the average failure rate of spindle box is predicted. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[357,218,672,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} \\\\bar {\\\\lambda} _ {s} = 0. 1 4 2 3 \\\\bar {\\\\lambda} _ {1} + 0. 1 2 4 8 \\\\bar {\\\\lambda} _ {2} + 0. 1 1 1 1 \\\\bar {\\\\lambda} _ {3} + 0. 1 2 1 3 \\\\bar {\\\\lambda} _ {4} \\\\\\\\ + 0. 1 0 6 5 \\\\bar {\\\\lambda} _ {5} + 0. 1 2 7 0 \\\\bar {\\\\lambda} _ {6} + 0. 0 9 2 1 \\\\bar {\\\\lambda} _ {7} + 0. 0 9 4 \\\\bar {\\\\lambda} _ {8} \\\\\\\\ + 0. 0 9 7 8 \\\\bar {\\\\lambda_ {9}} = 1. 3 4 \\\\times 1 0 ^ {- 4} \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[122,277,868,307]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the failure statistics of 15 spindle box produced by the enterprise in the past two years, the failure rate is $1.41 \\\\times 10^{-4}$ . The error between the predicted value and the actual value is $0.07 \\\\times 10^{-4}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,321,235,334]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6. Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[121,336,855,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"(1) In this paper, MAU is used to predict the reliability of the complex mechanical product, which can reflect the characteristic of \\\\\\\"action realize motion, motion complete function. Also, the number of MAU is relatively small than the number of parts and the analysis is much easier. \\\",\\\"(2) To evaluate the failure rate of MAU, the method takes into consideration the influence of parts quality, assembly technology, fault hazard level and fault frequency, which includes both the relevant data and expert opinion. It can avoid the difficulty and high cost for obtaining failure data of all the parts. \\\",\\\"(3) The application of the algorithm to the spindle box shows that this method can effectively predict the reliability of the equipment, and the error with actual value is relatively small. \\\"]\",\n \"page_idx\": \"12\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[122,486,282,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,501,870,530]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We wish to appreciate the reviewers for the valuable suggestions that helped to significantly improve the quality of our revised manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,531,872,576]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This paper is sponsored by the National Natural Science Foundation, China (No. 51705048; 51835001); the National Major Scientific and Technological Special Project for \\\"High-grade CNC and Basic Manufacturing Equipment\\\", China (2019ZX04005001). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[124,590,215,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[126,605,870,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] Xie LY 2014. Journal of Mechanical Engineering 50 14 27-36 \\\",\\\"[2] Huang LP, Gong ZL and Yue WH 2010 Advanced Materials Research 139-141 1060-1063 \\\",\\\"[3] Zhou H, Song Y and Zhang J 2013 The Proceedings of 2011 9th International Conference on Reliability, Maintainability and Safety 175-8. \\\",\\\"[4] Lee, SW, Lee HK 2008. Journal of Mechanical Science & Technology 22(5) 957-64 \\\",\\\"[5] Rozhin, Eskandarpour, Amin and Khodaei 2017 IEEE Transactions on Power Systems 33(1) 1139-41 \\\",\\\"[6] Arunima, Jaiswal, Ruchika and Malhotra 2018 Assurance Engineering & Management 9(1) 230-44 \\\",\\\"[7] Ran Y, Zhang GB and Z L 2016 Advances in Mechanical Engineering 8(1) 1-10 \\\",\\\"[8] Ran Y, Zhang W, Mu ZY and Zhang GB 2019 System Reliability, Intechopen 4 1-24 \\\",\\\"[9] Li DY, Li MQ and Zhang GB 2015 Journal of Mechanical Engineering 51(17) 146-55 \\\",\\\"[10] Zhang W, Zhang GB, Ran Y and Shao YM 2018 Advances in Mechanical Engineering 10(5) 1-11 \\\",\\\"[11] Li D, Zhang G and Li M 2015 Procedia CIRP 27 207-15 \\\",\\\"[12] Chen D, Fang ZG, Wu LF and Zhu XZ 2013 Journal of grey system 25(3) 105-14 \\\",\\\"[13] Shekhar C, Jain M, Raina A and Iqbal J 2018 International Journal of System Assurance Engineering and Management 9(2) 377-400 \\\",\\\"[14] Shan XJ, Huang M and Yi J 2013 Applied Mechanics and Materials 411-414 549-554 \\\",\\\"[15] Liu Y, Huang HZ and Ling D 2013 International Journal of Systems Science 44(3) 545-55 \\\"]\",\n \"page_idx\": \"12\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[112,66,213,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"QR2MSE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[784,66,880,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,80,438,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. 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\"bbox\": \"[494,939,512,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,133,873,630]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[16] Xu D, Wei Q and Chen Y 2015 Packaging and Manufacturing Technology 5(11) 1573-81 \\\",\\\"[17] Wang ZL, Zhang BC and Han XX 2015 Mathematical Problems in Engineering: Theory, Methods and Applications 1-8 \\\",\\\"[18] Hu CH, Si XS and Yang JB 2010 Expert Systems with Applications 37(3) 2550-62 \\\",\\\"[19] Zagirnyak M, Prus V, Somka O and Dolezel I 2015 Advances in electrical and electronic engineering 13(5) 447-52 \\\",\\\"[20] Lee S, Han SW and Lee HK 2015 Advanced Reliability Modeling II: Reliability Testing and Improvement 8(3) 533-40 \\\",\\\"[21] Li XB, Yang ZJ, Cheng DB, Liu JX, Cai ZG and Liu YZ 2013 Applied Mechanics and Materials 411-414 1809-1814 \\\",\\\"[22] Alsina EF, Chica M, Krzysztof T and Regattieri A 2018 International Journal of Advanced Manufacturing Technology 94(2) 2419-33 \\\",\\\"[23] Wang H and Jiang Y 2013 Mathematical Problems in Engineering 1-7 \\\",\\\"[24] Wu XD, Zhu ZY, Fan SS and S XL 2016 Optik- International Journal for Light and Electron Optics 127(3) 1491-6 \\\",\\\"[25] Lins ID, Mrcioidas CM, Zio E and Enrique LD 2012 Quality and Reliability Engineering International 28(2) 141-58 \\\",\\\"[26] Zhao W, Tao T, Zio E and Wang WB 2016 IEEE Transactions on Reliability 65(3) 1393-1405 \\\",\\\"[27] Tao T, Zio E and Zhao W 2018 Reliability Engineering & System Safety 177 35-49 \\\",\\\"[28] Lee SW, Choi HZ and Nam SH 2005 Key Engineering Materials 291-292 151-156 \\\",\\\"[29] Li LL, Zhao CT and Yang CW 2011 Applied Mechanics and Materials 48-49 891-895 \\\",\\\"[30] Ahn, Seok B 2016 International Journal of Management Science 67 177-85 \\\",\\\"[31] Gao JB, Liu FY and Zhang JF 2013 Entropy 15(9) 3396-418 \\\",\\\"[32] Yang Y, Khan F, Thodi P and Abbassi R 2017 Reliability Engineering & System Safety 159 214-222. \\\",\\\"[33] Abdullah TA, Hashim A and Baharudin AB 2013 Applied Mechanics and Materials 465 1026-33. \\\",\\\"[34] Nadjafi M, Farsi MA, Zio E and Mousavi AK 2018 Quality & Reliability Engineering International 34(6) 1142-57 \\\",\\\"[35] Wu Y, Jin A and Xie G 2018 American Journal of Public Health 108(12) 1592-8 \\\",\\\"[36] Vaidya OS and Kumar S 2006 European Journal of Operational Research 169(1) 1-29 \\\",\\\"[37] Wang YM and Chin KS 2006 Applied Mathematics and Computation 181(2) 1257-75 \\\",\\\"[38] Siebert and Jana 2018 Fuzzy Optimization & Decision Making 18(2) 175-97 \\\"]\",\n \"page_idx\": 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Series: Materials Science and Engineering \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[473,80,608,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1043 (2021) 042022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[636,80,882,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi:10.1088/1757-899X/1043/4/042022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,939,512,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1088/1757-899x/1043/4/042022"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Mathematics and Computational Science"},"sha256":{"kind":"string","value":"4088ab0e00774bd3f5b1ce2a73b7768cca8174d91eb3593918371e3e55455319"},"title":{"kind":"string","value":"Research on Reliability Prediction method of Complex Mechanical Product Based on Meta-action Unit"}}},{"rowIdx":144,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Adam Doskocz"},"content_list":{"kind":"list like","value":[{"bbox":"[84,81,211,98]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Review Article ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[84,117,223,133]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adam Doskocz* ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,139,880,201]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual state of the geodetic and cartographic resources and legislation in Poland ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[84,233,406,259]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1515/geo-2022-0458 received October 28, 2022; accepted January 01, 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,269,480,530]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: Official data, including national geodetic and cartographic resources, are integrated in a spatial reference system. This study outlines national resources in Poland as an important part of the spatial information infrastructure in the European Community. They also provide reference data, including: geodetic control networks, base map, and topographic maps, for other resources of spatial data infrastructure. The study presents changes in the methods of sharing geo-data and technical standards for their collecting in the last few years, and additionally also presents some aspects of progressing geodetic and cartographic resources and legislation in Poland. It was noted that modern national geoportal or regional and district resources and progress, especially in the form of their standardization of presentation, enable to promote the use of spatial data in Poland and their popularization among the international community. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,540,478,587]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: spatial data infrastructure, geodetic and cartographic resources, national geoportal, regional and district datasets, support of geo-data in Poland ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,636,243,655]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,674,480,803]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study presents the actual state of the resources and current legislation for surveying and other procedures of building databases of National spatial data infrastructure (NSDI) in Poland. The national databases are recorded in the State geodetic and cartographic resource portal, called as “Portal PZGiK” in Polish nomenclature [1]. Portal PZGiK is provided by the Head office of geodesy and cartography (Polish abbrev. GUGiK). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,233,894,606]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polish state geodetic and cartographic resources co-create datasets and databases of spatial data infrastructure (SDI) [2]. For the past few years, data are created and stored for the entire country, as part of large projects co-financed by the European Union. As a result of these projects, the following data are stored for the entire country: the national registry of base geodetic, gravimetric and magnetic control networks; land and buildings registry (it will be a real estate cadaster in the future); geodetic registry of utilities; national registry of boundaries and areas of the territorial division units; national registry of geographic names; registry of localities, streets, and addresses; registry of prices and values of real estate properties; topographic objects and general geographic objects; detailed geodetic control networks; aerial and satellite images; and orthophoto maps and digital terrain models. Databases of topographic objects are useful in creating standard cartographic products on 1:500-1:5,000 scales and will be developed and managed for urban and compact built-up areas as well as rural areas intended for development. All resources include metadata describing them and the services they perform in accordance with the Act on spatial information infrastructure [2]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,609,894,656]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The national geodetic and cartographic resources in Poland were created in recent decades using different coordinate systems and methods of data acquisition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,658,894,803]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All data are currently integrated and harmonized in the national spatial reference system [3]. The national geodetic and cartographic resources are an important part of the spatial information infrastructure in the European Community (INSPIRE) [4]. They are also reference data to other SDI resources, whose main geodetic elements include basic and detailed geodetic control networks, base maps, land and buildings registries, geodetic registries of utilities, and topographic maps [5]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,849,623,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[497,887,894,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work presents the progress in the last few years in the methods of producing digital map data and technical ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,40,176,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[660,40,895,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Geosciences 2023; 15: 20220458 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[915,40,932,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"a ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,849,468,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"* Corresponding author: Adam Doskocz, Department of Geodesy, Faculty of Geoengineering, Institute of Geodesy and Civil Engineering, University of Warmia and Mazury in Olsztyn, 1 Oczapowskiego Street, 10-719 Olsztyn, Poland, e-mail: adam.doskocz@uwm.edu.pl ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[84,930,884,952]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access. © 2023 the author(s), published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[97,84,500,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"standards for field surveys, and in addition, also presents some aspects of building geodetic and cartographic resources and legislation in Poland. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,133,502,297]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The national geodetic and cartographic resource in Poland is divided into three groups of centers of geodetic and cartographic documentation: the central resource, regional resources, and district resources. This is in accordance with the administrative structure of Poland in 1999, which involve [6]: 16 voivodeships, 308 powiats (districts), and 65 cities with powiat status and 2,489 gminas (including 11 gminas of the capital city of Warsaw). There are conventional structures of the resources and on-line access to geo-datasets and geo-ports (Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,84,915,295]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Main topics of methodology of the research presented in this work are related to analyzing the current status of the geodetic and cartographic resources and changes in legislation. Nowadays almost all data sources are in electronic form. So, in this work, the Polish regional and district datasets (portals) and national geoportal are highlighted. Furthermore, actual information about reference systems and frames, base geodetic control networks, spatial data infrastructure, large-scale map data, and technical standards of their acquisition are also presented. International projects in the field of spatial information, including standardization works, are also discussed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,348,915,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0081/53c81d5ee8e6c0fac5dce975c4b9c7d968b080a1330ae991bdd78c05e3173fa5.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":"<table><tr><td colspan=\"3\">Conventional division of the national geodetic and cartographic resources</td></tr><tr><td>Central resource (1 center)</td><td>Regional (voivodeship) resources (16 centers)</td><td>District resources (378 centers)</td></tr><tr><td colspan=\"3\">Organizational units maintaining the resources</td></tr><tr><td>Head surveyor of the country</td><td>Marshalls of Voivodeships</td><td>District chief officials</td></tr><tr><td colspan=\"3\">Access to geo-datasets and geo-portsals</td></tr><tr><td rowspan=\"16\">Head office of geodesy and cartography (GUGiK), https://www.gov.pl/web/gugik-en/geoportal-inspire</td><td>GEOPORTAL of Lower Silesian Voivodeship, https://geoportal.dolnyslask.pl/cat</td><td rowspan=\"16\">GUGiK's list with the register of spatial datasets and services provided in districts, https://integracja.gugik.gov.pl/eziudp/index.php? showall</td></tr><tr><td>GEOPORTAL of Kuyavian-Pomeranian Voivodeship, http://geoportal.infoteren.pl</td></tr><tr><td>GEOPORTAL of Lublin Voivodeship, https://gis.lubelskie.pl/portal</td></tr><tr><td>GEOPORTAL of Lubusz Voivodeship, http://www.rsipwl.lubuskie.pl</td></tr><tr><td>GEOPORTAL of Łódź Voivodeship, https://www.geoportal lodzkie.pl</td></tr><tr><td>GEOPORTAL of Lesser Poland Voivodeship, https://miip.geomalopolska.pl</td></tr><tr><td>GEOPORTAL of Masovian Voivodeship, https://msip.wrotamazowsza.pl</td></tr><tr><td>GEOPORTAL of Opole Voivodeship, https://mapy.opolskie.pl</td></tr><tr><td>GEOPORTAL of Subcarpathian Voivodeship, https://mapy.wodgik.rzeszow.pl</td></tr><tr><td>GEOPORTAL of Podlaskie Voivodeship, https://portale.wrotapodlasia.pl/wodgik/# legend</td></tr><tr><td>GEOPORTAL of Pomeranian Voivodeship, https://pomorskie.eu/mapy-gis</td></tr><tr><td>GEOPORTAL of Silesian Voivodeship, https://geoportal.orsip.pl/aplikacje</td></tr><tr><td>GEOPORTAL of Świątokrzyskie Voivodeship, https://portale.e-swietokrzyskie.pl/ SDI2020_GUGIK</td></tr><tr><td>GEOPORTAL of Warmian-Masurian Voivodeship, https://atlas.warmia.mazury.pl</td></tr><tr><td>GEOPORTAL of Wielkopolska Voivodeship, https://www.umww.pl/rodzaje-map</td></tr><tr><td>GEOPORTAL of West Pomeranian Voivodeship, https://sip-mapa.wzp.pl/egis</td></tr></table>","table_caption":"[\"Table 1: Analysis of the national geodetic and cartographic resource in Poland \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[100,39,114,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[166,40,258,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adam Doskocz ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[818,39,915,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[84,79,366,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 Results and discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[84,122,458,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1 National spatial reference system and reference frames ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,171,480,408]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polish joining the European Terrestrial Reference System and Frame was carried out by measuring 11 points by GPS in 1992 in the EUREF-POL92 campaign. In 1994-1995, another 360 points were measured for the POLREF network, which were then used as reference points for converting points of the state networks to the ETRF89. Today, according to the Polish regulations on the national spatial reference system, apart from the PL-ETRF2000 system, the PL-ETRF89 system is an applicable geodetic reference frame. The national spatial reference system in Poland consists of geodetic horizontal and vertical reference frames, coordinate systems, and projections [3]. The central point of access to the Polish part of infrastructure for spatial information in the European Community [4] is the service geoportal [5]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,409,480,620]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the service geoportal, we can find information about the actual state of reference frames and networks. The horizontal reference frames designated as PL-ETRF2000 and PL-ETRF89 are the mathematical and physical implementation of the European Terrestrial Reference System ETRS89. The system currently in force is PL-ETRF2000 with the implementation of epoch 2011.00. The result of physical implementation of PL-ETRF2000 is the European Permanent Network (EPN) with precisely designated coordinates and changes in these coordinates with time. The transfer into the territory of Poland and maintenance of the PL-ETRF2000 geodetic reference frame is supported by the EUPOS Active Geodetic Network (ASG-EUPOS) [7]. With ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,84,894,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the current status of legislation in Poland, from 2 October 2022, fees for using the ASG-EUPOS system services have been abolished [8]. As a result, almost the entire country already covers six correction systems. In addition to ASG-EUPOS, there are also five non-governmental networks: Leica SmartNet [9], RTKNet [10], TPI NETpro [11], VRSNet [12], and NadowskiNET [13]. Progress in correction systems enables real time GNSS positioning based on data from up to 500 reference stations. The development of GNSS systems has contributed to a significant increase in the accuracy and reliability of positioning. It significantly shortened the initialization time of the mobile receiver (rover) and made it possible to perform measurements in places with difficult access to satellite signals, in the so-called city canyons (e.g., in the vicinity of tall buildings or trees). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,330,894,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Today geo-data has been developing in the following plane rectangular coordinate systems [3], marked by symbols: PL-LAEA, PL-LCC, PL-UTM, PL-1992, and PL2000 (Table 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,395,894,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polish vertical reference frames are marked by symbols PL-KRON86-NH and PL-EVRF2007-NH. The vertical reference frame PL-EVRF2007-NH is associated with the tide-gauge in Amsterdam and should only be used in new projects realized from 1 January, 2014. The vertical reference frame PL-KRON86-NH is associated with the tide-gauge in Kronstadt and can be used until the implementation of the PL-EVRF2007-NH frame throughout the country until 31 December, 2023. This is due to the changing regulations that amend the regulation on the state system of spatial references [14]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,576,894,622]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Consequently, actual spatial (vertical) products of the digital elevation model (DEM) and the digital surface model (DSM), in the service of geoportal, will ultimately ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,674,895,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0105/fc2c7ee4ecfdb92a796243aa2877b572b9aa6b1acfe135885f53e87203f88e12.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>Coordinate system</td><td>Projection</td><td>Ellipsoid and axial meridian</td><td>Application</td></tr><tr><td>PL-LAEA</td><td>Azimuthal equal-area of the Lambert projection</td><td>GRS80 ellipsoid</td><td>For spatial analysis and reporting at the European level</td></tr><tr><td>PL-LCC</td><td>Conformal (equiangular) conic of the Lambert projection</td><td>GRS80 ellipsoid</td><td>For maps on 1:500,000 and smaller scales</td></tr><tr><td>PL-UTM</td><td>Transverse Mercator projection</td><td>GRS80, three-zone system (a width of 6° each) with 15°, 21°, and 27° meridians axial</td><td>For standard cartography works on scales from 1:10,000 to 1:250,000 (issue of marine maps and other maps dedicated to national security and defense)</td></tr><tr><td>PL-1992</td><td>Gauss-Krüger projection</td><td>GRS80, one-zone system with 19° meridian axial</td><td>For topographic maps</td></tr><tr><td>PL-2000</td><td>Gauss-Krüger projection</td><td>GRS80, four-zone system (a width of 3° each) with 15°, 18°, 21°, and 24° meridians axial</td><td>For large-scale maps</td></tr></table>","table_caption":"[\"Table 2: Plane rectangular coordinate systems currently used in Poland \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[82,40,176,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[381,40,826,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual state of the geodetic and cartographic resources and legislation ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[884,41,894,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[99,84,500,181]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"be presented in new layers: NMT-PL-EVRF2007-NH and NMPT-PL-EVRF2007-NH. There are more interesting tools for updating and publishing spatial datasets in geoportal: LIDAR measurement data, surface visibility, visibility along the line, terrain profile, landmass volume to plane, and volume of embarkment/excavation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[99,230,369,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2 Geodetic control network ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[97,264,500,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As is known, the main geodetic control network consists of points of the horizontal and the vertical networks. The coordinates of the horizontal base geodetic control network points mainly are determined by GNSS surveying and the heights of the points are usually determined by geometric precise leveling. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,363,500,509]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The base fundamental geodetic horizontal control network are stations of the ASG-EUPOS reference network, which belong to the network of permanent EPN stations. The points of the base fundamental geodetic horizontal control network meet the criteria established by the subcommittee EUREF and provide an average density of 1 point per $20,000\\mathrm{km}^2$ . The average error of the point's position should not exceed $0.01\\mathrm{m}$ and the error of the point's height should not be greater than $0.02\\mathrm{m}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,510,502,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The role of the receiving segment (ground control) of the ASG-EUPOS system is to collect the observational data from GNSS satellites and transfer them in real time to the calculation center. The segment consists of GNSS reference stations evenly distributed over Poland and neighboring countries [7]. According to the EUPOS standard, during the construction of the receiving segment, the following assumptions were made: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[99,641,500,754]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- the mean distance between stations is $70\\\\mathrm{km}$ \",\"- the existing EPN and IGS stations have been incorporated into the network of reference stations, \",\"- coordinates of the stations will be determined in the ETRS89 system and national systems, \",\"- only precise dual-frequency GNSS receivers have been used in the reference stations, \"]","page_idx":"3","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[512,84,915,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"- the locations of the reference stations were chosen to ensure convenient conditions for GNSS satellite observations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,148,915,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Next to the ASG-EUPOS system, where the total number of stations incorporated into the system is approximately 130, there are roughly 400 Polish commercial reference stations. Reference stations are mostly located on public administration buildings of the province and district levels, research institutes, and education buildings. Real-time services and post-processing services are provided in all reference systems (Table 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,281,915,443]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Corrections from reference networks are available on a specified TCP/IP address and port where before receiving data it is necessary to enter a username and password. When the system recognizes the user, it will enable the requested corrections. In the case of network corrections with a username and password, a receiver must send an approximate position in NMEA format to calculate corrections valid for this area (where NMEA is an acronym for the National Marine Electronics Association in United States of America). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,491,588,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3 SDI ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,525,915,622]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polish (national) SDI, according to the Act on Spatial information infrastructure [2], is established, maintained and developed by 12 leading bodies. Each leading body coordinates the work and assures the implementation within the scope of a specified theme related to the 34 themes of the SDI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,625,915,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Surveyor General of Poland plays a key role in the implementation process of the Polish NSDI. The implementation body of the Surveyor General is the Head office of geodesy and cartography that prepares and submits the government programs regarding the execution of tasks in the field of NSDI. 15 of the 34 themes specified by the directive on INSPIRE are implemented by the Head office of geodesy and cartography. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[99,812,915,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0333/6b7f1df0fc49054fcb06fc2d5b2fe9558806c401a26024874a235d3494de2d5d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Type of survey method</td><td>Path of data transmission</td><td>Estimated precision of measurements</td></tr><tr><td rowspan=\"2\">Kinematic (RTK/RTN)</td><td rowspan=\"2\">Real-time services internet GSM (GPRS)</td><td>0.03 m (horizontally)</td></tr><tr><td>0.05 m (vertically)</td></tr><tr><td>Kinematic (DGPS)</td><td></td><td>0.25–3.00 m</td></tr><tr><td>Static</td><td>Post-processing services internet</td><td>0.01–0.10 m</td></tr><tr><td>Static and kinematic</td><td></td><td></td></tr></table>","table_caption":"[\"Table 3: Services and type of measurements provided by the Polish reference networks \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[100,40,114,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[166,40,258,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adam Doskocz ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[818,40,915,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[78,84,482,163]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Another important player is the Ministry of Environment being the active leader of the implementation measures with regard to environmental data themes. In the Ministry of Environment, 14 themes are coordinated by 10 other central offices. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,166,482,230]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Considerable financial resources are mostly spent on the construction and development of a geoportal [5], and the development of modern sets (databases) of large-scale map data (Figure 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,232,485,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the context of creating and sharing geo-data (resources), the role of the \"Portal PZGiK\" system (mentioned in Section 1) is important. Portal PZGiK is a specific record of resources (resource materials), and includes [15] the name of the resource material; inventory identifier of the resource material; the date of acceptance of the material into the resource; identification of the application for surveying works or the contract designation; spatial location of the area to which the resource material relates; information about data format of the resource material; and information about the creator and information on access to the resource material. In the case of excluding geo-data from the resources, information about the archival category of the resource material; the signature and date of the protocol of excluding the materials from the resources; the date of excluding the material from the resources and the date of transferring the material to the national archives, or the date shredding of the non-archival materials are recorded. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,84,900,412]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geo-data stored in Portal PZGiK are described in the metadata profile by identifier in accordance with the applicable regulations. A registration identifier is assigned to the materials accepted into the resources, and then these materials are provided with an official clause. The resource material registration identifier consists of four parts (separated by dots), of which the first is the letter C – in the case of the central geodetic and cartographic resource (central resource), W – in the case of the voivodeship geodetic and cartographic resources (regional/voivodship resources), P – in the case of a district geodetic and cartographic resources (district/powiat resources); the second is the abbreviation PL – in the case of the central geodetic and cartographic resources, TERYT database identifier of the territorial division unit of the country (voivodship, powiat or municipal), competent for the authority keeping the record of materials – in the case of voivodeship and powiat geodetic and cartographic resources; the third is a four-digit number representing the year the material was accepted into the resources; and the fourth is the next natural number in a given calendar year. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[494,459,732,477]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.4 Large-scale map data ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[492,494,897,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Large-scale map data are stored in theme databases and are obligatory components of the national spatial information ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,557,895,895]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1: View of main information about the NSDI in Poland [5]. \"]","image_footnote":"[]","img_path":"images/0505/18d22ce1c6a21224b236bc9de53cf49bce2a7c061c7cc0a57d4b64f08f5be922.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,39,179,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[381,39,831,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual state of the geodetic and cartographic resources and legislation ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[884,40,894,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[102,85,499,147]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"system. Along with other spatial data, they together co-create three thematic groups of the Polish spatial information infrastructure [2]. The large-scale base map in Poland has been created from several data sources [1,15]: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,150,500,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- a real estate cadaster database EGiB, \",\"- the GESUT geodetic database of utilities, \",\"- the PRG national database of boundaries and areas of territorial division, \",\"- the BDPOG national database of base (first order) geometric control networks, \",\"- the BDSOG district's databases of detailed (second order) geodetic control networks, \",\"- the BDOT500 sets of topographical objects which ensure the creation of databases in the standard 1:500-1:5,000 cartographic scales. \"]","page_idx":"5","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[102,346,500,443]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In a modern digital form, typical large-scale cartographic products are created by compiling collected sets of data or databases. This approach facilitates the collection, maintenance, distribution, and use of the SDI. By reducing duplication, facilitating integration, and also respecting user needs, integration of data can result in savings [16,17]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,445,500,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We know that there are many methods of producing large-scale map data [18], which lead to different qualities of databases or maps. Accuracy and estimation of accuracy of the geo-databases guarantee that national geodetic and cartographic resources meet the relevant quality standards [19,20]. Moreover, it is essential to ensure the transparency of relations between the map producers and users and for developing trust in SDI through accuracy [21,22]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,592,500,754]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We have some new legislation for the theme of the large-scale cartographic products base (base map), called \"mapa zasadnicza\" in Polish [16]. In the new technical standard was characterized the database of topographic objects (Polish abbrev. BDOT500). The BDOT500 database collects information on buildings not listed in the a real estate cadaster database as well as construction objects permanently connected with the building; structures; fences; communication; land development; sports and recreation; waters; and landforms. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,756,500,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The attributes common to all objects of the BDOT500 database are method of obtaining information about the object, date of admission to the national geodetic and cartographic resources, and number of the technical reports with an identification of the application for surveying works or the contract designation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,854,500,918]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The following methods of obtaining information about the localization of objects of BDOT500 database are distinguished: direct measurement in relation to the reference network (O is used for letter's mark); vectorization (D is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,84,914,245]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"used for letter's mark); photogrammetric measurement (F is used for letter's mark); direct measurement with reference to objects, which are characterizing details with good identification in the field (M is used for letter's mark); another method of obtaining (I is used for letter's mark); and undefined method of acquisition (X is used for letter's mark). Moreover, with each object of the BDOT500 database can be associated information that defines the heights of characteristic points located on the elements of these objects. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,248,914,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In case of the geodetic database of utilities (Polish abbrev. GESUT), practically each object must be associated with information that defines the heights of characteristic points located on the elements of these objects [23]. The heights of the characteristic points of GESUT database objects are defined in the vertical reference frame PL-EVRF2007-NH. Whereas, the location of GESUT objects is determined in the PL-2000 plane rectangular coordinate system. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,395,914,491]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The geometric representation of GESUT objects, depending on their types, can be a point, a broken line, a set of lines (multiline), a polygon (multiangle), or a set of points (multipoint). The dimensions of the sections of GESUT objects (diameter, horizontal, and vertical dimensions) are given in millimeters. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,494,914,672]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to the abovementioned methods of obtaining information about the location of objects (in the BDOT500 database), in case of the GESUT database, three additional methods are distinguished: measurement with a wire detector (A is used for letter's mark); data obtained from the administrator of the utility (B is used for letter's mark); and documentation prepared on the so-called coordination meeting (K is used for letter's mark). The previously developed district's GESUT databases and the national GESUT database will be adjusted as per the applicable Regulation [23] by 31 December, 2022. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,674,914,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Next important geo-dataset is a real estate cadaster database (Polish abbrev. EGiB). Information with the methods of obtaining information about the localization of objects of the EGiB database also has great importance. In the light of the applicable regulations [21,24], the attribute related to the source of data about the location of the border point is of key importance by specifying the point position error, which is of fundamental importance for the correctness and reliability of the database. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,820,914,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In defining the cadastral parcel their boundary points, in accordance with new specification must be characterized attribute the way of obtaining data about the border point (Polish abbrev. SPD). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,887,914,918]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The boundary point takes the value of the SPD attribute as \"per specification\" in the case of geodetic field ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,39,114,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[166,40,258,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adam Doskocz ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[818,40,914,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[82,84,480,262]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"measurements preceded by demarcation of real estate or resumption of boundary signs and designation of boundary points; geodetic photogrammetric measurements of border points, the location of which has been previously determined, as well as photogrammetric measurements of boundary marks visible on aerial photos or on an orthophoto map as a result of their signaling before taking photos; division of real estate or merger and division of real estate, and by approved land consolidation or replacement projects. The boundary point takes the value of the SPD attribute as \"unspecified\" in all other cases. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,264,480,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However, in case of information on the compliance with the accuracy standards of the boundary point (attribute with the Polish abbrev. ISD), ISD attribute takes the value as \"satisfied\" when specifying the location of the point in relation to the points of the horizontal reference network, with an accuracy of not less than $0.10\\mathrm{m}$ . The boundary point takes the value of the ISD attribute as \"not satisfied\" in all other cases. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,395,480,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Exchange and sharing of geo-data (where EGiB, GESUT, and BDOT500 databases are of major importance) take place in electronic form using the services network and web portals (geoportals) with the use of the files in GML format. These files have been generated from ISO TC/211 UML class diagrams and which the Head Surveyor of the Country publishes as XML Schema Definition (XSD) application schemas in the interoperability repository [25]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,527,480,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sharing of geo-data takes place in reference to the regulations issued on the computerization of activities entities performing public tasks [26]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,621,468,654]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.5 International geospatial initiatives and INSPIRE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,674,480,770]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In author's opinion, the important issues for the NSDI are data sources, information about services, and new publication of them. Because the NSDI is strongly dependent on pre-existing infrastructures, it is necessary to present some characteristics of these infrastructures in some other regions and countries. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,771,480,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Initiation for Global SDI was provided by GSDI association [27]. The global association was the networking organization of academic and research institutions, government agencies, commercial geomatics companies, and national and regional associations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,854,480,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The GSDI Association in 2018 was wound up as a legal entity and was used as a financial resource to support the United Nations Committee of Experts on Global Geospatial Information Management (UN-GGIM) [28]. UN-GGIM aims ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,84,894,262]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"to address global challenges regarding the use of geospatial information, including the development agendas, and to serve as a body for global policymaking in the field of geospatial information management. The main purpose of UN-GGIM is to support the works of the global geospatial information stakeholders and assist in the coordination of relevant activities between the organizations. The current members of UN-GGIM are Geoscience and remote sensing society, International association of geodesy, International cartographic association, International federation of surveyors, and International geographical union. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,264,894,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"International map industry association, International society for digital earth, International society of photogrammetry and remote sensing, International union of geodesy and geophysics, and the International hydrographic office and the urban and regional information systems association are observing members. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,363,894,427]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The multi-national geospatial societies organization includes representatives from all continents, which are integrated in the regional board for Africa, Asia and Pacific, South America, North America, and Europe. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,428,894,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Europe, a major recent development has been the entering into force of the INSPIRE directive in May 2007, establishing an infrastructure for spatial information in Europe to support community environmental policies, and policies or activities which may have an impact on the environment. INSPIRE is based on the infrastructures for spatial information established and operated by the 28 Member States of the European Union (until 2019, the United Kingdom data displayed are from before Brexit). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,576,894,770]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The INSPIRE directive requires the commission to establish a community geo-portal and the Member States shall provide access to their infrastructures through the geo-portal as well as through any access points they themselves decide to operate. For territory of Member States of European Union to provide discovery and view services according to the INSPIRE Regulation on Network Services, a release of the INSPIRE geoportal was published for enhancing access to European spatial data [29]. The INSPIRE geoportal provides the means to search for spatial datasets and spatial data services of the officially registered discovery services of EU countries and some EFTA countries [30]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,771,894,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There is important the National Spatial Data Infrastructure (NSDI) of the United States of America, because US NSDI is a pioneering venture in the world-scale and is provided by the Federal geographic data committee (FGDC). FGDC is an interagency committee that promotes the coordinated development, use, sharing, and dissemination of geospatial data on a national basis [31]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[497,887,894,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In 2020, US geospatial platform (GeoPlatform, [32]), operating under the authority of the Geospatial Data Act ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,40,176,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[381,40,828,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual state of the geodetic and cartographic resources and legislation ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[884,40,894,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[102,84,499,180]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of 2018, transformed to establish its primary role which will be to discover geospatial data assets with special emphasis as the authorized source for all the official National geospatial data assets (NGDAs). The GeoPlatform provides streamlined access to NGDAs, across data themes as guided by the FGDC, and reduces data duplication. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,182,499,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Big datasets are produced with the support of the geological survey from US (USGS). The USGS is the science agency for the US Department of the Interior and is important for partners and customers for its natural science expertise and its vast earth and biological data holdings [33]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,281,499,394]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, the Open geospatial consortium (OGC) plays an important role in the business sector. The OGC is an international consortium of more than 500 businesses, government agencies, research organizations, and universities driven to make geospatial (location) information and services in FAIR strategy – “Findable, Accessible, Interoperable, and Reusable” [34]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,395,499,491]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The OGC activity for spatial data and their processing since 1994, what is evidence of the unique value which are collegial and efficient networking and standards producing organization. International and government organizations cooperate with the OGC both to advance the standards and to learn about them. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,494,499,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The leading standardization organization is the International organization for standardization (ISO). The ISO is an independent, non-governmental international organization with a membership of 167 national standard bodies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,576,499,640]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The ISO Technical Committee 211 (ISO/TC211) has developed the ISO 19100 family of standards, named \"Geographic information/Geomatics.\" There is a catalogue of standards provided by the Committee ISO/TC 211 [35]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,686,487,721]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.6 Normalization and technical standards for geo-data in Poland ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[102,740,499,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Poland, the organizational structure of the geo-data (spatial information infrastructure) was established by the transposition of the INSPIRE directive into Polish Law. Within the infrastructure, initiatives may be implemented creating regional, local, and thematic geo-portals on the condition of ensuring that they are inter-operational and in compliance with the Polish and INSPIRE implementing rules [17]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,871,499,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In accordance with the update of the geodetic and cartographic law [1], many of the geodetic and cartographic resources are available free of charge and without any ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,84,914,229]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"restrictions on use [36]. Some geo-data are currently available for download as follows: digital elevation model (Polish abbrev. NMT); digital surface model (Polish abbrev. NMPT); LIDAR data; 3D building models; Orthophoto maps; data of geodetic control network points (Polish abbrev BDPOG and BDSOG); database of topographic objects; database of general geographical objects; national registry of boundaries (Polish abbrev. PRG), and national registry of geographic names. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,232,914,312]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition, through the integration services in most cases, data may be downloaded separately. There is land and building register database (EGiB) which allows its users to generate a land and building register map for any area of the country [37]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,313,914,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The utilities network databases (GESUT) contain information about the existing and designed utility lines and related infrastructure [38]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,364,914,409]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the case of other data (topographic features) are collected in proper in BDOT500 database, which acquired its for make up a full composition of base map [39]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,412,914,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Much of the geo-data are shared from the Polish National Geoportal of SDI by the \"Data download\" section. Mostly NSDI data are distributed in Web map service (WMS) standard which complies with the specification of OGC standard. WMS standard (in version 1.3.0) and International Standard ISO 19128 are the same documents. This standard is applicable to pictorial presentation (renderings) of maps in a graphical format in accordance with the International organization for standardization and the Open geospatial consortium specifications [40,41]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,576,914,640]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As we know, the basic standardization document is a standard (the normative document), i.e., a non-legal act, but a document adopted by consensus and approved by an authorized organizational body [42]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,641,914,721]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of \"Geographic information,\" we have ISO [43], regional standardization (CEN, European Committee for Standardization [44]) and national standardization (for example: German - Deutsches Institut für Normung, DIN [45] and Polish - Polski Komitet Normalizacyjny, PKN [46]). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,723,914,786]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The normative documents are a valuable source of definition of specialist terms and therefore they deserve attention services of the German institute for standardization (DIN). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,789,914,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There are DIN-TERM [47] database for the terms and definitions from standards, draft standards, and specifications in the following languages: German, English, French, and Polish and the information portal developed by the German-Chinese Joint Committee of Industry and Trade [48]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,887,914,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Poland, the Technical Committee No. 297 for geographic information operates as part of the work of the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,40,114,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,40,257,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adam Doskocz ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[818,40,914,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[78,84,480,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"standardization committee (PKN). It covers all issues related to the modeling and design of data resources in spatial information systems and geo-data flow between different users and systems. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,150,480,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Modern knowledge in this area is included in more ISO standards of the 19100 series, adopted as European standards, as well as in the nation's standardization documents. For example, in the years 2014-2020, Head office of geodesy and cartography in Poland implemented the POWER project [49]. POWER task was carried out by providing an information and knowledge about geo-data for public administration and for people interested in the geographic information. In addition, from 2011, the e-Guide was available, including entries from Polish (PKN) normative documents [50]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,330,480,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the world today, there are three groups of data sources for acquisition of geo-data. Geo-data can be produced by different techniques: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,379,480,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- field surveying by using total station and GNSS for direct measurement from terrain surfaces and with the use of geo-radar and other apparatus for the measurement of underground features. \",\"- photogrammetry by using photogrammetric images and point clouds and photogrammetric instruments and applications. \",\"- cartographic digitization by using existing maps and survey notes. \"]","page_idx":"8","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[78,543,480,656]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Poland, geo-data are produced by various methods [18], and in accordance with the Regulation [51] standards were set out for geodetic works involving the technology of positioning of topographic points (especially for the largescale map data) using field measurements, photogrammetric surveying, and map digitizing (so-called cartographic surveying). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,658,480,722]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Field measurements and other methods of data acquisition should ensure adequate accuracy of geo-data points. The horizontal positioning were divided into three groups of accuracy: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,723,480,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- the 1st accuracy group, with an error not greater than $0.10\\\\mathrm{m}$ (i.e. the so-called \\\"well-defined\\\" points, inter alia: marks of boundary points, marks of control network points, buildings and engineering structures, including elements of utilities available for direct survey); \",\"- the 2nd accuracy group, with an error not greater than $0.30\\\\mathrm{m}$ (inter alia: ground buildings and construction devices in the form of embankments, excavations, dikes, levees, ditches, canals, artificial lakes, hidden elements of public utilities and land development components, particularly parks, lawns, playgrounds and recreation, single trees, and sports fields); \"]","page_idx":"8","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[494,84,895,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"- the 3rd accuracy group, with an error not greater than $0.50\\mathrm{m}$ (inter alia: contours of agricultural land and soil pits for the needs of soil classification, rivers, and lakes with natural boundary lines, forestry fields on forest areas, and national parks). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,182,895,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In case of elevation (height) surveying, accuracy should not be less than: $0.02\\mathrm{m}$ - for pipes and sewage devices; $0.05\\mathrm{m}$ - for objects and equipment of building and marked pickets in the field; $0.10\\mathrm{m}$ - for earthworks, flexible or electromagnetically measured underground utilities network, and unmarked pickets in the field. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,281,895,411]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In accordance with new legislation (paragraph 3. in [51]), measurements for the large-scale map geo-data are made using the methods, techniques, and technologies that ensure the above accuracies and the fulfilment of the conditions for performing the surveying works (jobs). The choice of the \"right way\" used for meeting the conditions for taking measurements and ensuring the required accuracy rests with the head of geodetic jobs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[494,440,648,459]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[492,477,895,542]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Currently distribution of geo-data are opening [36], and not only is it about open access to GIS data, but major changes have recently occurred in the provision of even cadastral data [52,53]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,543,895,656]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Countries improve the management of good governance approach and contribute to the development of regional and global SDIs by creating national SDI. In Poland, elements of the national geodetic and cartographic resources are key information to build SDI in accordance with the relevant principles defined by the European Commission [54]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,658,895,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work concerns the main geodetic elements of Polish SDI (i.e., base geodetic control networks, the base map, land and buildings register, geodetic register of utilities, and the topographic data), including methods of producing geo-data and technical standards for field measurements and other methods of data acquisition. Polish regional and district datasets (portals) and national geoportal, as well as international initiatives in the field of spatial information including standardization works, were also discussed in this work. Because today, it is important for building national SDI concepts to ensure the interoperability of their components for a variety of hardware-software platforms, for example, along with creating land administration system in \"Fit For Purpose\" strategy [55]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,887,895,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It should be noted that modern geodetic and cartographic resources and progress in legislation, in particular ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,179,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[379,39,828,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual state of the geodetic and cartographic resources and legislation ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[882,40,895,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[99,84,500,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"normalization work on the GML format, promote the use of spatial data in Poland and enable their popularization among the international community. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,148,500,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments: Author received no specific funding for this article and has declared that no competing interest exists. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,215,502,263]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding information: This research was funded by the Department of Geodesy, University of Warmia and Mazury in Olsztyn, Poland, statutory research no. 29.610.001-110. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[99,279,497,295]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflict of interest: Author states no conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,339,226,358]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[100,378,500,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] Act of Polish Parliament, Prawo geodezyjne i kartograficzne (The Geodetic and Cartographic Law). 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Journal of Laws on 2021, item 1390, Warsaw (in Polish). \",\"[25] Repository for interoperability with published application schemas; 2022. https://www.gov.pl/web/gugik/schematy-aplikacyjne-opublikowane-w-repozytorium-interoperacynyosci. \",\"[26] Act of Polish Parliament, O informatyzacje dzialność podmiotów realizujacych zadania publiczne (Computerization of activities entities performing public tasks). Journal of Laws on 2020, item 346, Warsaw (in Polish). \",\"[27] Global Spatial Data Infrastructure Association;2018. http://gsdiassociation.org. \",\"[28] United Nations Committee of Experts on Global Geospatial Information Management; 2022. https://ggim.un.org. \",\"[29] INSPIRE Geoportal of Infrastructure for Spatial Information in the European Community; 2022. http://inspire-geoportal.ec.europa.eu. \"]","page_idx":"9","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[100,40,121,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[174,40,265,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adam Doskocz ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[818,40,915,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[82,85,480,626]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[30] Kleomenis K, Stathopoulos N, Tsatsaris A, Chalkias C. A survey of the Geoinformatics use for census purposes and the INSPIRE maturity within Statistical Institutes of EU and EFTA countries. Ann GIS. 2019;25(2):167-78. \",\"[31] U.S. NSDI from Federal Geographic Data Committee; 2018. https://www.fgdc.gov/dataandservices/. \",\"[32] U.S. GeoPlatform provided by the member agencies of the Federal Geographic Data Committee; 2020. https://www.geoplatform.gov. \",\"[33] The United States Geological Survey (USGS); 2022. https:// www.usgs.gov/products. \",\"[34] The Open Geospatial Consortium (OGC); 2022. https://www.ogc.org. \",\"[35] Standards by ISO/TC 211 Geographic information/Geomatics; 2022. https://www.iso.org/committee/54904/x/catalogue/. \",\"[36] Izdebski W, Zwirowicz-Rutkowska A, Nowak da Costa J. Open data in spatial data infrastructure: the practices and experiences of Poland. Int J Digit Earth. 2021;14:1547-60. doi: 10.1080/17538947.2021.1952323. \",\"[37] Information page for the EGiB service; 2022 (in Polish and in English). https://www.geoportal.gov.pl/dane/dane-ewidencyjne. \",\"[38] Information page for the GESUT service; 2022 (in Polish and in English). https://www.geoportal.gov.pl/dane/uzbrojenieterenu. \",\"[39] Information page for the BDOT500 service; 2022 (in Polish and in English). https://www.geoportal.gov.pl/dane/bazdanych-obiektow-topografcznych-bdot500. \",\"[40] Information about WMS service from ISO the worldwide web; 2022. https://www.iso.org/obp/pi/#iso:std:iso:19128:ed-1:v1:en. \",\"[41] Information about WMS service from OGC the worldwide web; 2022. https://www.ogc.org/standards/wms. \",\"[42] Jaskowska M. Publiczne systemy informacyjne i zróda danych: przywodnik (Public information systems and data sources: a reference guide). Kraków: Jagiellonian Library; 2020. (in Polish with English metadata). https://ruj.uj.edu.pl/xmliu/handle/item/152126. \",\"[43] International Organization for Standardization: homepage; 2022. https://www.iso.org. \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[497,85,895,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[44] European Committee for Standardization: homepage; 2022. https://www.cencenelec.eu. \",\"[45] German Institute for Standardization: homepage; 2022. https://www.din.de/en. \",\"[46] Polish Committee for Standardization: homepage; 2022. https://www.pkn.pl/en. \",\"[47] DIN-TERMinology Portal: homepage; 2022. https://www.din.de/en/services/din-term/datenkategorieien. \",\"[48] Germany-China Standards Information Portal: homepage; 2022. http://cn-e_standards-portal.de/. \",\"[49] POWER project in Head Office of Geodesy and Cartography in Poland; 2021 (in Polish). http://power.gugik.gov.pl. \",\"[50] e-Guide to Polish Standards in the field of geographic information; 2021 (in Polish). http://e-przewodnik.gugik.gov.pl. \",\"[51] Regulation of the Ministry of Internal Affairs and Administration, W sprawie standardów technicznych wykonywania geodezyjnych pomiarów sytuacyjnych i wysokośćowych oraz opracowywnia i przykazywnia wyników tych pomiarów doaciousyjnego i kartografcznego (Regarding the technical standards perform geodetic altitude and situational measurements and compilation and transmission of the results of these measurements to the national geodetic and cartographic resource). Journal of Laws on 2020, item 1429, Warsaw (in Polish). \",\"[52] Bielecka E, Dukaczewski D, Janczar E. Spatial Data Infrastructure in Poland - lessons learnt from so far achievements. Geodesy and Cartography. Warsaw. 2018;67(1):3-20. \",\"[53] Trystula A, Dudzinska M, Zrobek R. Evaluation of the Completeness of Spatial Data Infrastructure in the Context of Cadastral Data Sharing. Land. 2020;9:272. doi: 10.3390/land9080272. \",\"[54] Klimach A, Dawidowicz A, Zrobek R. The Polish land administration system supporting good governance. Land Use Policy. 2018;79:547-55. \",\"[55] Dawidowicz A, Zysk E, Zrobek R. A Methodological Evaluation of the Polish Land Administration System Using the Fit-For-Purpose Approach. Geomat Env Eng. 2020;14(2):31-47. \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[82,39,178,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DE GRUYTER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[376,39,823,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual state of the geodetic and cartographic resources and legislation ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[878,40,895,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[84,81,211,98]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Review Article \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,117,223,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adam Doskocz* \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,139,880,201]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual state of the geodetic and cartographic resources and legislation in Poland \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,233,406,259]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1515/geo-2022-0458 received October 28, 2022; accepted January 01, 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,269,480,530]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: Official data, including national geodetic and cartographic resources, are integrated in a spatial reference system. This study outlines national resources in Poland as an important part of the spatial information infrastructure in the European Community. They also provide reference data, including: geodetic control networks, base map, and topographic maps, for other resources of spatial data infrastructure. The study presents changes in the methods of sharing geo-data and technical standards for their collecting in the last few years, and additionally also presents some aspects of progressing geodetic and cartographic resources and legislation in Poland. It was noted that modern national geoportal or regional and district resources and progress, especially in the form of their standardization of presentation, enable to promote the use of spatial data in Poland and their popularization among the international community. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,540,478,587]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: spatial data infrastructure, geodetic and cartographic resources, national geoportal, regional and district datasets, support of geo-data in Poland \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,636,243,655]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,674,480,803]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study presents the actual state of the resources and current legislation for surveying and other procedures of building databases of National spatial data infrastructure (NSDI) in Poland. The national databases are recorded in the State geodetic and cartographic resource portal, called as “Portal PZGiK” in Polish nomenclature [1]. Portal PZGiK is provided by the Head office of geodesy and cartography (Polish abbrev. GUGiK). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,233,894,606]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polish state geodetic and cartographic resources co-create datasets and databases of spatial data infrastructure (SDI) [2]. For the past few years, data are created and stored for the entire country, as part of large projects co-financed by the European Union. As a result of these projects, the following data are stored for the entire country: the national registry of base geodetic, gravimetric and magnetic control networks; land and buildings registry (it will be a real estate cadaster in the future); geodetic registry of utilities; national registry of boundaries and areas of the territorial division units; national registry of geographic names; registry of localities, streets, and addresses; registry of prices and values of real estate properties; topographic objects and general geographic objects; detailed geodetic control networks; aerial and satellite images; and orthophoto maps and digital terrain models. Databases of topographic objects are useful in creating standard cartographic products on 1:500-1:5,000 scales and will be developed and managed for urban and compact built-up areas as well as rural areas intended for development. All resources include metadata describing them and the services they perform in accordance with the Act on spatial information infrastructure [2]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,609,894,656]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The national geodetic and cartographic resources in Poland were created in recent decades using different coordinate systems and methods of data acquisition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,658,894,803]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All data are currently integrated and harmonized in the national spatial reference system [3]. The national geodetic and cartographic resources are an important part of the spatial information infrastructure in the European Community (INSPIRE) [4]. They are also reference data to other SDI resources, whose main geodetic elements include basic and detailed geodetic control networks, base maps, land and buildings registries, geodetic registries of utilities, and topographic maps [5]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,849,623,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,887,894,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work presents the progress in the last few years in the methods of producing digital map data and technical \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,40,176,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[660,40,895,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Geosciences 2023; 15: 20220458 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[915,40,932,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"a \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,849,468,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"* Corresponding author: Adam Doskocz, Department of Geodesy, Faculty of Geoengineering, Institute of Geodesy and Civil Engineering, University of Warmia and Mazury in Olsztyn, 1 Oczapowskiego Street, 10-719 Olsztyn, Poland, e-mail: adam.doskocz@uwm.edu.pl \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[84,930,884,952]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access. © 2023 the author(s), published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[97,84,500,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"standards for field surveys, and in addition, also presents some aspects of building geodetic and cartographic resources and legislation in Poland. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,133,502,297]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The national geodetic and cartographic resource in Poland is divided into three groups of centers of geodetic and cartographic documentation: the central resource, regional resources, and district resources. This is in accordance with the administrative structure of Poland in 1999, which involve [6]: 16 voivodeships, 308 powiats (districts), and 65 cities with powiat status and 2,489 gminas (including 11 gminas of the capital city of Warsaw). There are conventional structures of the resources and on-line access to geo-datasets and geo-ports (Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,84,915,295]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Main topics of methodology of the research presented in this work are related to analyzing the current status of the geodetic and cartographic resources and changes in legislation. Nowadays almost all data sources are in electronic form. So, in this work, the Polish regional and district datasets (portals) and national geoportal are highlighted. Furthermore, actual information about reference systems and frames, base geodetic control networks, spatial data infrastructure, large-scale map data, and technical standards of their acquisition are also presented. International projects in the field of spatial information, including standardization works, are also discussed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,348,915,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0081/53c81d5ee8e6c0fac5dce975c4b9c7d968b080a1330ae991bdd78c05e3173fa5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td colspan=\\\"3\\\">Conventional division of the national geodetic and cartographic resources</td></tr><tr><td>Central resource (1 center)</td><td>Regional (voivodeship) resources (16 centers)</td><td>District resources (378 centers)</td></tr><tr><td colspan=\\\"3\\\">Organizational units maintaining the resources</td></tr><tr><td>Head surveyor of the country</td><td>Marshalls of Voivodeships</td><td>District chief officials</td></tr><tr><td colspan=\\\"3\\\">Access to geo-datasets and geo-portsals</td></tr><tr><td rowspan=\\\"16\\\">Head office of geodesy and cartography (GUGiK), https://www.gov.pl/web/gugik-en/geoportal-inspire</td><td>GEOPORTAL of Lower Silesian Voivodeship, https://geoportal.dolnyslask.pl/cat</td><td rowspan=\\\"16\\\">GUGiK's list with the register of spatial datasets and services provided in districts, https://integracja.gugik.gov.pl/eziudp/index.php? showall</td></tr><tr><td>GEOPORTAL of Kuyavian-Pomeranian Voivodeship, http://geoportal.infoteren.pl</td></tr><tr><td>GEOPORTAL of Lublin Voivodeship, https://gis.lubelskie.pl/portal</td></tr><tr><td>GEOPORTAL of Lubusz Voivodeship, http://www.rsipwl.lubuskie.pl</td></tr><tr><td>GEOPORTAL of Łódź Voivodeship, https://www.geoportal lodzkie.pl</td></tr><tr><td>GEOPORTAL of Lesser Poland Voivodeship, https://miip.geomalopolska.pl</td></tr><tr><td>GEOPORTAL of Masovian Voivodeship, https://msip.wrotamazowsza.pl</td></tr><tr><td>GEOPORTAL of Opole Voivodeship, https://mapy.opolskie.pl</td></tr><tr><td>GEOPORTAL of Subcarpathian Voivodeship, https://mapy.wodgik.rzeszow.pl</td></tr><tr><td>GEOPORTAL of Podlaskie Voivodeship, https://portale.wrotapodlasia.pl/wodgik/# legend</td></tr><tr><td>GEOPORTAL of Pomeranian Voivodeship, https://pomorskie.eu/mapy-gis</td></tr><tr><td>GEOPORTAL of Silesian Voivodeship, https://geoportal.orsip.pl/aplikacje</td></tr><tr><td>GEOPORTAL of Świątokrzyskie Voivodeship, https://portale.e-swietokrzyskie.pl/ SDI2020_GUGIK</td></tr><tr><td>GEOPORTAL of Warmian-Masurian Voivodeship, https://atlas.warmia.mazury.pl</td></tr><tr><td>GEOPORTAL of Wielkopolska Voivodeship, https://www.umww.pl/rodzaje-map</td></tr><tr><td>GEOPORTAL of West Pomeranian Voivodeship, https://sip-mapa.wzp.pl/egis</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1: Analysis of the national geodetic and cartographic resource in Poland \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[100,39,114,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[166,40,258,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adam Doskocz \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[818,39,915,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[84,79,366,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 Results and discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,122,458,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1 National spatial reference system and reference frames \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,171,480,408]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polish joining the European Terrestrial Reference System and Frame was carried out by measuring 11 points by GPS in 1992 in the EUREF-POL92 campaign. In 1994-1995, another 360 points were measured for the POLREF network, which were then used as reference points for converting points of the state networks to the ETRF89. Today, according to the Polish regulations on the national spatial reference system, apart from the PL-ETRF2000 system, the PL-ETRF89 system is an applicable geodetic reference frame. The national spatial reference system in Poland consists of geodetic horizontal and vertical reference frames, coordinate systems, and projections [3]. The central point of access to the Polish part of infrastructure for spatial information in the European Community [4] is the service geoportal [5]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,409,480,620]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the service geoportal, we can find information about the actual state of reference frames and networks. The horizontal reference frames designated as PL-ETRF2000 and PL-ETRF89 are the mathematical and physical implementation of the European Terrestrial Reference System ETRS89. The system currently in force is PL-ETRF2000 with the implementation of epoch 2011.00. The result of physical implementation of PL-ETRF2000 is the European Permanent Network (EPN) with precisely designated coordinates and changes in these coordinates with time. The transfer into the territory of Poland and maintenance of the PL-ETRF2000 geodetic reference frame is supported by the EUPOS Active Geodetic Network (ASG-EUPOS) [7]. With \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,84,894,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the current status of legislation in Poland, from 2 October 2022, fees for using the ASG-EUPOS system services have been abolished [8]. As a result, almost the entire country already covers six correction systems. In addition to ASG-EUPOS, there are also five non-governmental networks: Leica SmartNet [9], RTKNet [10], TPI NETpro [11], VRSNet [12], and NadowskiNET [13]. Progress in correction systems enables real time GNSS positioning based on data from up to 500 reference stations. The development of GNSS systems has contributed to a significant increase in the accuracy and reliability of positioning. It significantly shortened the initialization time of the mobile receiver (rover) and made it possible to perform measurements in places with difficult access to satellite signals, in the so-called city canyons (e.g., in the vicinity of tall buildings or trees). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,330,894,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Today geo-data has been developing in the following plane rectangular coordinate systems [3], marked by symbols: PL-LAEA, PL-LCC, PL-UTM, PL-1992, and PL2000 (Table 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,395,894,573]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polish vertical reference frames are marked by symbols PL-KRON86-NH and PL-EVRF2007-NH. The vertical reference frame PL-EVRF2007-NH is associated with the tide-gauge in Amsterdam and should only be used in new projects realized from 1 January, 2014. The vertical reference frame PL-KRON86-NH is associated with the tide-gauge in Kronstadt and can be used until the implementation of the PL-EVRF2007-NH frame throughout the country until 31 December, 2023. This is due to the changing regulations that amend the regulation on the state system of spatial references [14]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,576,894,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Consequently, actual spatial (vertical) products of the digital elevation model (DEM) and the digital surface model (DSM), in the service of geoportal, will ultimately \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,674,895,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0105/fc2c7ee4ecfdb92a796243aa2877b572b9aa6b1acfe135885f53e87203f88e12.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Coordinate system</td><td>Projection</td><td>Ellipsoid and axial meridian</td><td>Application</td></tr><tr><td>PL-LAEA</td><td>Azimuthal equal-area of the Lambert projection</td><td>GRS80 ellipsoid</td><td>For spatial analysis and reporting at the European level</td></tr><tr><td>PL-LCC</td><td>Conformal (equiangular) conic of the Lambert projection</td><td>GRS80 ellipsoid</td><td>For maps on 1:500,000 and smaller scales</td></tr><tr><td>PL-UTM</td><td>Transverse Mercator projection</td><td>GRS80, three-zone system (a width of 6° each) with 15°, 21°, and 27° meridians axial</td><td>For standard cartography works on scales from 1:10,000 to 1:250,000 (issue of marine maps and other maps dedicated to national security and defense)</td></tr><tr><td>PL-1992</td><td>Gauss-Krüger projection</td><td>GRS80, one-zone system with 19° meridian axial</td><td>For topographic maps</td></tr><tr><td>PL-2000</td><td>Gauss-Krüger projection</td><td>GRS80, four-zone system (a width of 3° each) with 15°, 18°, 21°, and 24° meridians axial</td><td>For large-scale maps</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2: Plane rectangular coordinate systems currently used in Poland \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[82,40,176,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[381,40,826,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual state of the geodetic and cartographic resources and legislation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[884,41,894,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[99,84,500,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"be presented in new layers: NMT-PL-EVRF2007-NH and NMPT-PL-EVRF2007-NH. There are more interesting tools for updating and publishing spatial datasets in geoportal: LIDAR measurement data, surface visibility, visibility along the line, terrain profile, landmass volume to plane, and volume of embarkment/excavation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[99,230,369,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2 Geodetic control network \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,264,500,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As is known, the main geodetic control network consists of points of the horizontal and the vertical networks. The coordinates of the horizontal base geodetic control network points mainly are determined by GNSS surveying and the heights of the points are usually determined by geometric precise leveling. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,363,500,509]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The base fundamental geodetic horizontal control network are stations of the ASG-EUPOS reference network, which belong to the network of permanent EPN stations. The points of the base fundamental geodetic horizontal control network meet the criteria established by the subcommittee EUREF and provide an average density of 1 point per $20,000\\\\mathrm{km}^2$ . The average error of the point's position should not exceed $0.01\\\\mathrm{m}$ and the error of the point's height should not be greater than $0.02\\\\mathrm{m}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,510,502,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The role of the receiving segment (ground control) of the ASG-EUPOS system is to collect the observational data from GNSS satellites and transfer them in real time to the calculation center. The segment consists of GNSS reference stations evenly distributed over Poland and neighboring countries [7]. According to the EUPOS standard, during the construction of the receiving segment, the following assumptions were made: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[99,641,500,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- the mean distance between stations is $70\\\\\\\\mathrm{km}$ \\\",\\\"- the existing EPN and IGS stations have been incorporated into the network of reference stations, \\\",\\\"- coordinates of the stations will be determined in the ETRS89 system and national systems, \\\",\\\"- only precise dual-frequency GNSS receivers have been used in the reference stations, \\\"]\",\n \"page_idx\": \"3\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[512,84,915,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"- the locations of the reference stations were chosen to ensure convenient conditions for GNSS satellite observations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,148,915,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Next to the ASG-EUPOS system, where the total number of stations incorporated into the system is approximately 130, there are roughly 400 Polish commercial reference stations. Reference stations are mostly located on public administration buildings of the province and district levels, research institutes, and education buildings. Real-time services and post-processing services are provided in all reference systems (Table 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,281,915,443]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Corrections from reference networks are available on a specified TCP/IP address and port where before receiving data it is necessary to enter a username and password. When the system recognizes the user, it will enable the requested corrections. In the case of network corrections with a username and password, a receiver must send an approximate position in NMEA format to calculate corrections valid for this area (where NMEA is an acronym for the National Marine Electronics Association in United States of America). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,491,588,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3 SDI \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,525,915,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polish (national) SDI, according to the Act on Spatial information infrastructure [2], is established, maintained and developed by 12 leading bodies. Each leading body coordinates the work and assures the implementation within the scope of a specified theme related to the 34 themes of the SDI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,625,915,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Surveyor General of Poland plays a key role in the implementation process of the Polish NSDI. The implementation body of the Surveyor General is the Head office of geodesy and cartography that prepares and submits the government programs regarding the execution of tasks in the field of NSDI. 15 of the 34 themes specified by the directive on INSPIRE are implemented by the Head office of geodesy and cartography. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[99,812,915,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0333/6b7f1df0fc49054fcb06fc2d5b2fe9558806c401a26024874a235d3494de2d5d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Type of survey method</td><td>Path of data transmission</td><td>Estimated precision of measurements</td></tr><tr><td rowspan=\\\"2\\\">Kinematic (RTK/RTN)</td><td rowspan=\\\"2\\\">Real-time services internet GSM (GPRS)</td><td>0.03 m (horizontally)</td></tr><tr><td>0.05 m (vertically)</td></tr><tr><td>Kinematic (DGPS)</td><td></td><td>0.25–3.00 m</td></tr><tr><td>Static</td><td>Post-processing services internet</td><td>0.01–0.10 m</td></tr><tr><td>Static and kinematic</td><td></td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3: Services and type of measurements provided by the Polish reference networks \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[100,40,114,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[166,40,258,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adam Doskocz \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[818,40,915,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[78,84,482,163]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Another important player is the Ministry of Environment being the active leader of the implementation measures with regard to environmental data themes. In the Ministry of Environment, 14 themes are coordinated by 10 other central offices. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,166,482,230]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Considerable financial resources are mostly spent on the construction and development of a geoportal [5], and the development of modern sets (databases) of large-scale map data (Figure 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,232,485,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the context of creating and sharing geo-data (resources), the role of the \\\"Portal PZGiK\\\" system (mentioned in Section 1) is important. Portal PZGiK is a specific record of resources (resource materials), and includes [15] the name of the resource material; inventory identifier of the resource material; the date of acceptance of the material into the resource; identification of the application for surveying works or the contract designation; spatial location of the area to which the resource material relates; information about data format of the resource material; and information about the creator and information on access to the resource material. In the case of excluding geo-data from the resources, information about the archival category of the resource material; the signature and date of the protocol of excluding the materials from the resources; the date of excluding the material from the resources and the date of transferring the material to the national archives, or the date shredding of the non-archival materials are recorded. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,84,900,412]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geo-data stored in Portal PZGiK are described in the metadata profile by identifier in accordance with the applicable regulations. A registration identifier is assigned to the materials accepted into the resources, and then these materials are provided with an official clause. The resource material registration identifier consists of four parts (separated by dots), of which the first is the letter C – in the case of the central geodetic and cartographic resource (central resource), W – in the case of the voivodeship geodetic and cartographic resources (regional/voivodship resources), P – in the case of a district geodetic and cartographic resources (district/powiat resources); the second is the abbreviation PL – in the case of the central geodetic and cartographic resources, TERYT database identifier of the territorial division unit of the country (voivodship, powiat or municipal), competent for the authority keeping the record of materials – in the case of voivodeship and powiat geodetic and cartographic resources; the third is a four-digit number representing the year the material was accepted into the resources; and the fourth is the next natural number in a given calendar year. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[494,459,732,477]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.4 Large-scale map data \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,494,897,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Large-scale map data are stored in theme databases and are obligatory components of the national spatial information \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,557,895,895]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1: View of main information about the NSDI in Poland [5]. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0505/18d22ce1c6a21224b236bc9de53cf49bce2a7c061c7cc0a57d4b64f08f5be922.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,39,179,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[381,39,831,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual state of the geodetic and cartographic resources and legislation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[884,40,894,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[102,85,499,147]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"system. Along with other spatial data, they together co-create three thematic groups of the Polish spatial information infrastructure [2]. The large-scale base map in Poland has been created from several data sources [1,15]: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,150,500,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- a real estate cadaster database EGiB, \\\",\\\"- the GESUT geodetic database of utilities, \\\",\\\"- the PRG national database of boundaries and areas of territorial division, \\\",\\\"- the BDPOG national database of base (first order) geometric control networks, \\\",\\\"- the BDSOG district's databases of detailed (second order) geodetic control networks, \\\",\\\"- the BDOT500 sets of topographical objects which ensure the creation of databases in the standard 1:500-1:5,000 cartographic scales. \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[102,346,500,443]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In a modern digital form, typical large-scale cartographic products are created by compiling collected sets of data or databases. This approach facilitates the collection, maintenance, distribution, and use of the SDI. By reducing duplication, facilitating integration, and also respecting user needs, integration of data can result in savings [16,17]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,445,500,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We know that there are many methods of producing large-scale map data [18], which lead to different qualities of databases or maps. Accuracy and estimation of accuracy of the geo-databases guarantee that national geodetic and cartographic resources meet the relevant quality standards [19,20]. Moreover, it is essential to ensure the transparency of relations between the map producers and users and for developing trust in SDI through accuracy [21,22]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,592,500,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We have some new legislation for the theme of the large-scale cartographic products base (base map), called \\\"mapa zasadnicza\\\" in Polish [16]. In the new technical standard was characterized the database of topographic objects (Polish abbrev. BDOT500). The BDOT500 database collects information on buildings not listed in the a real estate cadaster database as well as construction objects permanently connected with the building; structures; fences; communication; land development; sports and recreation; waters; and landforms. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,756,500,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The attributes common to all objects of the BDOT500 database are method of obtaining information about the object, date of admission to the national geodetic and cartographic resources, and number of the technical reports with an identification of the application for surveying works or the contract designation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,854,500,918]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The following methods of obtaining information about the localization of objects of BDOT500 database are distinguished: direct measurement in relation to the reference network (O is used for letter's mark); vectorization (D is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,84,914,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"used for letter's mark); photogrammetric measurement (F is used for letter's mark); direct measurement with reference to objects, which are characterizing details with good identification in the field (M is used for letter's mark); another method of obtaining (I is used for letter's mark); and undefined method of acquisition (X is used for letter's mark). Moreover, with each object of the BDOT500 database can be associated information that defines the heights of characteristic points located on the elements of these objects. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,248,914,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In case of the geodetic database of utilities (Polish abbrev. GESUT), practically each object must be associated with information that defines the heights of characteristic points located on the elements of these objects [23]. The heights of the characteristic points of GESUT database objects are defined in the vertical reference frame PL-EVRF2007-NH. Whereas, the location of GESUT objects is determined in the PL-2000 plane rectangular coordinate system. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,395,914,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The geometric representation of GESUT objects, depending on their types, can be a point, a broken line, a set of lines (multiline), a polygon (multiangle), or a set of points (multipoint). The dimensions of the sections of GESUT objects (diameter, horizontal, and vertical dimensions) are given in millimeters. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,494,914,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to the abovementioned methods of obtaining information about the location of objects (in the BDOT500 database), in case of the GESUT database, three additional methods are distinguished: measurement with a wire detector (A is used for letter's mark); data obtained from the administrator of the utility (B is used for letter's mark); and documentation prepared on the so-called coordination meeting (K is used for letter's mark). The previously developed district's GESUT databases and the national GESUT database will be adjusted as per the applicable Regulation [23] by 31 December, 2022. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,674,914,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Next important geo-dataset is a real estate cadaster database (Polish abbrev. EGiB). Information with the methods of obtaining information about the localization of objects of the EGiB database also has great importance. In the light of the applicable regulations [21,24], the attribute related to the source of data about the location of the border point is of key importance by specifying the point position error, which is of fundamental importance for the correctness and reliability of the database. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,820,914,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In defining the cadastral parcel their boundary points, in accordance with new specification must be characterized attribute the way of obtaining data about the border point (Polish abbrev. SPD). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,887,914,918]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The boundary point takes the value of the SPD attribute as \\\"per specification\\\" in the case of geodetic field \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,39,114,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[166,40,258,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adam Doskocz \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[818,40,914,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[82,84,480,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"measurements preceded by demarcation of real estate or resumption of boundary signs and designation of boundary points; geodetic photogrammetric measurements of border points, the location of which has been previously determined, as well as photogrammetric measurements of boundary marks visible on aerial photos or on an orthophoto map as a result of their signaling before taking photos; division of real estate or merger and division of real estate, and by approved land consolidation or replacement projects. The boundary point takes the value of the SPD attribute as \\\"unspecified\\\" in all other cases. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,264,480,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However, in case of information on the compliance with the accuracy standards of the boundary point (attribute with the Polish abbrev. ISD), ISD attribute takes the value as \\\"satisfied\\\" when specifying the location of the point in relation to the points of the horizontal reference network, with an accuracy of not less than $0.10\\\\mathrm{m}$ . The boundary point takes the value of the ISD attribute as \\\"not satisfied\\\" in all other cases. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,395,480,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Exchange and sharing of geo-data (where EGiB, GESUT, and BDOT500 databases are of major importance) take place in electronic form using the services network and web portals (geoportals) with the use of the files in GML format. These files have been generated from ISO TC/211 UML class diagrams and which the Head Surveyor of the Country publishes as XML Schema Definition (XSD) application schemas in the interoperability repository [25]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,527,480,573]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sharing of geo-data takes place in reference to the regulations issued on the computerization of activities entities performing public tasks [26]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,621,468,654]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.5 International geospatial initiatives and INSPIRE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,674,480,770]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In author's opinion, the important issues for the NSDI are data sources, information about services, and new publication of them. Because the NSDI is strongly dependent on pre-existing infrastructures, it is necessary to present some characteristics of these infrastructures in some other regions and countries. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,771,480,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Initiation for Global SDI was provided by GSDI association [27]. The global association was the networking organization of academic and research institutions, government agencies, commercial geomatics companies, and national and regional associations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,854,480,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The GSDI Association in 2018 was wound up as a legal entity and was used as a financial resource to support the United Nations Committee of Experts on Global Geospatial Information Management (UN-GGIM) [28]. UN-GGIM aims \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,84,894,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"to address global challenges regarding the use of geospatial information, including the development agendas, and to serve as a body for global policymaking in the field of geospatial information management. The main purpose of UN-GGIM is to support the works of the global geospatial information stakeholders and assist in the coordination of relevant activities between the organizations. The current members of UN-GGIM are Geoscience and remote sensing society, International association of geodesy, International cartographic association, International federation of surveyors, and International geographical union. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,264,894,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"International map industry association, International society for digital earth, International society of photogrammetry and remote sensing, International union of geodesy and geophysics, and the International hydrographic office and the urban and regional information systems association are observing members. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,363,894,427]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The multi-national geospatial societies organization includes representatives from all continents, which are integrated in the regional board for Africa, Asia and Pacific, South America, North America, and Europe. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,428,894,573]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Europe, a major recent development has been the entering into force of the INSPIRE directive in May 2007, establishing an infrastructure for spatial information in Europe to support community environmental policies, and policies or activities which may have an impact on the environment. INSPIRE is based on the infrastructures for spatial information established and operated by the 28 Member States of the European Union (until 2019, the United Kingdom data displayed are from before Brexit). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,576,894,770]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The INSPIRE directive requires the commission to establish a community geo-portal and the Member States shall provide access to their infrastructures through the geo-portal as well as through any access points they themselves decide to operate. For territory of Member States of European Union to provide discovery and view services according to the INSPIRE Regulation on Network Services, a release of the INSPIRE geoportal was published for enhancing access to European spatial data [29]. The INSPIRE geoportal provides the means to search for spatial datasets and spatial data services of the officially registered discovery services of EU countries and some EFTA countries [30]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,771,894,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There is important the National Spatial Data Infrastructure (NSDI) of the United States of America, because US NSDI is a pioneering venture in the world-scale and is provided by the Federal geographic data committee (FGDC). FGDC is an interagency committee that promotes the coordinated development, use, sharing, and dissemination of geospatial data on a national basis [31]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[497,887,894,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In 2020, US geospatial platform (GeoPlatform, [32]), operating under the authority of the Geospatial Data Act \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,40,176,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[381,40,828,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual state of the geodetic and cartographic resources and legislation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[884,40,894,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[102,84,499,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of 2018, transformed to establish its primary role which will be to discover geospatial data assets with special emphasis as the authorized source for all the official National geospatial data assets (NGDAs). The GeoPlatform provides streamlined access to NGDAs, across data themes as guided by the FGDC, and reduces data duplication. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,182,499,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Big datasets are produced with the support of the geological survey from US (USGS). The USGS is the science agency for the US Department of the Interior and is important for partners and customers for its natural science expertise and its vast earth and biological data holdings [33]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,281,499,394]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, the Open geospatial consortium (OGC) plays an important role in the business sector. The OGC is an international consortium of more than 500 businesses, government agencies, research organizations, and universities driven to make geospatial (location) information and services in FAIR strategy – “Findable, Accessible, Interoperable, and Reusable” [34]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,395,499,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The OGC activity for spatial data and their processing since 1994, what is evidence of the unique value which are collegial and efficient networking and standards producing organization. International and government organizations cooperate with the OGC both to advance the standards and to learn about them. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,494,499,573]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The leading standardization organization is the International organization for standardization (ISO). The ISO is an independent, non-governmental international organization with a membership of 167 national standard bodies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,576,499,640]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The ISO Technical Committee 211 (ISO/TC211) has developed the ISO 19100 family of standards, named \\\"Geographic information/Geomatics.\\\" There is a catalogue of standards provided by the Committee ISO/TC 211 [35]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,686,487,721]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.6 Normalization and technical standards for geo-data in Poland \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,740,499,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Poland, the organizational structure of the geo-data (spatial information infrastructure) was established by the transposition of the INSPIRE directive into Polish Law. Within the infrastructure, initiatives may be implemented creating regional, local, and thematic geo-portals on the condition of ensuring that they are inter-operational and in compliance with the Polish and INSPIRE implementing rules [17]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,871,499,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In accordance with the update of the geodetic and cartographic law [1], many of the geodetic and cartographic resources are available free of charge and without any \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,84,914,229]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"restrictions on use [36]. Some geo-data are currently available for download as follows: digital elevation model (Polish abbrev. NMT); digital surface model (Polish abbrev. NMPT); LIDAR data; 3D building models; Orthophoto maps; data of geodetic control network points (Polish abbrev BDPOG and BDSOG); database of topographic objects; database of general geographical objects; national registry of boundaries (Polish abbrev. PRG), and national registry of geographic names. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,232,914,312]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition, through the integration services in most cases, data may be downloaded separately. There is land and building register database (EGiB) which allows its users to generate a land and building register map for any area of the country [37]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,313,914,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The utilities network databases (GESUT) contain information about the existing and designed utility lines and related infrastructure [38]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,364,914,409]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the case of other data (topographic features) are collected in proper in BDOT500 database, which acquired its for make up a full composition of base map [39]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,412,914,573]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Much of the geo-data are shared from the Polish National Geoportal of SDI by the \\\"Data download\\\" section. Mostly NSDI data are distributed in Web map service (WMS) standard which complies with the specification of OGC standard. WMS standard (in version 1.3.0) and International Standard ISO 19128 are the same documents. This standard is applicable to pictorial presentation (renderings) of maps in a graphical format in accordance with the International organization for standardization and the Open geospatial consortium specifications [40,41]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,576,914,640]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As we know, the basic standardization document is a standard (the normative document), i.e., a non-legal act, but a document adopted by consensus and approved by an authorized organizational body [42]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,641,914,721]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of \\\"Geographic information,\\\" we have ISO [43], regional standardization (CEN, European Committee for Standardization [44]) and national standardization (for example: German - Deutsches Institut für Normung, DIN [45] and Polish - Polski Komitet Normalizacyjny, PKN [46]). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,723,914,786]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The normative documents are a valuable source of definition of specialist terms and therefore they deserve attention services of the German institute for standardization (DIN). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,789,914,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There are DIN-TERM [47] database for the terms and definitions from standards, draft standards, and specifications in the following languages: German, English, French, and Polish and the information portal developed by the German-Chinese Joint Committee of Industry and Trade [48]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,887,914,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Poland, the Technical Committee No. 297 for geographic information operates as part of the work of the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,40,114,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,40,257,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adam Doskocz \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[818,40,914,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[78,84,480,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"standardization committee (PKN). It covers all issues related to the modeling and design of data resources in spatial information systems and geo-data flow between different users and systems. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,150,480,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Modern knowledge in this area is included in more ISO standards of the 19100 series, adopted as European standards, as well as in the nation's standardization documents. For example, in the years 2014-2020, Head office of geodesy and cartography in Poland implemented the POWER project [49]. POWER task was carried out by providing an information and knowledge about geo-data for public administration and for people interested in the geographic information. In addition, from 2011, the e-Guide was available, including entries from Polish (PKN) normative documents [50]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,330,480,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the world today, there are three groups of data sources for acquisition of geo-data. Geo-data can be produced by different techniques: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,379,480,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- field surveying by using total station and GNSS for direct measurement from terrain surfaces and with the use of geo-radar and other apparatus for the measurement of underground features. \\\",\\\"- photogrammetry by using photogrammetric images and point clouds and photogrammetric instruments and applications. \\\",\\\"- cartographic digitization by using existing maps and survey notes. \\\"]\",\n \"page_idx\": \"8\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[78,543,480,656]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Poland, geo-data are produced by various methods [18], and in accordance with the Regulation [51] standards were set out for geodetic works involving the technology of positioning of topographic points (especially for the largescale map data) using field measurements, photogrammetric surveying, and map digitizing (so-called cartographic surveying). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,658,480,722]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Field measurements and other methods of data acquisition should ensure adequate accuracy of geo-data points. The horizontal positioning were divided into three groups of accuracy: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,723,480,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- the 1st accuracy group, with an error not greater than $0.10\\\\\\\\mathrm{m}$ (i.e. the so-called \\\\\\\"well-defined\\\\\\\" points, inter alia: marks of boundary points, marks of control network points, buildings and engineering structures, including elements of utilities available for direct survey); \\\",\\\"- the 2nd accuracy group, with an error not greater than $0.30\\\\\\\\mathrm{m}$ (inter alia: ground buildings and construction devices in the form of embankments, excavations, dikes, levees, ditches, canals, artificial lakes, hidden elements of public utilities and land development components, particularly parks, lawns, playgrounds and recreation, single trees, and sports fields); \\\"]\",\n \"page_idx\": \"8\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[494,84,895,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"- the 3rd accuracy group, with an error not greater than $0.50\\\\mathrm{m}$ (inter alia: contours of agricultural land and soil pits for the needs of soil classification, rivers, and lakes with natural boundary lines, forestry fields on forest areas, and national parks). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,182,895,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In case of elevation (height) surveying, accuracy should not be less than: $0.02\\\\mathrm{m}$ - for pipes and sewage devices; $0.05\\\\mathrm{m}$ - for objects and equipment of building and marked pickets in the field; $0.10\\\\mathrm{m}$ - for earthworks, flexible or electromagnetically measured underground utilities network, and unmarked pickets in the field. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,281,895,411]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In accordance with new legislation (paragraph 3. in [51]), measurements for the large-scale map geo-data are made using the methods, techniques, and technologies that ensure the above accuracies and the fulfilment of the conditions for performing the surveying works (jobs). The choice of the \\\"right way\\\" used for meeting the conditions for taking measurements and ensuring the required accuracy rests with the head of geodetic jobs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[494,440,648,459]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,477,895,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Currently distribution of geo-data are opening [36], and not only is it about open access to GIS data, but major changes have recently occurred in the provision of even cadastral data [52,53]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,543,895,656]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Countries improve the management of good governance approach and contribute to the development of regional and global SDIs by creating national SDI. In Poland, elements of the national geodetic and cartographic resources are key information to build SDI in accordance with the relevant principles defined by the European Commission [54]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,658,895,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work concerns the main geodetic elements of Polish SDI (i.e., base geodetic control networks, the base map, land and buildings register, geodetic register of utilities, and the topographic data), including methods of producing geo-data and technical standards for field measurements and other methods of data acquisition. Polish regional and district datasets (portals) and national geoportal, as well as international initiatives in the field of spatial information including standardization works, were also discussed in this work. Because today, it is important for building national SDI concepts to ensure the interoperability of their components for a variety of hardware-software platforms, for example, along with creating land administration system in \\\"Fit For Purpose\\\" strategy [55]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,887,895,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It should be noted that modern geodetic and cartographic resources and progress in legislation, in particular \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,179,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[379,39,828,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual state of the geodetic and cartographic resources and legislation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[882,40,895,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[99,84,500,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"normalization work on the GML format, promote the use of spatial data in Poland and enable their popularization among the international community. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,148,500,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments: Author received no specific funding for this article and has declared that no competing interest exists. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,215,502,263]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding information: This research was funded by the Department of Geodesy, University of Warmia and Mazury in Olsztyn, Poland, statutory research no. 29.610.001-110. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[99,279,497,295]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflict of interest: Author states no conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,339,226,358]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,378,500,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] Act of Polish Parliament, Prawo geodezyjne i kartograficzne (The Geodetic and Cartographic Law). 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Trans GIS. 2021;25:642-71. \\\",\\\"[23] Regulation of the Ministry of Development, Labor and Technology, W sprawie geodezynej ewidencji sieci uzbrojenia terenu (Regarding the geodetic database of utilities). Journal of Laws on 2021, item 1374, Warsaw (in Polish). \\\",\\\"[24] Regulation of the Ministry of Development, Labor and Technology, W sprawie edificenci gruntów i budynków (Regarding the real estate cadaster]. Journal of Laws on 2021, item 1390, Warsaw (in Polish). \\\",\\\"[25] Repository for interoperability with published application schemas; 2022. https://www.gov.pl/web/gugik/schematy-aplikacyjne-opublikowane-w-repozytorium-interoperacynyosci. \\\",\\\"[26] Act of Polish Parliament, O informatyzacje dzialność podmiotów realizujacych zadania publiczne (Computerization of activities entities performing public tasks). Journal of Laws on 2020, item 346, Warsaw (in Polish). \\\",\\\"[27] Global Spatial Data Infrastructure Association;2018. http://gsdiassociation.org. \\\",\\\"[28] United Nations Committee of Experts on Global Geospatial Information Management; 2022. https://ggim.un.org. \\\",\\\"[29] INSPIRE Geoportal of Infrastructure for Spatial Information in the European Community; 2022. http://inspire-geoportal.ec.europa.eu. \\\"]\",\n \"page_idx\": \"9\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[100,40,121,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[174,40,265,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adam Doskocz \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[818,40,915,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[82,85,480,626]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[30] Kleomenis K, Stathopoulos N, Tsatsaris A, Chalkias C. A survey of the Geoinformatics use for census purposes and the INSPIRE maturity within Statistical Institutes of EU and EFTA countries. Ann GIS. 2019;25(2):167-78. \\\",\\\"[31] U.S. NSDI from Federal Geographic Data Committee; 2018. https://www.fgdc.gov/dataandservices/. \\\",\\\"[32] U.S. GeoPlatform provided by the member agencies of the Federal Geographic Data Committee; 2020. https://www.geoplatform.gov. \\\",\\\"[33] The United States Geological Survey (USGS); 2022. https:// www.usgs.gov/products. \\\",\\\"[34] The Open Geospatial Consortium (OGC); 2022. https://www.ogc.org. \\\",\\\"[35] Standards by ISO/TC 211 Geographic information/Geomatics; 2022. https://www.iso.org/committee/54904/x/catalogue/. \\\",\\\"[36] Izdebski W, Zwirowicz-Rutkowska A, Nowak da Costa J. Open data in spatial data infrastructure: the practices and experiences of Poland. Int J Digit Earth. 2021;14:1547-60. doi: 10.1080/17538947.2021.1952323. \\\",\\\"[37] Information page for the EGiB service; 2022 (in Polish and in English). https://www.geoportal.gov.pl/dane/dane-ewidencyjne. \\\",\\\"[38] Information page for the GESUT service; 2022 (in Polish and in English). https://www.geoportal.gov.pl/dane/uzbrojenieterenu. \\\",\\\"[39] Information page for the BDOT500 service; 2022 (in Polish and in English). https://www.geoportal.gov.pl/dane/bazdanych-obiektow-topografcznych-bdot500. \\\",\\\"[40] Information about WMS service from ISO the worldwide web; 2022. https://www.iso.org/obp/pi/#iso:std:iso:19128:ed-1:v1:en. \\\",\\\"[41] Information about WMS service from OGC the worldwide web; 2022. https://www.ogc.org/standards/wms. \\\",\\\"[42] Jaskowska M. Publiczne systemy informacyjne i zróda danych: przywodnik (Public information systems and data sources: a reference guide). Kraków: Jagiellonian Library; 2020. (in Polish with English metadata). https://ruj.uj.edu.pl/xmliu/handle/item/152126. \\\",\\\"[43] International Organization for Standardization: homepage; 2022. https://www.iso.org. \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[497,85,895,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[44] European Committee for Standardization: homepage; 2022. https://www.cencenelec.eu. \\\",\\\"[45] German Institute for Standardization: homepage; 2022. https://www.din.de/en. \\\",\\\"[46] Polish Committee for Standardization: homepage; 2022. https://www.pkn.pl/en. \\\",\\\"[47] DIN-TERMinology Portal: homepage; 2022. https://www.din.de/en/services/din-term/datenkategorieien. \\\",\\\"[48] Germany-China Standards Information Portal: homepage; 2022. http://cn-e_standards-portal.de/. \\\",\\\"[49] POWER project in Head Office of Geodesy and Cartography in Poland; 2021 (in Polish). http://power.gugik.gov.pl. \\\",\\\"[50] e-Guide to Polish Standards in the field of geographic information; 2021 (in Polish). http://e-przewodnik.gugik.gov.pl. \\\",\\\"[51] Regulation of the Ministry of Internal Affairs and Administration, W sprawie standardów technicznych wykonywania geodezyjnych pomiarów sytuacyjnych i wysokośćowych oraz opracowywnia i przykazywnia wyników tych pomiarów doaciousyjnego i kartografcznego (Regarding the technical standards perform geodetic altitude and situational measurements and compilation and transmission of the results of these measurements to the national geodetic and cartographic resource). Journal of Laws on 2020, item 1429, Warsaw (in Polish). \\\",\\\"[52] Bielecka E, Dukaczewski D, Janczar E. Spatial Data Infrastructure in Poland - lessons learnt from so far achievements. Geodesy and Cartography. Warsaw. 2018;67(1):3-20. \\\",\\\"[53] Trystula A, Dudzinska M, Zrobek R. Evaluation of the Completeness of Spatial Data Infrastructure in the Context of Cadastral Data Sharing. Land. 2020;9:272. doi: 10.3390/land9080272. \\\",\\\"[54] Klimach A, Dawidowicz A, Zrobek R. The Polish land administration system supporting good governance. Land Use Policy. 2018;79:547-55. \\\",\\\"[55] Dawidowicz A, Zysk E, Zrobek R. A Methodological Evaluation of the Polish Land Administration System Using the Fit-For-Purpose Approach. Geomat Env Eng. 2020;14(2):31-47. \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[82,39,178,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DE GRUYTER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[376,39,823,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual state of the geodetic and cartographic resources and legislation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[878,40,895,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1515/geo-2022-0458"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Earth and Atmospheric Sciences"},"sha256":{"kind":"string","value":"2f0ac772a815729d160d192a3a7f01b16d6d05093ebbc9f4b70a9ba51e49a68a"},"title":{"kind":"string","value":"The actual state of the geodetic and cartographic resources and legislation in Poland"}}},{"rowIdx":145,"cells":{"abstract":{"kind":"string","value":"Disturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft-host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein-graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts."},"author":{"kind":"string","value":"Carlijn V C Bouten|Eline E van Haaften|Sjeng Quicken|Wouter Huberts|Nicholas A Kurniawan"},"content_list":{"kind":"list like","value":[{"bbox":"[73,134,354,149]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[389,132,445,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,157,927,255]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,268,815,306]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Eline E. van Haaften $^{1,2}$ , Sjeng Quicken $^{3}$ , Wouter Huberts $^{3}$ , Carlijn V. C. Bouten $^{1,2\\boxtimes}$ & Nicholas A. Kurniawan $^{1,2}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,358,690,607]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft-host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein-graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,17,416,88]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"communications biology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,104,161,122]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[806,104,927,122]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,902,905,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. $^{2}$ Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, The Netherlands. $^{3}$ Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. $\\text{©}$ email: C.V.C.Bouten@tue.nl ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,957,668,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[917,957,927,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[67,61,490,234]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A major clinical problem in hemodialysis therapy for end-stage renal-diseased patients is vascular access dysfunction. Vascular access for long-term hemodialysis is achieved through native arteriovenous (AV) fistula or synthetic arteriovenous graft (AVG). The primary cause of vascular access dysfunction in matured AV fistulas and AVGs is venous stenosis as a result of neointimal hyperplasia $(\\mathrm{NIH})^{1}$ . The pathogenesis of venous NIH in vascular access is well described and thought to be initiated by vessel damage, graft bioincompatibility (for AVGs), uremia, and fluid wall shear stress. These factors result in downstream effects such as oxidative stress, inflammation, and endothelial dysfunction, causing the migration and proliferation of smooth muscle cells to the intima. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,235,492,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"High shear stresses (HSS) are persistently present in AVGs and AV fistulas, even years after vessel creation. Several studies have reported that regions with high wall shear stresses (in the range of $5 - 10\\mathrm{Pa}$ ) correspond to NIH formation[3-5]. On the other hand, Krishnamoorthy et al. has suggested an inverse correlation between wall shear stress (in the range of $5 - 80\\mathrm{Pa}$ during peak flow) and stenosis formation[6]. It has also been proposed that low and oscillatory shear stress (in the range of $< 0.1 - 1\\mathrm{Pa}$ ) favors sites of stenosis[7] and that the temporal gradient of shear stress (in the range of $+0.5\\mathrm{Pa}/$ week up to $3.5\\mathrm{Pa}$ ) correlates with intimal medial thickening[8,9]. These seemingly inconsistent findings raise important questions about both the mechanistic foundation and the validity of the conjecture that wall shear stress stimulates the initiation and development of NIH in vascular access vessels. Indeed, systematic reviews reveal that the clinical evidence for this disturbed flow theory is weaker than generally believed and that so far very little is known about how altered flow is related to the cellular processes underlying $\\mathrm{NIH}^{10,11}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,476,490,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The need for mechanistic insights in (patho)physiological situations is especially critical with the emergence of a relatively new paradigm in regenerative medicine: in situ tissue engineering. This strategy hinges on the implantation of directly functional, bioresorbable, cell-free scaffolds, e.g., to be used as AVGs, which direct tissue regeneration at the locus of implantation to grow the neotissue into a state of mechanical homeostasis, presumably reducing the risk of NIH. The merit of the tissue engineering approach was recently highlighted in a study by Kirkton et al., where the authors implanted a bioengineered, acellular, human vessel as a hemodialysis conduit in patients with end-stage renal disease[12]. These vessels completely recellularized in this complex in vivo environment and transformed into a functional, living tissue, allowing repeated cannulation for years. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,663,490,836]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The new tissue has, so to say, \"emerged\" from its complex in vivo environment, whose convolution of individual factors, such as the interaction between cells and their 3D environment, paracrine, and juxtracrine signals from other cells, and response to mechanical forces, determined the resulting tissue properties. Intriguingly, these factors also affect the secretion of proteinases (e.g., MMPs and TIMPs), cytokines (e.g., MCP-1 and IL-6), and growth factors (e.g., TGF- $\\beta$ 1), which are known to be involved in NIH formation[10]. To advance this promising therapeutic development, it is of paramount importance to dissect this complexity, because the knowledge about the role of each factor and the interplay between these factors provides crucial design parameters for guiding the developing tissue toward mechanical homeostasis[13]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,837,490,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the present study, we introduce a numerical-experimental approach to systematically investigate how neotissue develops under the influence of the demanding hemodynamic environment in regenerating AVG scaffolds (Fig. 1). To quantitatively parameterize this environment, we use computational fluid dynamics (CFD) and fluid-structure interaction (FSI) modeling of a clinically derived vein-graft anastomosis. We then simulate this environment using our recently developed in vitro model ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,60,926,182]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"system $^{14}$ . This in vitro system is used to mimic the (early) proinflammatory stages of scaffold-driven in situ tissue formation, based on (1) the co-culture of human tissue-producing vascular cells and macrophages, which are (2) seeded in electrospun grafts, and (3) cultured in a bioreactor platform that allows for the independent control of wall shear stress and strain. This unique approach allows the delineation of the roles of biomechanical tissue environment and cellular responses, as well as their interplay, in scaffold-guided vascular tissue formation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,182,927,315]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The findings revealed that various wall shear stress metrics (low, high, and oscillatory), in the presence of cyclic strain, differently regulate NIH- and tissue growth-related protein secretion, tissue growth, and remodeling. In particular, oscillatory shear stress promoted the formation of a dense and disorganized collagen network. Together, these insights confirm the causative relationship between different shear stress modes and vascular tissue growth and remodeling in 3D cyclically stretched constructs, and contribute to an improved understanding of scaffold-guided tissue regeneration and the initiation mechanism of NIH in vascular access vessels. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,335,667,347]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results and discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,349,927,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Hemodynamics at the NIH-prone sites in the AVG. In the early stages of in situ scaffold-guided vascular regeneration, the scaffold largely determines the mechanical performance of the overall construct. To quantitatively understand the hemodynamic environment in the NIH-prone sites of these scaffolds when implanted as AVG, we computed the local hemodynamics using numerical models (Fig. 2a). For this purpose, a realistic AVG geometry was reconstructed from 15 months postoperative computed tomography angiography (CTA) scans and 2-weeks preoperative ultrasound diameter measurements of a single renal-diseased patient. For detailed information regarding the model reconstruction and numerical simulations, the reader is referred to the \"Methods\". ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,510,927,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The flow disturbances at the perianastomotic region at the venous site are known to cause the most common graft-related complications. These flow disturbances are associated with the local deformations and local shear stresses of the venous perianastomotic wall. To accurately estimate these local stresses and strains, we developed an FSI model of this region, which took into account the temporally varying flow-induced wall deformations as well as the consequent flow profiles. The graft (0.63 mm wall thickness[15]) and the vein (0.385 mm wall thickness[15-17]) were modeled as a Neo-Hookean material, with a Young's modulus of 1.5 MPa for the graft[15,18] and 0.455 MPa for the vein[15]. A CFD model of the full geometry with a rigid wall assumption was used to obtain proper boundary conditions for the FSI model and to estimate the wall shear stresses in the graft. At the inlet boundary of the CFD model, a Doppler ultrasound-based velocity profile was prescribed, whereas at the proximal venous outlet a zero-pressure boundary condition was prescribed[19]. To mimic the peripheral bed and collateral venous flow, a six elements lumped parameter model was coupled to the distal arterial and venous outlets. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,777,927,870]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"These simulations revealed that the shear stresses have time-averaged values of around $5\\mathrm{Pa}$ with a low oscillatory shear index (Fig. 2c). The strains around the venous anastomotic border are in the order of $1\\%$ with extremes up to $2\\%$ at the anastomosis (Fig. 2b). To the best of our knowledge, this is the first study that quantifies wall shear stresses and strains in AVGs, giving a unique insight into the biomechanical environment inside these AVGs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,890,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Integrating computational output into in vitro model. The biomechanical environment in the AVGs, as quantified from these computational outputs, were mimicked in our in vitro platform to recapitulate the local hemodynamics in vascular ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[467,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 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\"]","image_footnote":"[]","img_path":"images/0816/c9c377bada423e68250df3c6cdcb9522277f1a33d5aa8634ed4181f863216f41.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[245,335,386,436]","code_body":null,"code_caption":null,"image_caption":"[\"c in vitro model \",\"directly after seeding 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\"]","image_footnote":"[]","img_path":"images/0910/c8653af7ff99952cb542fca74a5ba33813e1abccb8151428216c43484eeb2ddb.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[430,310,601,434]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0456/0409e9f6648e2b220a0092f9c3e92b6ed8191e671f21cc5165b9fa64762399cf.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[628,76,794,149]","code_body":null,"code_caption":null,"image_caption":"[\"vein-graft anastomosis \"]","image_footnote":"[]","img_path":"images/0050/216c41b3ef60a53dc4aef3e40b1c8d6efb3972111914c0782cbb2d9d44f92245.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[685,154,731,208]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0788/d89776c716175e1721e9e48e13d4868b0f5ce55e0ce74687a90503863d2425b9.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[643,221,744,278]","code_body":null,"code_caption":null,"image_caption":"[\"disorganized matrix \"]","image_footnote":"[\"$\\\\nabla$ proteinases $\\\\nabla$ growth \",\"▲ remodeling \"]","img_path":"images/0800/f6918d532e5c4cac1235349e77f37f420b9835ffefd26fa5cd395281a53880f0.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[616,271,736,335]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0347/4dc0b3a45c19bde8a0e4783318da18a6d05e952140e5069e869d7fa4321d5580.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[673,341,737,347]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"organized matrix ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[643,347,742,461]","code_body":null,"code_caption":null,"image_caption":"[\"after hemodynamic loading and culture \",\"Fig. 1 Proposed role of shear stress on in vivo neointimal hyperplasia, as revealed from a combined in silico and in vitro study. a In vivo, neointimal hyperplasia at the venous anastomosis of vascular access grafts is a common occurrence. This pathology is presumably driven by shear stress. b Using in silico models (i.e., computational fluid dynamic (CFD) and fluid-structure interaction (FSI) models), the mechanical environment (i.e., the shear stresses and strains) in vascular access grafts is computed. c The results of these in silico models are used to define the boundary conditions for the in vitro model (i.e., a 3D scaffold containing macrophages and (myo)fibroblasts), in which the computed shear stresses and strains are recapitulated. After 14 days of dynamic culture, allowing for (myo)fibroblast proliferation and tissue formation, oscillatory shear stress resulted in a reduction of several proteinases and upregulation of growth and remodeling markers, which was accompanied by a dense and disorganized appositional matrix structure. This in contrast to high shear stress, which led to a strongly aligned appositional matrix. Note that in the in vitro study the shear stress and matrix alignment did not occur at the luminal side but at the outside of the scaffold. b is reproduced from Quicken et al. $^{15}$ with permission. \"]","image_footnote":"[\"$\\\\nabla$ proteinases \",\"growth \",\"- remodeling \"]","img_path":"images/0038/62bd56b84df13964b032f33456cd86f797abca0d41bccc7dba0327216e0c68c3.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,618,490,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"access vessels, i.e., the shear stresses and strains, allowing us to directly correlate to a biological response. This approach provides possibilities to test mechanistic hypotheses that are unaccessible in conventional in vivo studies, where the correlation between local hemodynamics, derived from computational models, and tissue composition, derived from histological stainings, is indirect and often only qualitative<sup>9</sup>. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,710,490,911]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A selection of the computed hemodynamic parameters at the vein-graft anastomosis, representing a single snapshot of the spatiotemporal hemodynamic profile in this venous perianastomotic region, served as boundary conditions of the in vitro experiments (Fig. 2d). We selected a biomechanical condition that falls between the 15th and 100th percentiles of the strain and shear stress datasets (blue dotted lines in Fig. 2b ( $\\sim 2\\%$ ), c ( $\\sim 3$ Pa)), referred to as the HSS condition. Given the hypothesis that shear stress is the driving factor of NIH, we selected one other shear stress metric that is proposed to correlate with NIH: oscillating shear stress $(\\mathrm{OSS}, \\pm 3\\mathrm{Pa})$ . To test the effects of HSS and OSS on neotissue development and NIH-involved protein secretion in our in vitro model of scaffold-guided vascular growth, we compared against a physiological (venous) low shear stress $(\\mathrm{LSS}, \\sim 0.5\\mathrm{Pa})$ control, as described by Malek et al[20]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,911,490,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The in vitro model consists of a cell-laden tubular scaffold construct mounted around impermeable silicone tubing and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,618,929,726]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"centered in a glass tube in a multi-cue bioreactor. The resulting annular channel is perfused with medium at a constant pressure gradient to apply laminar shear stress (in the HSS and LSS groups), or at an $1\\mathrm{Hz}$ alternating pressure gradient to apply oscillatory shear stress (in the OSS group). The silicone tubing is cyclically pressurized up to a constant pressure at $1\\mathrm{Hz}$ to apply circumferential stretch. For detailed description of the bioreactor, the reader is referred to our earlier work[21,22]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,742,927,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The biomechanical environment during in vitro culture. The vascular scaffolds for the in vitro experiments, with a wall thickness of $200\\mu \\mathrm{m}$ and inner diameter of $3\\mathrm{mm}$ , were produced using electrospinning from poly(ε-caprolactone) bis-urea (PCLBU, Fig. 3a). This polymer is soft, tough, biodegradable, and easy to functionalize, and therefore an attractive biomaterial for in situ tissue engineering[23]. The resulting scaffolds, with a Young's modulus of $3\\mathrm{MPa}^{14}$ , exhibited an isotropic microstructure with $\\sim 5\\mu \\mathrm{m}$ fiber diameter (measured at the scaffold surface), which remained stable during the course of the culture, independent of the applied loading condition (Fig. 3b, c). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,890,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to the fiber diameter, the morphology of the scaffold fibers remained unaffected (Fig. 3b), indicating that no scaffold degradation occurred at the scaffold surface. The degree of degradation was indeed expected to be minor in the present ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,23,529,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[830,17,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,957,665,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[917,957,927,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[90,65,344,416]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0432/bcfad4ace02f339e97f1d8c0c8ef6886d627901019e8b5ac55e23ab3f6e5a24f.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[347,63,892,168]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0579/5c14f4ff5477816df2dc84eaaf29868df18128862521de40aad7502a92d22cb2.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[347,189,890,398]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0126/495aab43dd20910b97f5d955fc5fc754de4187bb2df5b73a6c7c52906ddad3c5.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,421,905,579]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2 Computational characterization of the biomechanical environment in an AVG as input for scaffold-driven neotissue formation in vitro. \"]","image_footnote":"[\"a Geometry of the arteriovenous graft (AVG), looped between the axillary artery and axillary vein, that was used for the computational model (humerus inserted as a reference, venous anastomotic region indicated by rectangle). b Fluid-structure interaction (FSI) simulations and c computational fluid dynamics (CFD) simulations to compute the local strains and shear stresses in the AVG, respectively (histograms and associated percentile plots showing the distribution of the quantified read-out parameters ( $\\\\varepsilon$ strain, TAWSS time-averaged wall shear stress, OSI oscillatory shear index). The dashed lines in the percentile plots correspond to the boundary conditions of the high shear stress (HSS) group in the in vitro experiments). d The computational results guide the in vitro experiments by defining the relevant boundary conditions (HSS high shear stress, OSS oscillating shear stress, LSS low shear stress). (Myo)fibroblasts and PMA-stimulated THP-1 cells (macrophages) are co-seeded in the scaffolds using fibrin. After 3 days of static culture, the constructs are exposed to HSS, OSS, or LSS during 14 days, all in the presence of strain. After the dynamic culture, constructs and supernatants are collected and processed for further analysis. a is derived from Quicken et al. $^{19}$ with permission. \"]","img_path":"images/0787/da701948075f196998a7d947eba50a0649ebbdbd0e319c8cfd18aa8f5225a239.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,742,489,823]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"study, as we used $\\sim 10\\times$ lower cell seeding density compared to a previous study that investigated cell-induced scaffold degradation using THP-1-derived marophages $^{24}$ . Future research can be further directed to examine degradation at the center of the scaffold, for example using Raman spectroscopy on cross-sections $^{25}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,823,490,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To mimic the early phase of the in situ scaffold environment, scaffolds were seeded with a 2:1 mixture of human THP-1-derived macrophages and primary vascular-derived (myo)fibroblasts (mFBs) using fibrin as a cell carrier. Following 3 days of static culture, the cell-seeded constructs were cultured for 14 days in Xanthan Gum (X-gum)-enriched medium containing L-ascorbic acid 2-phosphate (AA2P) under various shear stress conditions in the presence of low cyclic circumferential strain $(2.3\\pm 0.4\\%)$ at $1\\mathrm{Hz}$ Fig.3d), mimicking the predicted strain ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,742,926,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"values in AVGs as computed by the FSI simulations (Fig. 2b). X-gum was added to match medium viscosity to blood viscosity (about $4 \\cdot 10^{-3} \\mathrm{Pa} \\cdot \\mathrm{s}$ for a wall shear rate of $\\sim 200 \\mathrm{~s}^{-1}$ [26], while AA2P was added to stimulate matrix formation[27]. Rheology measurements indicated that the viscosity of the X-gum-enriched medium was $\\sim 2.5$ -fold higher compared to that of standard medium, confirming that medium viscosity was increased toward the range of blood viscosity (Fig. 3e)[26]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,851,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Samples in the HSS and OSS conditions were exposed to an average (absolute) shear rate of $1216 \\pm 128 \\, \\mathrm{s}^{-1}$ , and samples in the LSS condition to $93 \\pm 31 \\, \\mathrm{s}^{-1}$ (left panels in Fig. 3f, g). The applied strains and shear rates were successfully maintained over the complete culture period, except at day 4 in the LSS condition where the shear rate dropped slightly to $\\approx 60 \\, \\mathrm{s}^{-1}$ (left panel in Fig. 3g). Using the quantified viscosity of the X-gum-enriched ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[468,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 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decellularization for each experimental condition, and of an 8-day statically cultured cell-free sample (bare). c Quantification of scaffold fiber diameter at the outside of the (decellularized) constructs ( $n = 30$ fibers/condition). d Temporal variations in cyclic stretch for all loading conditions ( $n = 13$ or 14/day). e Shear rate dependent viscosity in X-gum-enriched medium (red squares, $n = 3$ ), standard medium (blue triangles, $n = 3$ ), and water (yellow circles, $n = 3$ ). The $*$ indicates blood viscosity at $200\\\\mathrm{s}^{-1}$ . f, g Temporal variations in shear rate (left axis, $n = 6$ , 7, or 9/day), viscosity (right axis, $n = 3$ or 5/day), and shear stress (right, derived from the actual (measured) medium viscosity) in the high, oscillating, and low shear stress conditions. Bars and black dots represent mean, error bars and gray area indicate standard deviation, boxplots contain $50\\\\%$ of the data with median highlighted by central mark ( $*p < 0.05$ , $* * p < 0.01$ ). \"]","image_footnote":"[]","img_path":"images/0928/16e9f611a66d3f1538603611bcaa48665910c70bb74e61b4e14529276fc4b333.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,594,490,714]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"medium, the shear rate applied to the samples translated to a shear stress of $(\\pm) 3.2 \\pm 0.3$ Pa for the HSS (unidirectional) and OSS (complete flow reversal) condition (right panel in Fig. 3f), of which the magnitude is within the range of expected shear stress values in AVGs as computed by the CFD simulations (Fig. 2c). For the LSS condition, this translated to $0.44 \\pm 0.12$ Pa (right panel in Fig. 3g), which is within the range of $0.1 - 0.6$ Pa in healthy veins[20]. The applied shear stresses remained stable over time. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,714,490,797]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"These results demonstrate that we were able to keep the biomechanical cellular environment, in terms of passive cues (via the scaffold fibers) and active cues (via the shear stresses and strains), stable and at the required level. This precise experimental control allowed us to directly correlate the biological response to the applied loading regime. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,823,490,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Oscillatory shear stress activates macrophages and (myo) fibroblasts. Using this dynamic in vitro setup, we quantified the cell and tissue growth and characterized the phenotypes of the cells in response to the different types of shear stress. The dynamic co-culture led to an overall increase of the construct mass with time, especially for the samples exposed to HSS and OSS (Fig. 4a). At day 14, scaffolds were completely populated with cells in all conditions and an increasing, but non-significant $(p = 0.143)$ , trend of cell content with high $(81\\%)$ and OSS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,594,927,649]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(118%) compared to LSS was observed (Fig. 4b). However, the variation in DNA content within the groups was large, and no clear difference between the appearance and proliferative state of cells could be observed (Fig. 4c, d). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,649,929,808]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The appositional cell/matrix layer (i.e., the side that was exposed to the flow) aligned in the direction parallel to the flow (Fig. 4e, f). This layer contained elongated cells with stress fibers (top row in Fig. 4f). At the other side of the scaffold, cells with a more rounded morphology were observed (bottom row in Fig. 4f). Elongated cells stained positive for vimentin, indicating that the outside of the constructs was populated primarily by the mFBs (Fig. 5a). CD45, as an indicator of the macrophages, was mostly found in the middle layers of the constructs and to a lesser extent compared to vimentin. This was to be expected as a result of (myo)fibroblast proliferation and a possible reduction in macrophage number (e.g., as a result of apoptosis and transdifferentiation). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,809,929,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Previously, it has been shown in vivo that OSS ( $\\approx 14$ Pa; range of $60\\mathrm{Pa}$ ) induces smooth muscle cell-rich plaque formation, while LSS ( $\\approx 10$ Pa) induces the occurrence of M1-polarized macrophage-rich plaques in the carotid artery in mice[28-30]. Note that the seemingly large discrepancy between these magnitudes of wall shear stress and the definition of \"LSS\" we used in this study is attributable to the known inverse relationship between animal size and wall shear stress[31], and to the physiological difference in wall shear stress between arteries and veins. 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\"]","image_footnote":"[]","img_path":"images/0301/60195d6f0356da181d5d4021a7252bf47ca8731354d2245ba49a24e9db640d24.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[642,210,768,306]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0844/4e78ccb58f439c9787fb5ef5bc189eb0f5c62bbbad24f66b73eeef833600f9a5.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[778,210,904,306]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0254/ef259e3c7cb6be246b734f8961e7ac26c1f3f0a558d51b1b4f3109682fbb511b.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[485,310,633,434]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0932/ad65406c94c39daecfc149e3005704ae56efe27ce8907fd1b849234c1e2c685b.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[642,310,768,434]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0990/3e519a842abc29863ab4d6735d7e59df5a28f11c8c49cd8006a8af0552d89dc8.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[776,310,904,434]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4 Cell and tissue growth at day 14 under different types of shear stress. a Overall construct mass/surface at day 14 normalized to scaffold mass/ surface prior to seeding (dashed line indicates no change, $^{**}p < 0.01$ $^{**}p < 0.0001$ tested with a one sample t-test). b Total DNA content per tissue construct. c Hematoxylin and eosin-stained cross-sections. d Localization of Ki67-positive cells (Ki67 in green, scaffold material in blue, dashed lines indicate construct borders). e Scanning electron microscope image of the cell and tissue morphology. f In-plane visualization of the F-actin cytoskeleton (actin in green, nuclei in red, and scaffold fibers in blue). Bars represent mean $\\\\pm$ standard deviation. HSS high shear stress condition $(3.2\\\\mathrm{Pa},n = 4)$ ,OSS oscillatory shear stress condition $(\\\\pm 3.2\\\\mathrm{Pa},n = 5)$ , LSS low shear stress condition $(0.4\\\\mathrm{Pa},n = 5)$ \"]","image_footnote":"[]","img_path":"images/0873/847a23fd7e899f7993e806b258be9690350e887d2d0cfeed1d1785f7e921f768.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,554,490,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"macrophage polarization, we examined the relative expression of M1 and M2 macrophage markers at HSS and OSS compared to LSS. Interestingly, we did not detect a polarization toward an M1 or M2 macrophage phenotype (Fig. 5b). Only CD68 (pan-macrophage marker) and IL10 (anti-inflammatory marker) were more clearly activated with OSS $(p = 0.0216$ and $p = 0.1224$ , respectively), and to a lesser extent with HSS $(p = 0.1819$ and $p = 0.6740$ , respectively, Fig. 5c). Similar to the dualistic macrophage phenotype, the phenotype of the mFBs could not be uniquely attributed to be either synthetic or contractile. Instead, we found simultaneous upregulation of S100A4 (synthetic marker) and smoothelin (contractile marker), and downregulation of calponin (contractile marker) with OSS $(p = 0.0350$ , $p = 0.0082$ , and $p > 0.9999$ , respectively) and HSS $(p = 0.1024$ , $p = 0.8686$ , and $p = 0.1096$ , respectively, Fig. 5c). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,755,492,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Contrary to the gene-level analysis of MCP-1 $(p = 0.0075)$ , TNF- $\\alpha$ $(p = 0.2423)$ , and IL-6 $(p = 0.1763)$ , at the protein level these cytokines were lower expressed in the OSS group compared to the LSS group, although the variation within each group was large (Supplementary Fig. S2). With respect to growth factors (TGF- $\\beta$ 1 $(p = 0.1203)$ , CTGF $(p = 0.9973)$ ) and proteinases (MMP-1 $(p = 0.0122)$ , MMP-9 $(p = 0.0378)$ , TIMP-1 $(p = 0.0075)$ ), similar trends as seen for the cytokines were observed, which were significant for the proteinases, but not for the growth factors (Supplementary Fig. S2b). However, this quantification only represents a single snapshot in time, while similar work has shown that protein and RNA expressions are highly dynamic in nature[14]. In addition, the discrepancy between gene and protein secretion could indicate that the translation from RNA to protein is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,554,927,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"differently regulated, or that the protein stability in the culture medium is reduced in HSS and OSS conditions $^{32}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,580,927,649]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Together, the results suggest that OSS activates mFBs and macrophages to grow new tissue in terms of both cell number and matrix. Moreover, the reduction of proteinase secretion in the OSS group suggests a suppressed tissue-remodeling environment, favoring neotissue formation rather than tissue degradation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,663,927,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Oscillatory shear stress promotes disorganized tissue growth. Next, we sought to investigate the effect of the different shear stress metrics on tissue formation and remodeling. Overall, the gene expression of all growth and remodeling markers, with the exception of $TGFB1$ , was (non-significantly) elevated with OSS compared to HSS (Fig. 6a). The expression of collagen type I/III, decorin, versican, fibrillin 1, MMP1, MMP2, and TIMP1/2 was also higher compared to the LSS condition, which was statistically significant for decorin $(p = 0.0385)$ and MMP1 $(p = 0.0122)$ . Interestingly, with OSS the gene expression of TIMP1 and MMP9 was relatively high compared to the expression at the protein level (Supplementary Fig. S2b). In addition, MMP1 and MMP9 expression followed a similar trend at the protein level, but not at the gene level (Supplementary Fig. S2b), suggesting different posttranscriptional mechanisms between the loading conditions. TGF- $\\beta$ has been found to be an important posttranscriptional regulator of $\\mathrm{MMPs}^{33}$ . However, these mechanisms are complex and interrelated, complicating the comparison of the different MMPs, TIMPs, and growth factors to one another. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,916,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Collagen staining and hydroxyproline (HYP) quantification revealed that, compared to unidirectional shear stress (i.e., LSS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[468,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,957,78,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[226,957,823,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[90,60,594,349]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0242/2da0a5bd19035313881358dcc14831aea916ee5f7258b344a5b7d6b21148dd85.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[603,62,905,349]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0379/ae8644f8f80953df3add5b1b712078bea75701eb32789dc8168fc05e152b9449.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[87,354,890,456]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5 Phenotypical characterization of the cells in the vascular constructs at day 14. a Representative cross-sections for each experimental group stained for CD45 (green) and vimentin (red) for the localization of macrophages and (myo)fibroblasts, respectively (nuclei are indicated in the lower panel in blue). b Relative gene expression compared to the low shear stress condition (indicated by the circle at 1) for macrophage-related genes (left part of the polar plot) and (myo)fibroblast-related genes (right part of the polar plot, $n \\\\geq 3 / \\\\text{group}$ ). The dots and shaded areas indicate, respectively, the $50^{\\\\text{th}}$ and $25^{\\\\text{th}} - 75^{\\\\text{th}}$ percentiles. c Boxplots for a selection of phenotypical-related genes ( $n = 3, 4$ , or 5, $^* p < 0.05$ , $^{**} p < 0.01$ ). Boxplots contain $50\\\\%$ of the data with median highlighted by central mark. HSS high shear stress condition (3.2 Pa), OSS oscillatory shear stress condition ( $\\\\pm 3.2$ Pa), LSS low shear stress condition (0.4 Pa). See Supplementary Fig. S1 for all boxplots of the gene expression data. \"]","image_footnote":"[]","img_path":"images/0270/b7875aa0d5ecb6d4244a6c6515f5efc368f50e2a403568eb88c22b5fe313e357.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,569,490,744]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and HSS), OSS seemed to stimulate the synthesis of more and thicker collagen fibers (Fig. 6b, d). The differences in HYP content, however, are small and not significant. Collagen fibers are especially suited to resist in vivo loading and slowly take over the load-bearing properties of the resorbing scaffold. However, this process can result in scar-like tissue if collagen production happens too fast. HSS stimulated relatively more collagen type I formation while $\\alpha$ -SMA-positive cells were predominantly detected at the tissue borders with LSS (Fig. 6c). Together, these observations are in line with the increased expression of growth markers at the gene level (Fig. 6a) and may have been further stimulated by the decreased levels of proteinases in the culture medium (Supplementary Fig. S2b). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,744,492,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We then focused on the neotissue organization in the appositional tissue layer which was in direct exposure to the shear stress and whose thickness was highest with HSS $(p = 0.0205$ compared to LSS, Fig. 6b, e). The collagen fibers were mainly oriented at an angle between $80^{\\circ}$ and $90^{\\circ}$ in all groups (i.e., parallel to the flow direction), and compared to LSS, consistently more aligned in the HSS condition, despite the limited differences in proteinase secretion (Supplementary Fig. S2b). In contrast, the peak in the OSS condition was much broader compared to LSS and HSS, indicating that the collagen is deposited with a substantially higher in-plane fiber dispersion when the flow is not unidirectionally applied. Based on these findings, we conclude that the collagen fiber dispersion in the superficial collagen layer is a direct result of flow-induced shear stress, rather than an indirect result of the secreted proteinases. On the other hand, the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,569,927,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"overall collagen fiber orientation is not necessarily mediated by shear stress alone, as the presence of cyclic strain has also contributed to this fiber orientation $^{14}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,609,929,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to tissue growth and remodeling by the mFBs, we aimed at scaffold degradation that is mainly induced by the macrophages. As the macrophages resided in the center of the scaffold and not at the surface, prohibiting the assessment of scaffold degradation by SEM, we examined the expression of genetic markers responsible for scaffold degradation. In the OSS group, NFKB1 (a protein complex involved in oxidative stress) was upregulated compared to LSS (Supplementary Fig. S3, $p = 0.0044$ ). LIPA (lysosomal lipase) followed a similar trend. On the other hand, NOX2 (ROS generating NADPH Oxidase 2 complex), which is involved in oxidative degradation, followed a decreasing, albeit non-significant, trend in the HSS condition. Although this could indicate enhanced oxidative and enzymatic degradative capacity of the macrophages with OSS, a previous study showed that the expression of these genes could not explain the differences in macrophage-driven scaffold mass loss, making it difficult to directly relate gene expression to scaffold degradation[24,34]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,875,584,888]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,888,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study aimed to elucidate how neotissue develops under the influence of the hemodynamic environment in regenerating AVGs via a combined in silico and in vitro approach (Fig. 1). With this approach, the hemodynamic environment could be ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,23,529,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[830,17,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE 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6 Changes to matrix growth, remodeling, and organization in response to shear stress. a Relative gene expression compared to the low shear stress condition (indicated by the circle at 1) for markers related to growth (i.e., collagenous matrix, proteoglycan, and elastic matrix formation), as well as markers related to remodeling. The dots and shaded areas indicate, respectively, the 50th and 25th-75th percentiles. See Supplementary Fig. S1 for all boxplots of the gene expression data. b Total hydroxyproline (left) and glycosaminoglycan (middle) content normalized to total construct mass, and quantification of the thickness of the appositional collagen layer on top of the scaffold from the confocal z-stacks in e (right, $^* p < 0.05$ ). Representative sections of each experimental group stained for (c) $\\\\alpha$ SMA (green), collagen I (red), and DAPI (blue) and (d) Picrosirius red (visualized under polarized light). e Confocal visualization of the collagen structure. f Overlay plot and g separate histograms quantifying the angular collagen distribution in the appositional matrix layer for each condition (directions of applied shear stress $(90^{\\\\circ})$ and stretch $(0^{\\\\circ})$ indicated by the arrows in c-e. Bars represent mean $\\\\pm$ standard deviation. HSS high shear stress condition $(3.2\\\\mathrm{Pa}, n = 4)$ , OSS oscillatory shear stress condition $(\\\\pm 3.2\\\\mathrm{Pa}, n = 5)$ , LSS low shear stress condition $(0.4\\\\mathrm{Pa}, n = 4$ or 5). \"]","image_footnote":"[]","img_path":"images/0372/07f49ea6063af9a9af4cb0eef64ddc12fd05a8b130f5964658286c2cc238af89.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[67,676,490,769]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"controlled in a systematic way and biological responses could be directly measured, allowing the identification of causal relationships between hemodynamic parameters and the venous remodeling process. Relevant hemodynamic parameters were selected according to currently existing theories on venous remodeling (i.e., OSS and $\\mathrm{HSS^{10}}$ ), while the exact magnitudes were derived from CFD and FSI simulations (Fig. 1a, b). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,769,492,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Using these in vitro dynamic co-cultures, we demonstrated that, compared to unidirectional shear stress (i.e., LSS and HSS), OSS activates both cell types to grow and remodel a tissue with a dense and disorganized structure (Fig. 1c). Furthermore, the secretion of NIH-related proteins was lower in the OSS and HSS conditions, indicating that the interaction between the different cell types and their mechanical environment resulted in a microenvironment that likely favored neotissue formation rather than tissue degradation. Here, it should be noted that other (complex) shear stress theories exist as well (e.g., spatial and/or temporal gradients in shear stress $^{10}$ ), and that the cellular composition and phenotypes may differ in patients requiring vascular access, which should be the subject of future investigation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,676,927,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Taken together, we identified oscillatory shear stress as a moderate, but progressive stimulator of cell proliferation and neotissue formation, even in the presence of cyclic strain. This is remarkable, because it was previously shown that laminar shear stress can have a stabilizing effect on strain-induced neotissue formation[14], making oscillatory shear stress a potential target to inhibit venous NIH and avoid excessive tissue formation. In the future, integration of these findings on cell mechano-response in the presence of complex hemodynamic situations into a computational framework of growth and remodeling can lead to the exciting possibility to predict the scaffold and venous (mal) adaptation to altered hemodynamics[35,36]. A thorough understanding of these mechanisms is essential to successfully translate in situ tissue engineering into a therapeutic approach as a solution to reduce vascular access dysfunction in patients with end-stage renal disease. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,907,571,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,921,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AVG geometry reconstruction. Realistic axillary artery to axillary vein loop AVG geometries were used as input for the CFD and FSI models. These geometries were ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[468,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,957,78,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[226,957,823,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[67,62,492,205]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"reconstructed using clinical data of a single patient and assumed constant-diameter vessels. For the CFD AVG model, vessel paths and AVG configuration were assumed to remain relatively constant after AVG creation. As such, these AVG characteristics were extracted from a 15-month postoperative CTA scan by means of vessel-centerline extraction. Since vessel diameters may have changed significantly in the period between AVG creation and the CTA scan, 2-weeks preoperative ultrasound diameter measurements were used to estimate arterial and venous diameters (6.6 and $7.7\\mathrm{mm}$ , respectively). Graft diameter was set to $6\\mathrm{mm}$ . For the FSI model a similar approach was taken, though for this model zero-pressure vessel diameters needed to be imposed. The zero-pressure venous diameter was set to $7.1\\mathrm{mm}$ , which was approximated using estimates of the average blood pressure at the time of ultrasound diameter measurements[15]. Zero-pressure graft diameter was set to $6\\mathrm{mm}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,218,490,338]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Simulations. The CFD equations were solved by using the OASIS<sup>37</sup> solver as implemented in the open-source finite element package FEniCS<sup>38</sup>. A mesh-independent solution was obtained at $3.1 \\cdot 10^{6}$ tetrahedral Taylor-Hood elements and a time step of $1 \\cdot 10^{-4}$ s. The FSI model was solved by using the Unicorn<sup>39</sup> solver that was also implemented in FEniCS. A mesh-independent solution was obtained at $2.5 \\cdot 10^{6}$ and $0.6 \\cdot 10^{6}$ linear tetrahedral elements in the fluid and solid domain, respectively. Blood was modeled as Newtonian fluid with a kinematic viscosity of $3.3 \\cdot 10^{-6} \\mathrm{~m}^2 \\mathrm{~s}^{-2}$ for the CFD simulations and $4.5 \\cdot 10^{-6} \\mathrm{~m}^2 \\mathrm{~s}^{-2}$ for the FSI simulations. From the CFD simulations, exposure to wall shear stress in the perianastomotic region was quantified using the time-averaged wall shear stress magnitude: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[196,343,489,370]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathrm {T A W S S} = \\frac {1}{T} \\int_ {0} ^ {T} | | \\vec {\\tau} (t, \\vec {x}) | | \\mathrm {d t} \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[67,375,489,401]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\vec{\\tau}(t, \\vec{x})$ represents the local WSS vector and $T$ the duration of the cardiac cycle. Exposure to oscillatory wall shear stress was assessed using the OSI: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[189,405,489,437]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathrm {O S I} = \\frac {1}{2} \\left(1 - \\frac {\\left| \\left| \\int_ {0} ^ {T} \\vec {\\tau} (t , \\vec {x}) \\mathrm {d t} \\right| \\right|}{\\int_ {0} ^ {T} \\left| \\left| \\vec {\\tau} (t , \\vec {x}) \\right| \\right| \\mathrm {d t}}\\right) \\tag {2}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[67,441,480,475]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which ranges between 0 (unidirectional WSS) and 0.5 (purely oscillatory WSS). From the FSI simulations, wall strain was computed over the inner and outer surface of the graft wall according to: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[236,480,489,512]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\varepsilon = \\sqrt {\\frac {A _ {\\mathrm {n}} - A _ {0}}{A _ {0}}} \\tag {3}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[67,517,492,583]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"here, $A_0$ is the initial area of each surface element on the graft wall, whereas $A_{\\mathrm{n}}$ is the surface area of each element during the cardiac cycle. Finally, $\\varepsilon$ was averaged over the complete cardiac cycle. The $\\varepsilon$ strain metric is equivalent to engineering strain and combines both longitudinal and circumferential strain in a single scalar metric. For detailed information regarding the methodology of the simulations, the reader is referred to Quicken et al.[15,19]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,597,492,783]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scaffold preparation. Tubular scaffolds ( $\\phi 3\\mathrm{mm}$ , $2\\mathrm{cm}$ in length, $200\\mu \\mathrm{m}$ wall thickness) were electrospun from PCL-BU (SyMO-Chem, Eindhoven, The Netherlands) in a climate-controlled cabinet ( $25^{\\circ}\\mathrm{C}$ and $30\\%$ relative humidity; IME Technologies, Geldrop, The Netherlands). Briefly, $15\\%$ (w/w) PCL-BU was dissolved in $85\\%$ (w/w) $\\mathrm{CHCl}_3$ (Sigma, 372978) and delivered via a charged nozzle $(-1\\mathrm{kV})$ at a flow rate of $40\\mu \\mathrm{l}\\mathrm{min}^{-1}$ onto a positively charged $(16\\mathrm{kV})$ rotating cylindrical mandrel ( $\\phi 3\\mathrm{mm}$ , $500\\mathrm{rpm}$ ). The distance between the nozzle and the mandrel was kept constant at $16\\mathrm{cm}$ . The resulting scaffolds were removed from the mandrel, dried in vacuo overnight, and placed over silicone tubing ( $\\phi 2.8\\mathrm{mm}$ ). The scaffold-wrapped silicone tubing was mounted in the bioreactor, sterilized by UV exposure (30 min/side), wetted in sterile $\\mathrm{H}_2\\mathrm{O}$ , and incubated at $37^{\\circ}\\mathrm{C}$ in complete medium (1:1 advanced Dulbecco's Modified Eagle Medium (a-DMEM):Roswell Park Memorial Institute 1640 (RPMI-1640) (Gibco, 124910 and A10491) with $10\\%$ fetal bovine serum (FBS; Greiner, Alphen aan den Rijn, The Netherlands), $1\\%$ penicillin/streptomycin (P/S; Lonza, DE17-602E), $0.5\\%$ GlutaMax (Gibco, 35050), and $0.25\\mathrm{mgml}^{-1}$ AA2P (Sigma, A8960)) overnight to allow for protein adsorption. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,797,492,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Myo)fibroblast cell culture. Vascular cells were isolated from surgical leftover of human vena saphena magna and used in accordance to the Dutch guidelines for secondary-use materials. The cells were expanded conforming conventional protocols[40]. Due to their structural properties, these cells have earlier been characterized as myofibroblasts[40,41]. However, a subpopulation of these cells do not express $\\alpha$ -SMA, which is more characteristic for fibroblasts[41]. Therefore, we refer to these cells as mFBs. mFBs were cultured in a-DMEM containing $10\\%$ FBS, $1\\%$ P/S, and $1\\%$ GlutaMax in a standard culture incubator $(37^{\\circ}\\mathrm{C}, 5\\% \\mathrm{CO}_2)$ and passaged at $80\\%$ confluency. Culture medium was changed every 3-4 days. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,910,492,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"THP-1 cell culture. Human monocytic THP-1 cells (Sigma Aldrich, lot# 16K052) were cultured and expanded in suspension at a cell density of $(0.5 - 1.5)\\cdot 10^{6}$ cells $\\mathrm{ml}^{-1}$ culture medium (RPMI-1640 containing $10\\%$ FBS and $1\\%$ P/S) in a standard culture ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,62,927,86]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"incubator $(37^{\\circ}\\mathrm{C}, 5\\% \\mathrm{CO}_{2})$ . Culture medium was changed three times per week. The cells tested negative on routinely performed (monthly) mycoplasm tests. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,99,929,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell seeding. After cell expansion, the mFBs (passage 6) and THP-1 cells (passage 10 after thawing) were seeded in the pre-wetted scaffolds using fibrin as a cell carrier[42]. Prior to seeding, the THP-1 cells were primed for $15\\mathrm{min}$ in $50\\mathrm{ngml}^{-1}$ phorbol 12-myristate 13-acetate (Sigma, P8139)-enriched culture medium to stimulate macrophage differentiation. To co-seed the cells into the porous scaffold, cells $(15\\cdot 10^{6}\\mathrm{mFBscm}^{-3})$ and $30\\cdot 10^{6}$ THP-1 cells $\\mathrm{cm}^{-3}$ ) were added to a mixture of bovine fibrinogen $(10\\mathrm{mgml}^{-1}$ ; Sigma, F8630) and bovine thrombin $(10\\mathrm{IUml}^{-1}$ ; Sigma, T4648), and carefully pipetted in two steps onto two opposing sides of the scaffold. Directly after pipetting the cell suspension, the cell-seeded scaffold was manually rotated until the suspension was completely absorbed by the scaffold[21,22]. To complete fibrin polymerization, the cell-seeded constructs were transferred to a $15\\mathrm{ml}$ tube and kept in an incubator $(37^{\\circ}\\mathrm{C},5\\% \\mathrm{CO}_{2})$ for $30\\mathrm{min}$ , after which the tubes were filled with $8\\mathrm{ml}$ of complete medium. To allow for cell adhesion to the scaffold fibers, the constructs were statically cultured in these tubes for 3 days prior to exposing the constructs to the different hemodynamic loading conditions (Fig. 2d). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,289,929,485]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Shear stress and strain application. After 3 days of static culture, the constructs were mounted in the culture chambers of the bioreactor for the application of hemodynamic loading[21,22]. To determine the loading conditions that mimic the conditions in vivo, we first examined the expected hemodynamic loads at the vein-graft anastomosis, as computed from the CFD and FSI simulations[15,19]. The samples were allocated to the different experimental conditions in a non-blinded, random way. The medium reservoirs were filled with $50\\mathrm{ml}$ of complete medium, which was supplemented with $0.7\\mathrm{mgml}^{-1}$ X-gum (Sigma, G1253) to increase the medium viscosity toward the range of blood viscosity[26]. To correct for possible medium evaporation during culture, the culture medium was supplemented up to $50\\mathrm{ml}$ with sterile $\\mathrm{H}_2\\mathrm{O}$ every 4 days, after which $25\\mathrm{ml}$ of medium was replaced by fresh, X-gum-supplemented complete medium. After 14 days of dynamic culture, the tubular constructs were harvested, sectioned according to a cutting scheme (Supplementary Fig. S4), and stored at $4^{\\circ}\\mathrm{C}$ (after $15\\mathrm{min}$ fixing in $3.7\\%$ formaldehyde and $3\\times 5\\mathrm{min}$ washing in PBS) or $-30^{\\circ}\\mathrm{C}$ (after snap-freezing in liquid nitrogen) until further analysis. Supernatants from the culture medium after centrifugation $(300\\times g,5\\mathrm{min})$ at days 1, 4, 8, and 14 were stored at $-30^{\\circ}\\mathrm{C}$ until further analysis. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,500,929,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Xanthan gum sterilization and dissolving. In a sterile environment, X-gum was spread on a weighing paper in a large petri dish and UV-sterilized (10 min on two sides). After UV exposure, the X-gum was transferred to a pre-weighed $50\\mathrm{ml}$ tube, and weighed again to determine the X-gum mass in a sterile way. Then, $70\\%$ EtOH was added at a concentration of $1.4\\mu \\mathrm{l}\\mathrm{mg}^{-1}$ X-gum and the resulting suspension was transferred to 1:1 a-DMEM:RPMI-1640 at a concentration of $1.4\\mathrm{mg}\\mathrm{ml}^{-1}$ . The sterilized X-gum was dissolved on a magnetic hot plate stirrer (4 h at $40^{\\circ}\\mathrm{C}$ ), resulting in a viscous solution. To prepare the X-gum-supplemented complete medium, this viscous solution was diluted $2\\times$ with 1:1 a-DMEM:RPMI-1640 to which the rest of the supplements were added (10% FBS, 1% P/S, 0.25 mg ml $^{-1}$ AA2P). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,624,929,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viscosity measurements. To determine the shear stresses associated with the applied shear rates during the experiment, the viscous behavior of the supernatants (with and without X-gum) was quantified using a cone-plate rheometer $(\\phi 50\\mathrm{mm})$ at $37^{\\circ}\\mathrm{C}$ (ARES, Rheometric Scientific, 1 technical replicate/sample). The viscosity $\\eta$ was measured at shear rates $\\dot{\\gamma}$ varying from $10\\mathrm{s}^{-1}$ until $1500\\mathrm{s}^{-1}$ (6 measurements per decade). The resulting viscosity-shear rate curves were linearly interpolated to determine the viscosities at low shear rate $(\\dot{\\gamma}\\approx 100\\mathrm{s}^{-1})$ and high shear rate $(\\dot{\\gamma}\\approx 1200\\mathrm{s}^{-1})$ (Matlab, The Mathworks, Natick, MA). The shear stress was calculated via: $\\tau (\\dot{\\gamma}) = \\dot{\\gamma}\\cdot \\eta (\\dot{\\gamma})$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,737,929,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Biochemical assays. The snap-frozen samples were used for quantification of DNA, glycosaminoglycan (GAG), and HYP content (two technical replicates/ sample). After determination of the sample dry mass and surface (see \"Determination of total mass\"), samples were reduced to a fine powder using a microdismembrator (Sartorius) for sample digestion. Briefly, the samples were placed in cryovials containing 4 microbeads, frozen in liquid nitrogen, and disrupted at $3000~\\mathrm{rpm}$ for $60~s$ . To digest the sample, the powder was mixed with $500\\mu l$ digestion buffer $(100\\mathrm{mM}$ phosphate buffer $\\left(\\mathrm{pH} = 6.5\\right)$ , $5\\mathrm{mM}$ L-cysteine (C-1276), $5\\mathrm{mM}$ ethylenediamine tetraacetic acid (ED2SS), $140\\mu \\mathrm{g}\\mathrm{ml}^{-1}$ papain (P4762); all from Sigma), transferred to a fresh Eppendorf tube, and incubated overnight at $60^{\\circ}\\mathrm{C}$ . Prior to measurement of DNA, GAG, and HYP content, the samples were centrifuged at $12,000~\\mathrm{rpm}$ for $10\\mathrm{min}$ . From the supernatant, DNA was quantified using the Qubit dsDNA BR assay kit (Life Technologies, Q32853) according to the manufacturer's protocol. GAG was quantified using a modified dimethyl methylene blue (DMMB) $^{43}$ assay with Shark chondroitin sulfate (Sigma, C4348) as a standard. Briefly, $40\\mu l$ of the supernatant and standards were mixed with $150\\mu l$ DMMB solution in a 96-well plate. The absorbance was measured using a microplate reader $(540\\mathrm{nm}$ , Synergy HTX, Biotek). HYP, as a measure of collagen, was quantified with a Chloramin-T assay $^{44}$ with trans-4-hydroxyproline as a reference (Sigma, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,23,529,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[830,17,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,957,665,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[917,957,927,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[67,62,490,129]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"H5534). Before assaying, the samples were first hydrolyzed in $16\\mathrm{M}$ sodium hydroxide (Merck, B1438798). The absorbance was measured using a microplate reader $(550\\mathrm{nm}$ , Synergy HTX, Biotek). DNA, GAG, and HYP values were normalized to the sample dry mass. Normalized DNA was multiplied by the sample total mass to obtain DNA content per sample (see \"Determination of total mass\"). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,144,490,245]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Determination of total mass. To obtain the mass/surface, samples were weighed using a digital balance (XS105 dual-range analytical balance, Mettler Toledo, Switzerland) and photographed together with a ruler (one technical replicate/sample). The surfaces were measured from the photographs using ImageJ (v1.48, U.S. NIH, Bethesda, MD, USA). To estimate the increase in construct mass during culture, the mass/surface of the lyophilized samples at day 14 (see \"Biochemical assays\") was normalized to the initial mass/surface prior to seeding. To estimate the total sample mass at day 14, the mass/surface of the lyophilized samples was multiplied by the total surface of the samples $(15\\mathrm{mm}\\times 1.5\\pi \\mathrm{mm})$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,259,490,368]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scanning electron microscopy (SEM). Cell, tissue, and scaffold fiber morphology were assessed from SEM images (three predefined locations/sample). The formalin-fixed samples were placed in $0.25\\%$ glutaraldehyde $(1\\mathrm{h})$ , dehydrated in an ordered series of ethanol dilutions, and dried in vacuo overnight. After visualization of the cell and tissue morphology in low vacuum using a $10\\mathrm{kV}$ electron beam (Quanta 600F, FEI, Hillsboro, OR, USA), half of the samples were decellularized in $4.6\\%$ sodium hypochlorite $(15\\mathrm{min})$ , washed in $\\mathrm{H}_2\\mathrm{O}$ $(2\\times 5\\mathrm{min})$ , and dried in vacuo overnight to visualize the scaffold fiber morphology. Together with the non-decellularized samples, samples were gold-sputtered and visualized in high vacuum using a $10\\mathrm{kV}$ electron beam. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,384,490,570]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Immunohistochemistry. Cross-sections $(7\\mu \\mathrm{m})$ cryosections from formalin-fixed samples) were washed in PBS $(3\\times 5\\mathrm{min})$ , permeabilized in $0.5\\%$ Triton X-100 $(30\\mathrm{min})$ , and blocked for non-specific binding in $5\\%$ goat serum containing $1\\%$ BSA $(30\\mathrm{min})$ . The sections were then incubated with primary antihuman polyclonal antibodies against Ki67 (rabbit IgG, 1:200, Thermoscientific, RB-1510-P0), CD45 (mouse IgG1, 1:1000, Abcam, ab33533), vimentin (mouse IgM, 1:2000, Abcam, ab20346), $\\alpha$ SMA (rabbit IgG, 1:600, Abcam, ab5694), or collagen I (mouse IgG1, 1:200, Sigma, c2456), in $10\\times$ diluted block solution (overnight at $4^{\\circ}\\mathrm{C}$ ). After washing in PBS $(3\\times 5\\mathrm{min})$ , the sections were incubated with 1:500 secondary goat antibodies labeled with Alexa-488 conjugate (antimouse IgG1 (for CD45, Molecular Probes, A21121) or antirabbit IgG (for $\\alpha$ SMA, Molecular Probes, A11008)) or Alexa-647 conjugate (antimouse IgM (for vimentin, Jackson Immunoresearch, 115-605-075) or antimouse IgG1 (for collagen I and Ki67, Molecular Probes, A21240)), in $10\\times$ diluted block solution $(60\\mathrm{min})$ . Nuclei were stained with $4^{\\prime},6$ -diamidino-2-phenylindole (1:500, Sigma). The stained sections were mounted in mowiol (Sigma, 81381) and visualized with an inverted epifluorescent microscope (Zeiss Axiovert 200M, $\\times 20 / 0.5$ Plan-Neofluar lens, three sections/sample). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,586,490,675]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fluorescence stainings. Actin and collagen structures in formalin-fixed whole-mount samples were labeled with phalloidin-Atto 488 (1:200, Sigma) and CNA35-OG488 $(1\\mu \\mathrm{M}^{45})$ , respectively. Nuclei in the actin-stained samples were labeled with propidium iodide $(7\\mu \\mathrm{M}$ , Molecular Probes, P3566). The stained samples were kept in PBS and visualized with a confocal laser scanning microscope (Leica TCS SP5X with a $\\times 40 / 1.1$ HCX PL Apo CS lens). The collagen orientation in each sample was quantified from two $z$ -stacks $(\\approx 50\\mu \\mathrm{m})$ recorded at two predefined locations using in-house developed software[21]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,689,489,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Histological analysis. Overall matrix content and fibrillar collagen in cross-sections $(7\\mu \\mathrm{m}$ cryosections from formalin-fixed samples) were assessed from hematoxylin and eosin and Picrosiirus red stains, respectively. Images were acquired with a bright field microscope (Zeiss Axio Observer Z1 with a $\\times 20 / 0.8$ Plan-Apochromat lens, three sections/sample). Picrosiirus-stained sections were also imaged with polarized light to assess the birefringence of the collagen fibrils. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,771,490,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gene expression. The snap-frozen samples were disrupted in a microdismembrator (see \"Biochemical assays\") and lysed in RLT lysis buffer (5 min, on ice). To isolate the RNA, the lysates were further processed using the Qiagen RNeasy kit with an additional DNase treatment (30 min, Qiagen, 74106). RNA was eluted in $30\\mu \\mathrm{l}$ RNAse-free $\\mathrm{H}_2\\mathrm{O}$ and quantified with a spectrophotometer (NanoDrop, ND-1000, Isogen Life Science, The Netherlands). Total RNA was reverse-transcribed into cDNA in a thermal cycler (protocol: $65^{\\circ}\\mathrm{C}$ (5 min), on ice (2 min) while adding the enzyme mixture, $37^{\\circ}\\mathrm{C}$ (2 min), $25^{\\circ}\\mathrm{C}$ (1 min), $37^{\\circ}\\mathrm{C}$ (50 min), and $70^{\\circ}\\mathrm{C}$ (15 min)). The reaction solution consisted of $200\\mathrm{ng}$ RNA, $1\\mu \\mathrm{l}$ dNTPs (10 mM, Invitrogen), $1\\mu \\mathrm{l}$ random primers ( $50\\mathrm{ng}\\mu \\mathrm{l}^{-1}$ , Promega, C1181), $2\\mu \\mathrm{l}$ 0.1M DTT, $4\\mu \\mathrm{l}5\\times$ first strand buffer, and $1\\mu \\mathrm{l}$ M-MLV Reverse Transcriptase $(200\\mathrm{U}\\mu \\mathrm{l}^{-1}$ , Invitrogen, 28025-013), which was supplemented to $20\\mu \\mathrm{l}$ with RNAse-free $\\mathrm{H}_2\\mathrm{O}$ . qPCR was performed in a $10\\mu \\mathrm{l}$ reaction mix (two technical replicates/sample), containing $3\\mu \\mathrm{l}100\\times$ diluted cDNA, $500\\mathrm{nM}$ primer (forward and reversed, see Supplementary Table S1), and $5\\mu \\mathrm{l}$ SYBR Green Supermix ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,62,927,173]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Bio-Rad, 170-8886). Gene expression was normalized to GAPDH, identified as being most stable. $C_t$ values were acquired by exposing the reaction mixtures to the following thermal protocol: $95^{\\circ}\\mathrm{C}$ (3 min), 40 cycles of $95^{\\circ}\\mathrm{C}$ (20 s), $60^{\\circ}\\mathrm{C}$ (20 s), and $72^{\\circ}\\mathrm{C}$ (30 s), $95^{\\circ}\\mathrm{C}$ (1 min), and $65^{\\circ}\\mathrm{C}$ (1 min), concluded with a melting curve measurement. $C_t$ values were normalized for the housekeeping gene $(\\Delta C_t)$ and control $(\\Delta \\Delta C_t$ , LSS condition), and the $2^{-\\Delta \\Delta C_t}$ formula was applied to calculate relative fold gene expressions of the genes listed in Supplementary Table S2. Datapoints were excluded if the melting curve was off, if $>0.5 C_t$ difference between technical replicates, or if the blanco was off in comparison to the measured $C_t$ value. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,187,927,299]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ELISA. Intimal hyperplasia-related proteins (Supplementary Table S2) were quantified from the supernatants at day 14 using a Luminex-based multiplex immunoassay (Multiplex core facility of the laboratory for Translational Immunology, UMC Utrecht, the Netherlands, one technical replicate/sample). In short, the supernatants were consecutively incubated with antibody-conjugated MagPlex microspheres $(1\\mathrm{h})$ , biotinylated antibodies $(1\\mathrm{h})$ , and streptavidin-phycoerythrin $(10\\mathrm{min}$ , diluted in high performance ELISA buffer (Sanquin)). Fluorescence intensity was measured using a FLEXMAP 3D system and analyzed by five-parametric curve fitting using Bio-Plex Manager software (Bio-Rad, version 6.1.1). Protein concentrations were normalized to the average DNA content per condition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,310,927,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Statistics and reproducibility. To each loading condition in the culture experiment, $n = 5$ constructs from two separate experimental runs were assigned to allow for statistical analysis. No experimental-specific outcomes were observed. During the experiment, one sample from the HSS group dropped out due to experimental difficulties, resulting in $n = 4$ constructs for this group. Technical replicates were defined as repeated measurements of the same sample to assess the reproducibility of the analysis, and do not count to the total $n$ . All data are presented either as mean ± standard deviation or as boxplots using Matlab (Matlab R2017; The Mathworks, Natick, MA) or Prism (GraphPad, La Jolla, CA, USA). Statistical analysis was performed to test for significant differences between the different shear stress modes with respect to biomechanical loading, biochemical content, gene expression, and cytokine secretion using a two-sided non-parametric Kruskal-Wallis test with a Dunn's multiple comparison test (GraphPad, La Jolla, CA, USA). Shear stress data were obtained by multiplying the daily average of the shear rate $(\\bar{\\gamma})$ with the daily average of the viscosity $(\\bar{\\eta}(\\bar{\\gamma}))$ . The standard deviation for shear stress was estimated based on error propagation. Gene expression data were logarithmically transformed prior to statistical analysis. Statistical significance was assumed for $p < 0.05$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,523,927,546]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,561,621,574]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,574,910,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The source data underlying the graphs and charts presented in the main figures are available in the Supplementary Data file. The raw data are available from the corresponding author upon reasonable request. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,622,623,636]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Code availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,636,927,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All computational methods used in this paper to perform the CFD and FSI simulations were peer-reviewed and are extensively described in Quicken et al. [15,19]. The data and methods required to reproduce Fig. 2a-c from the simulation results can be obtained from a DOI-minting repository [46]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,696,816,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 24 July 2020; Accepted: 31 March 2021; Published online: 10 May 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,767,586,778]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,780,927,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Shiu, Y. T., Rotmans, J. I., Geelhoed, W. J., Pike, D. B. & Lee, T. 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Computational study on the haemodynamic and mechanical benefits of electrospun polyurethane dialysis grafts. Biomech. Model Mechanobiol. 19, 713-722 (2020). \",\"16. Decorato, I. et al. Numerical simulation of the fluid structure interactions in a compliant patient-specific arteriovenous fistula. Int. J. Num. Methods Biomed. Eng. 30, 143-159 (2014). \",\"17. Guess, W. P. et al. Fluid-structure interaction modelling and stabilisation of a patient-specific arteriovenous access fistula. ArXiv https://arxiv.org/abs/1704.07753 (2017). \",\"18. Montini-Ballarin, F., Abraham, G. A. & Caracciolo, P. C. Mechanical Behavior of Polyurethane-based Small-diameter Vascular Grafts, 451-477 (Woodhead Publishing, 2016). \",\"19. Quicken, S., Delhaas, T., Mees, B. M. E. & Huberts, W. Haemodynamic optimisation of a dialysis graft design using a global optimisation approach. Int. J. Numer. Method Biomed. Eng. 37, e3423 (2020). \",\"20. Malek, A. M., Alper, S. L. & Izumo, S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 282, 2035-2042 (1999). \",\"21. van Haaften, E. E. et al. Decoupling the effect of shear stress and stretch on tissue growth & remodeling in a vascular graft. Tissue Eng. Part C. 24, 418-429 (2018). \",\"22. Koch, S. E. et al. A multi-cue bioreactor to evaluate the inflammatory and regenerative capacity of biomaterials under flow and stretch. J. Vis. Exp. 166, e61824 (2020). \",\"23. Wisse, E. et al. Molecular recognition in poly(ε-caprolactone)-based thermoplastic elastomers. Biomacromolecules 7, 3385-3395 (2006). \",\"24. Wissing, T. B. et al. Hemodynamic loads distinctively impact the secretory profile of biomaterial-activated macrophages - implications for in situ vascular tissue engineering. Biomater. Sci. 8, 132-147 (2019). \",\"25. Butler, H. J. et al. Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 11, 664-687 (2016). \",\"26. van den Broek, C. N. et al. Medium with blood-analog mechanical properties for cardiovascular tissue culturing. *Biorheology* **45**, 651–661 (2008). \",\"27. Hata, R. & Senoo, H. L-ascorbic acid 2-phosphate stimulates collagen accumulation, cell proliferation, and formation of a three-dimensional tissue like substance by skin fibroblasts. J. Cell Physiol. 138, 8-16 (1989). \",\"28. Cheng, C. et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 113, 2744-2753 (2006). \",\"29. Cheng, C. et al. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J. Clin. Invest. 117, 616-626 (2007). \",\"30. Seneviratne, A. N. et al. Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques. J. Mol. Cell Cardiol. 89, 168-172 (2015). \",\"31. Cheng, C. et al. Large variations in absolute wall shear stress levels within one species and between species. Atherosclerosis 195, 225-235 (2007). \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[507,63,927,521]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"32. Vogel, C. & Marcotte, E. M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227-232 (2012). \",\"33. Yan, C. & Boyd, D. B. Regulation of matrix metalloproteinase gene expression. J. Cell Physiol. 211, 19-26 (2007). \",\"34. Wissing, T. B. et al. Macrophage-driven biomaterial degradation depends on scaffold microarchitecture. Front. Bioeng. Biotechnol. 7, 87 (2019). \",\"35. Ramachandra, A. B., Humphrey, J. D. & Marsden, A. L. Gradual loading ameliorates maladaptation in computational simulations of vein graft growth and remodelling. J. R. Soc. Interface 14, 20160995 (2017). \",\"36. Ramachandra, A. B., Sankaran, S., Humphrey, J. D. & Marsden, A. L. Computational simulation of the adaptive capacity of vein grafts in response to increased pressure. J. Biomech. Eng. 137, 31009 (2015). \",\"37. Mortensen, M. & Valen-Sendstad, K. Oasis: a high-level/high-performance open source Navier-Stokes solver. Comput. Phys. Commun. 188, 177-188 (2015). \",\"38. Logg, A., Mardal, K. & Wells, G. N. Automated Solution of Differential Equations by the Finite Element Method, Vol. 84 (Springer-Verlag, 2012). \",\"39. Hoffman, J. et al. *Unicorn: parallel adaptive finite element simulation of turbulent flow and fluid-structure interaction for deforming domains and complex geometry*. Comput. Fluid **80**, 310–319 (2013). \",\"40. Schnell, A. M. et al. Optimal cell source for cardiovascular tissue engineering: venous vs. aortic human myofibroblasts. Thorac. Cardiovasc. Surg. 49, 221-225 (2001). \",\"41. Mol, A. et al. Autologous human tissue-engineered heart valves: prospects for systemic application. Circulation 114, 152-158 (2006). \",\"42. Mol, A. et al. Fibrin as a cell carrier in cardiovascular tissue engineering applications. Biomaterials 26, 3113-3121 (2005). \",\"43. Farndale, R. W., Buttle, D. J. & Barrett, A. J. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim. Biophys. Acta 883, 173-177 (1986). \",\"44. Huszar, G., Maiocco, J. & Naftolin, F. Monitoring of collagen and collagen fragments in chromatography of protein mixtures. *Anal. Biochem.* **105**, 424–429 (1980). \",\"45. Boerboom, R. A. et al. High resolution imaging of collagen organisation and synthesis using a versatile collagen specific probe. J. Struct. Biol. 159, 392-399 (2007). \",\"46. van Haaften, E. E et al. Data underlying the publication: Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue, 4TU.ResearchData [Computed software] https://doi.org/10.4121/14292383.v1 (2021). \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[505,539,643,552]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,552,927,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors would like to thank Suzanne Koch and Tamar Wissing for their assistance in the in vitro experiments, Marina van Doeselaar and Marloes Janssen-van den Broek for their assistance in the sample analysis, and Anthal Smits for the fruitful discussions. This study is financially supported by ZonMw as part of the LSH 2Treat program (436001003) and the Dutch Kidney Foundation (14a2d507). N.A.K. acknowledges support from the European Research Council (851960). We gratefully acknowledge the Gravitation Program \"Materials Driven Regeneration\", funded by the Netherlands Organization for Scientific Research (024.003.013). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,657,653,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author contributions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,668,927,737]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C.V.C.B. and N.A.K. contributed equally. Author contributions according to the CRediT Taxonomy are as follows: conceptualization: all; formal analysis: E.E.v.H., C.V.C.B., and N.A.K.; investigation: E.E.v.H. and S.Q.; software: S.Q. and W.H.; funding acquisition: C.V.C.B.; supervision: N.A.K., C.V.C.B., and W.H.; visualization: E.E.v.H.; writing—original draft preparation: E.E.v.H.; writing—review and editing: all. All authors have approved the final article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,751,648,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Competing interests ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,765,927,799]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"N.A.K. is an Editorial Board Member for Communications Biology, but was not involved in the editorial review of, nor the decision to publish this article. Other authors declare no competing interests. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,814,665,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Additional information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,827,900,850]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s42003-021-02065-6. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,860,875,872]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Correspondence and requests for materials should be addressed to C.V.C.B. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,883,917,895]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reprints and permission information is available at http://www.nature.com/reprints ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,902,927,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,23,529,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[828,17,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,957,665,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[910,957,926,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[68,62,142,83]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0087/668258bf0012eec6c4eadcff7f8d72fac67f946cd1b278f48852ff5de9f314ee.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[146,63,489,86]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,86,489,189]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,209,179,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© The Author(s) 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[468,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,957,85,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[228,957,823,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[73,134,354,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[389,132,445,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,157,927,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,268,815,306]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Eline E. van Haaften $^{1,2}$ , Sjeng Quicken $^{3}$ , Wouter Huberts $^{3}$ , Carlijn V. C. Bouten $^{1,2\\\\boxtimes}$ & Nicholas A. Kurniawan $^{1,2}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,358,690,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft-host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein-graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,17,416,88]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"communications biology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,104,161,122]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[806,104,927,122]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,902,905,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. $^{2}$ Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, The Netherlands. $^{3}$ Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. $\\\\text{©}$ email: C.V.C.Bouten@tue.nl \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,957,668,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[917,957,927,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[67,61,490,234]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A major clinical problem in hemodialysis therapy for end-stage renal-diseased patients is vascular access dysfunction. Vascular access for long-term hemodialysis is achieved through native arteriovenous (AV) fistula or synthetic arteriovenous graft (AVG). The primary cause of vascular access dysfunction in matured AV fistulas and AVGs is venous stenosis as a result of neointimal hyperplasia $(\\\\mathrm{NIH})^{1}$ . The pathogenesis of venous NIH in vascular access is well described and thought to be initiated by vessel damage, graft bioincompatibility (for AVGs), uremia, and fluid wall shear stress. These factors result in downstream effects such as oxidative stress, inflammation, and endothelial dysfunction, causing the migration and proliferation of smooth muscle cells to the intima. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,235,492,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"High shear stresses (HSS) are persistently present in AVGs and AV fistulas, even years after vessel creation. Several studies have reported that regions with high wall shear stresses (in the range of $5 - 10\\\\mathrm{Pa}$ ) correspond to NIH formation[3-5]. On the other hand, Krishnamoorthy et al. has suggested an inverse correlation between wall shear stress (in the range of $5 - 80\\\\mathrm{Pa}$ during peak flow) and stenosis formation[6]. It has also been proposed that low and oscillatory shear stress (in the range of $< 0.1 - 1\\\\mathrm{Pa}$ ) favors sites of stenosis[7] and that the temporal gradient of shear stress (in the range of $+0.5\\\\mathrm{Pa}/$ week up to $3.5\\\\mathrm{Pa}$ ) correlates with intimal medial thickening[8,9]. These seemingly inconsistent findings raise important questions about both the mechanistic foundation and the validity of the conjecture that wall shear stress stimulates the initiation and development of NIH in vascular access vessels. Indeed, systematic reviews reveal that the clinical evidence for this disturbed flow theory is weaker than generally believed and that so far very little is known about how altered flow is related to the cellular processes underlying $\\\\mathrm{NIH}^{10,11}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,476,490,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The need for mechanistic insights in (patho)physiological situations is especially critical with the emergence of a relatively new paradigm in regenerative medicine: in situ tissue engineering. This strategy hinges on the implantation of directly functional, bioresorbable, cell-free scaffolds, e.g., to be used as AVGs, which direct tissue regeneration at the locus of implantation to grow the neotissue into a state of mechanical homeostasis, presumably reducing the risk of NIH. The merit of the tissue engineering approach was recently highlighted in a study by Kirkton et al., where the authors implanted a bioengineered, acellular, human vessel as a hemodialysis conduit in patients with end-stage renal disease[12]. These vessels completely recellularized in this complex in vivo environment and transformed into a functional, living tissue, allowing repeated cannulation for years. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,663,490,836]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The new tissue has, so to say, \\\"emerged\\\" from its complex in vivo environment, whose convolution of individual factors, such as the interaction between cells and their 3D environment, paracrine, and juxtracrine signals from other cells, and response to mechanical forces, determined the resulting tissue properties. Intriguingly, these factors also affect the secretion of proteinases (e.g., MMPs and TIMPs), cytokines (e.g., MCP-1 and IL-6), and growth factors (e.g., TGF- $\\\\beta$ 1), which are known to be involved in NIH formation[10]. To advance this promising therapeutic development, it is of paramount importance to dissect this complexity, because the knowledge about the role of each factor and the interplay between these factors provides crucial design parameters for guiding the developing tissue toward mechanical homeostasis[13]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,837,490,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the present study, we introduce a numerical-experimental approach to systematically investigate how neotissue develops under the influence of the demanding hemodynamic environment in regenerating AVG scaffolds (Fig. 1). To quantitatively parameterize this environment, we use computational fluid dynamics (CFD) and fluid-structure interaction (FSI) modeling of a clinically derived vein-graft anastomosis. We then simulate this environment using our recently developed in vitro model \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,60,926,182]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"system $^{14}$ . This in vitro system is used to mimic the (early) proinflammatory stages of scaffold-driven in situ tissue formation, based on (1) the co-culture of human tissue-producing vascular cells and macrophages, which are (2) seeded in electrospun grafts, and (3) cultured in a bioreactor platform that allows for the independent control of wall shear stress and strain. This unique approach allows the delineation of the roles of biomechanical tissue environment and cellular responses, as well as their interplay, in scaffold-guided vascular tissue formation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,182,927,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The findings revealed that various wall shear stress metrics (low, high, and oscillatory), in the presence of cyclic strain, differently regulate NIH- and tissue growth-related protein secretion, tissue growth, and remodeling. In particular, oscillatory shear stress promoted the formation of a dense and disorganized collagen network. Together, these insights confirm the causative relationship between different shear stress modes and vascular tissue growth and remodeling in 3D cyclically stretched constructs, and contribute to an improved understanding of scaffold-guided tissue regeneration and the initiation mechanism of NIH in vascular access vessels. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,335,667,347]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results and discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,349,927,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Hemodynamics at the NIH-prone sites in the AVG. In the early stages of in situ scaffold-guided vascular regeneration, the scaffold largely determines the mechanical performance of the overall construct. To quantitatively understand the hemodynamic environment in the NIH-prone sites of these scaffolds when implanted as AVG, we computed the local hemodynamics using numerical models (Fig. 2a). For this purpose, a realistic AVG geometry was reconstructed from 15 months postoperative computed tomography angiography (CTA) scans and 2-weeks preoperative ultrasound diameter measurements of a single renal-diseased patient. For detailed information regarding the model reconstruction and numerical simulations, the reader is referred to the \\\"Methods\\\". \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,510,927,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The flow disturbances at the perianastomotic region at the venous site are known to cause the most common graft-related complications. These flow disturbances are associated with the local deformations and local shear stresses of the venous perianastomotic wall. To accurately estimate these local stresses and strains, we developed an FSI model of this region, which took into account the temporally varying flow-induced wall deformations as well as the consequent flow profiles. The graft (0.63 mm wall thickness[15]) and the vein (0.385 mm wall thickness[15-17]) were modeled as a Neo-Hookean material, with a Young's modulus of 1.5 MPa for the graft[15,18] and 0.455 MPa for the vein[15]. A CFD model of the full geometry with a rigid wall assumption was used to obtain proper boundary conditions for the FSI model and to estimate the wall shear stresses in the graft. At the inlet boundary of the CFD model, a Doppler ultrasound-based velocity profile was prescribed, whereas at the proximal venous outlet a zero-pressure boundary condition was prescribed[19]. To mimic the peripheral bed and collateral venous flow, a six elements lumped parameter model was coupled to the distal arterial and venous outlets. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,777,927,870]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"These simulations revealed that the shear stresses have time-averaged values of around $5\\\\mathrm{Pa}$ with a low oscillatory shear index (Fig. 2c). The strains around the venous anastomotic border are in the order of $1\\\\%$ with extremes up to $2\\\\%$ at the anastomosis (Fig. 2b). To the best of our knowledge, this is the first study that quantifies wall shear stresses and strains in AVGs, giving a unique insight into the biomechanical environment inside these AVGs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,890,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Integrating computational output into in vitro model. The biomechanical environment in the AVGs, as quantified from these computational outputs, were mimicked in our in vitro platform to recapitulate the local hemodynamics in vascular \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[467,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,957,80,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[226,957,823,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[233,99,364,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"a in vivo situation \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0816/c9c377bada423e68250df3c6cdcb9522277f1a33d5aa8634ed4181f863216f41.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[245,335,386,436]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"c in vitro model \\\",\\\"directly after seeding \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0142/acafcc3c0a83069822289498adac432a6a2ef20c1a33419ac9956654ead96d9e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n 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\"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[685,154,731,208]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0788/d89776c716175e1721e9e48e13d4868b0f5ce55e0ce74687a90503863d2425b9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[643,221,744,278]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"disorganized matrix \\\"]\",\n \"image_footnote\": \"[\\\"$\\\\\\\\nabla$ proteinases $\\\\\\\\nabla$ growth \\\",\\\"▲ remodeling \\\"]\",\n \"img_path\": \"images/0800/f6918d532e5c4cac1235349e77f37f420b9835ffefd26fa5cd395281a53880f0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[616,271,736,335]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0347/4dc0b3a45c19bde8a0e4783318da18a6d05e952140e5069e869d7fa4321d5580.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[673,341,737,347]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"organized matrix \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[643,347,742,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"after hemodynamic loading and culture \\\",\\\"Fig. 1 Proposed role of shear stress on in vivo neointimal hyperplasia, as revealed from a combined in silico and in vitro study. a In vivo, neointimal hyperplasia at the venous anastomosis of vascular access grafts is a common occurrence. This pathology is presumably driven by shear stress. b Using in silico models (i.e., computational fluid dynamic (CFD) and fluid-structure interaction (FSI) models), the mechanical environment (i.e., the shear stresses and strains) in vascular access grafts is computed. c The results of these in silico models are used to define the boundary conditions for the in vitro model (i.e., a 3D scaffold containing macrophages and (myo)fibroblasts), in which the computed shear stresses and strains are recapitulated. After 14 days of dynamic culture, allowing for (myo)fibroblast proliferation and tissue formation, oscillatory shear stress resulted in a reduction of several proteinases and upregulation of growth and remodeling markers, which was accompanied by a dense and disorganized appositional matrix structure. This in contrast to high shear stress, which led to a strongly aligned appositional matrix. Note that in the in vitro study the shear stress and matrix alignment did not occur at the luminal side but at the outside of the scaffold. b is reproduced from Quicken et al. $^{15}$ with permission. \\\"]\",\n \"image_footnote\": \"[\\\"$\\\\\\\\nabla$ proteinases \\\",\\\"growth \\\",\\\"- remodeling \\\"]\",\n \"img_path\": \"images/0038/62bd56b84df13964b032f33456cd86f797abca0d41bccc7dba0327216e0c68c3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,618,490,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"access vessels, i.e., the shear stresses and strains, allowing us to directly correlate to a biological response. This approach provides possibilities to test mechanistic hypotheses that are unaccessible in conventional in vivo studies, where the correlation between local hemodynamics, derived from computational models, and tissue composition, derived from histological stainings, is indirect and often only qualitative<sup>9</sup>. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,710,490,911]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A selection of the computed hemodynamic parameters at the vein-graft anastomosis, representing a single snapshot of the spatiotemporal hemodynamic profile in this venous perianastomotic region, served as boundary conditions of the in vitro experiments (Fig. 2d). We selected a biomechanical condition that falls between the 15th and 100th percentiles of the strain and shear stress datasets (blue dotted lines in Fig. 2b ( $\\\\sim 2\\\\%$ ), c ( $\\\\sim 3$ Pa)), referred to as the HSS condition. Given the hypothesis that shear stress is the driving factor of NIH, we selected one other shear stress metric that is proposed to correlate with NIH: oscillating shear stress $(\\\\mathrm{OSS}, \\\\pm 3\\\\mathrm{Pa})$ . To test the effects of HSS and OSS on neotissue development and NIH-involved protein secretion in our in vitro model of scaffold-guided vascular growth, we compared against a physiological (venous) low shear stress $(\\\\mathrm{LSS}, \\\\sim 0.5\\\\mathrm{Pa})$ control, as described by Malek et al[20]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,911,490,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The in vitro model consists of a cell-laden tubular scaffold construct mounted around impermeable silicone tubing and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,618,929,726]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"centered in a glass tube in a multi-cue bioreactor. The resulting annular channel is perfused with medium at a constant pressure gradient to apply laminar shear stress (in the HSS and LSS groups), or at an $1\\\\mathrm{Hz}$ alternating pressure gradient to apply oscillatory shear stress (in the OSS group). The silicone tubing is cyclically pressurized up to a constant pressure at $1\\\\mathrm{Hz}$ to apply circumferential stretch. For detailed description of the bioreactor, the reader is referred to our earlier work[21,22]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,742,927,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The biomechanical environment during in vitro culture. The vascular scaffolds for the in vitro experiments, with a wall thickness of $200\\\\mu \\\\mathrm{m}$ and inner diameter of $3\\\\mathrm{mm}$ , were produced using electrospinning from poly(ε-caprolactone) bis-urea (PCLBU, Fig. 3a). This polymer is soft, tough, biodegradable, and easy to functionalize, and therefore an attractive biomaterial for in situ tissue engineering[23]. The resulting scaffolds, with a Young's modulus of $3\\\\mathrm{MPa}^{14}$ , exhibited an isotropic microstructure with $\\\\sim 5\\\\mu \\\\mathrm{m}$ fiber diameter (measured at the scaffold surface), which remained stable during the course of the culture, independent of the applied loading condition (Fig. 3b, c). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,890,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to the fiber diameter, the morphology of the scaffold fibers remained unaffected (Fig. 3b), indicating that no scaffold degradation occurred at the scaffold surface. The degree of degradation was indeed expected to be minor in the present \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,529,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[830,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,957,665,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[917,957,927,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[90,65,344,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0432/bcfad4ace02f339e97f1d8c0c8ef6886d627901019e8b5ac55e23ab3f6e5a24f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[347,63,892,168]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0579/5c14f4ff5477816df2dc84eaaf29868df18128862521de40aad7502a92d22cb2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[347,189,890,398]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0126/495aab43dd20910b97f5d955fc5fc754de4187bb2df5b73a6c7c52906ddad3c5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,421,905,579]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2 Computational characterization of the biomechanical environment in an AVG as input for scaffold-driven neotissue formation in vitro. \\\"]\",\n \"image_footnote\": \"[\\\"a Geometry of the arteriovenous graft (AVG), looped between the axillary artery and axillary vein, that was used for the computational model (humerus inserted as a reference, venous anastomotic region indicated by rectangle). b Fluid-structure interaction (FSI) simulations and c computational fluid dynamics (CFD) simulations to compute the local strains and shear stresses in the AVG, respectively (histograms and associated percentile plots showing the distribution of the quantified read-out parameters ( $\\\\\\\\varepsilon$ strain, TAWSS time-averaged wall shear stress, OSI oscillatory shear index). The dashed lines in the percentile plots correspond to the boundary conditions of the high shear stress (HSS) group in the in vitro experiments). d The computational results guide the in vitro experiments by defining the relevant boundary conditions (HSS high shear stress, OSS oscillating shear stress, LSS low shear stress). (Myo)fibroblasts and PMA-stimulated THP-1 cells (macrophages) are co-seeded in the scaffolds using fibrin. After 3 days of static culture, the constructs are exposed to HSS, OSS, or LSS during 14 days, all in the presence of strain. After the dynamic culture, constructs and supernatants are collected and processed for further analysis. a is derived from Quicken et al. $^{19}$ with permission. \\\"]\",\n \"img_path\": \"images/0787/da701948075f196998a7d947eba50a0649ebbdbd0e319c8cfd18aa8f5225a239.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,742,489,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"study, as we used $\\\\sim 10\\\\times$ lower cell seeding density compared to a previous study that investigated cell-induced scaffold degradation using THP-1-derived marophages $^{24}$ . Future research can be further directed to examine degradation at the center of the scaffold, for example using Raman spectroscopy on cross-sections $^{25}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,823,490,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To mimic the early phase of the in situ scaffold environment, scaffolds were seeded with a 2:1 mixture of human THP-1-derived macrophages and primary vascular-derived (myo)fibroblasts (mFBs) using fibrin as a cell carrier. Following 3 days of static culture, the cell-seeded constructs were cultured for 14 days in Xanthan Gum (X-gum)-enriched medium containing L-ascorbic acid 2-phosphate (AA2P) under various shear stress conditions in the presence of low cyclic circumferential strain $(2.3\\\\pm 0.4\\\\%)$ at $1\\\\mathrm{Hz}$ Fig.3d), mimicking the predicted strain \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,742,926,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"values in AVGs as computed by the FSI simulations (Fig. 2b). X-gum was added to match medium viscosity to blood viscosity (about $4 \\\\cdot 10^{-3} \\\\mathrm{Pa} \\\\cdot \\\\mathrm{s}$ for a wall shear rate of $\\\\sim 200 \\\\mathrm{~s}^{-1}$ [26], while AA2P was added to stimulate matrix formation[27]. Rheology measurements indicated that the viscosity of the X-gum-enriched medium was $\\\\sim 2.5$ -fold higher compared to that of standard medium, confirming that medium viscosity was increased toward the range of blood viscosity (Fig. 3e)[26]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,851,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Samples in the HSS and OSS conditions were exposed to an average (absolute) shear rate of $1216 \\\\pm 128 \\\\, \\\\mathrm{s}^{-1}$ , and samples in the LSS condition to $93 \\\\pm 31 \\\\, \\\\mathrm{s}^{-1}$ (left panels in Fig. 3f, g). The applied strains and shear rates were successfully maintained over the complete culture period, except at day 4 in the LSS condition where the shear rate dropped slightly to $\\\\approx 60 \\\\, \\\\mathrm{s}^{-1}$ (left panel in Fig. 3g). Using the quantified viscosity of the X-gum-enriched \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[468,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n 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\"code_caption\": null,\n \"image_caption\": \"[\\\"d \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0438/7423d516eb8bf490e6ab927716204c283992a0688a84bab472b2f69e3415819a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[636,196,875,333]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"e \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0883/6817fa40911ff91c0ee4893a378abe12d0f7e05059fdb99f103673fd6eb7a659.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[97,350,495,471]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"f \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0167/428890c01e9b2d5a837e7b837416555b872180d2664b4d307b62f1743448e02b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,350,904,471]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"9 \\\",\\\"Fig. 3 In vitro modeling of scaffold-guided vascular growth. a Electrospun PCL-BU vascular scaffold prior to culture ( $\\\\\\\\phi 3\\\\\\\\mathrm{mm}$ ). b Scanning electron microscopy images of dynamically cultured samples after decellularization for each experimental condition, and of an 8-day statically cultured cell-free sample (bare). c Quantification of scaffold fiber diameter at the outside of the (decellularized) constructs ( $n = 30$ fibers/condition). d Temporal variations in cyclic stretch for all loading conditions ( $n = 13$ or 14/day). e Shear rate dependent viscosity in X-gum-enriched medium (red squares, $n = 3$ ), standard medium (blue triangles, $n = 3$ ), and water (yellow circles, $n = 3$ ). The $*$ indicates blood viscosity at $200\\\\\\\\mathrm{s}^{-1}$ . f, g Temporal variations in shear rate (left axis, $n = 6$ , 7, or 9/day), viscosity (right axis, $n = 3$ or 5/day), and shear stress (right, derived from the actual (measured) medium viscosity) in the high, oscillating, and low shear stress conditions. Bars and black dots represent mean, error bars and gray area indicate standard deviation, boxplots contain $50\\\\\\\\%$ of the data with median highlighted by central mark ( $*p < 0.05$ , $* * p < 0.01$ ). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0928/16e9f611a66d3f1538603611bcaa48665910c70bb74e61b4e14529276fc4b333.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,594,490,714]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"medium, the shear rate applied to the samples translated to a shear stress of $(\\\\pm) 3.2 \\\\pm 0.3$ Pa for the HSS (unidirectional) and OSS (complete flow reversal) condition (right panel in Fig. 3f), of which the magnitude is within the range of expected shear stress values in AVGs as computed by the CFD simulations (Fig. 2c). For the LSS condition, this translated to $0.44 \\\\pm 0.12$ Pa (right panel in Fig. 3g), which is within the range of $0.1 - 0.6$ Pa in healthy veins[20]. The applied shear stresses remained stable over time. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,714,490,797]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"These results demonstrate that we were able to keep the biomechanical cellular environment, in terms of passive cues (via the scaffold fibers) and active cues (via the shear stresses and strains), stable and at the required level. This precise experimental control allowed us to directly correlate the biological response to the applied loading regime. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,823,490,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Oscillatory shear stress activates macrophages and (myo) fibroblasts. Using this dynamic in vitro setup, we quantified the cell and tissue growth and characterized the phenotypes of the cells in response to the different types of shear stress. The dynamic co-culture led to an overall increase of the construct mass with time, especially for the samples exposed to HSS and OSS (Fig. 4a). At day 14, scaffolds were completely populated with cells in all conditions and an increasing, but non-significant $(p = 0.143)$ , trend of cell content with high $(81\\\\%)$ and OSS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,594,927,649]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(118%) compared to LSS was observed (Fig. 4b). However, the variation in DNA content within the groups was large, and no clear difference between the appearance and proliferative state of cells could be observed (Fig. 4c, d). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,649,929,808]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The appositional cell/matrix layer (i.e., the side that was exposed to the flow) aligned in the direction parallel to the flow (Fig. 4e, f). This layer contained elongated cells with stress fibers (top row in Fig. 4f). At the other side of the scaffold, cells with a more rounded morphology were observed (bottom row in Fig. 4f). Elongated cells stained positive for vimentin, indicating that the outside of the constructs was populated primarily by the mFBs (Fig. 5a). CD45, as an indicator of the macrophages, was mostly found in the middle layers of the constructs and to a lesser extent compared to vimentin. This was to be expected as a result of (myo)fibroblast proliferation and a possible reduction in macrophage number (e.g., as a result of apoptosis and transdifferentiation). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,809,929,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Previously, it has been shown in vivo that OSS ( $\\\\approx 14$ Pa; range of $60\\\\mathrm{Pa}$ ) induces smooth muscle cell-rich plaque formation, while LSS ( $\\\\approx 10$ Pa) induces the occurrence of M1-polarized macrophage-rich plaques in the carotid artery in mice[28-30]. Note that the seemingly large discrepancy between these magnitudes of wall shear stress and the definition of \\\"LSS\\\" we used in this study is attributable to the known inverse relationship between animal size and wall shear stress[31], and to the physiological difference in wall shear stress between arteries and veins. To test whether different biomechanical environments can indeed influence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,529,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[830,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n 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\"[485,310,633,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0932/ad65406c94c39daecfc149e3005704ae56efe27ce8907fd1b849234c1e2c685b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[642,310,768,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0990/3e519a842abc29863ab4d6735d7e59df5a28f11c8c49cd8006a8af0552d89dc8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[776,310,904,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4 Cell and tissue growth at day 14 under different types of shear stress. a Overall construct mass/surface at day 14 normalized to scaffold mass/ surface prior to seeding (dashed line indicates no change, $^{**}p < 0.01$ $^{**}p < 0.0001$ tested with a one sample t-test). b Total DNA content per tissue construct. c Hematoxylin and eosin-stained cross-sections. d Localization of Ki67-positive cells (Ki67 in green, scaffold material in blue, dashed lines indicate construct borders). e Scanning electron microscope image of the cell and tissue morphology. f In-plane visualization of the F-actin cytoskeleton (actin in green, nuclei in red, and scaffold fibers in blue). Bars represent mean $\\\\\\\\pm$ standard deviation. HSS high shear stress condition $(3.2\\\\\\\\mathrm{Pa},n = 4)$ ,OSS oscillatory shear stress condition $(\\\\\\\\pm 3.2\\\\\\\\mathrm{Pa},n = 5)$ , LSS low shear stress condition $(0.4\\\\\\\\mathrm{Pa},n = 5)$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0873/847a23fd7e899f7993e806b258be9690350e887d2d0cfeed1d1785f7e921f768.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,554,490,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"macrophage polarization, we examined the relative expression of M1 and M2 macrophage markers at HSS and OSS compared to LSS. Interestingly, we did not detect a polarization toward an M1 or M2 macrophage phenotype (Fig. 5b). Only CD68 (pan-macrophage marker) and IL10 (anti-inflammatory marker) were more clearly activated with OSS $(p = 0.0216$ and $p = 0.1224$ , respectively), and to a lesser extent with HSS $(p = 0.1819$ and $p = 0.6740$ , respectively, Fig. 5c). Similar to the dualistic macrophage phenotype, the phenotype of the mFBs could not be uniquely attributed to be either synthetic or contractile. Instead, we found simultaneous upregulation of S100A4 (synthetic marker) and smoothelin (contractile marker), and downregulation of calponin (contractile marker) with OSS $(p = 0.0350$ , $p = 0.0082$ , and $p > 0.9999$ , respectively) and HSS $(p = 0.1024$ , $p = 0.8686$ , and $p = 0.1096$ , respectively, Fig. 5c). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,755,492,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Contrary to the gene-level analysis of MCP-1 $(p = 0.0075)$ , TNF- $\\\\alpha$ $(p = 0.2423)$ , and IL-6 $(p = 0.1763)$ , at the protein level these cytokines were lower expressed in the OSS group compared to the LSS group, although the variation within each group was large (Supplementary Fig. S2). With respect to growth factors (TGF- $\\\\beta$ 1 $(p = 0.1203)$ , CTGF $(p = 0.9973)$ ) and proteinases (MMP-1 $(p = 0.0122)$ , MMP-9 $(p = 0.0378)$ , TIMP-1 $(p = 0.0075)$ ), similar trends as seen for the cytokines were observed, which were significant for the proteinases, but not for the growth factors (Supplementary Fig. S2b). However, this quantification only represents a single snapshot in time, while similar work has shown that protein and RNA expressions are highly dynamic in nature[14]. In addition, the discrepancy between gene and protein secretion could indicate that the translation from RNA to protein is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,554,927,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"differently regulated, or that the protein stability in the culture medium is reduced in HSS and OSS conditions $^{32}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,580,927,649]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Together, the results suggest that OSS activates mFBs and macrophages to grow new tissue in terms of both cell number and matrix. Moreover, the reduction of proteinase secretion in the OSS group suggests a suppressed tissue-remodeling environment, favoring neotissue formation rather than tissue degradation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,663,927,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Oscillatory shear stress promotes disorganized tissue growth. Next, we sought to investigate the effect of the different shear stress metrics on tissue formation and remodeling. Overall, the gene expression of all growth and remodeling markers, with the exception of $TGFB1$ , was (non-significantly) elevated with OSS compared to HSS (Fig. 6a). The expression of collagen type I/III, decorin, versican, fibrillin 1, MMP1, MMP2, and TIMP1/2 was also higher compared to the LSS condition, which was statistically significant for decorin $(p = 0.0385)$ and MMP1 $(p = 0.0122)$ . Interestingly, with OSS the gene expression of TIMP1 and MMP9 was relatively high compared to the expression at the protein level (Supplementary Fig. S2b). In addition, MMP1 and MMP9 expression followed a similar trend at the protein level, but not at the gene level (Supplementary Fig. S2b), suggesting different posttranscriptional mechanisms between the loading conditions. TGF- $\\\\beta$ has been found to be an important posttranscriptional regulator of $\\\\mathrm{MMPs}^{33}$ . However, these mechanisms are complex and interrelated, complicating the comparison of the different MMPs, TIMPs, and growth factors to one another. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,916,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Collagen staining and hydroxyproline (HYP) quantification revealed that, compared to unidirectional shear stress (i.e., LSS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[468,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,957,78,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[226,957,823,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[90,60,594,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0242/2da0a5bd19035313881358dcc14831aea916ee5f7258b344a5b7d6b21148dd85.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[603,62,905,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0379/ae8644f8f80953df3add5b1b712078bea75701eb32789dc8168fc05e152b9449.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[87,354,890,456]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5 Phenotypical characterization of the cells in the vascular constructs at day 14. a Representative cross-sections for each experimental group stained for CD45 (green) and vimentin (red) for the localization of macrophages and (myo)fibroblasts, respectively (nuclei are indicated in the lower panel in blue). b Relative gene expression compared to the low shear stress condition (indicated by the circle at 1) for macrophage-related genes (left part of the polar plot) and (myo)fibroblast-related genes (right part of the polar plot, $n \\\\\\\\geq 3 / \\\\\\\\text{group}$ ). The dots and shaded areas indicate, respectively, the $50^{\\\\\\\\text{th}}$ and $25^{\\\\\\\\text{th}} - 75^{\\\\\\\\text{th}}$ percentiles. c Boxplots for a selection of phenotypical-related genes ( $n = 3, 4$ , or 5, $^* p < 0.05$ , $^{**} p < 0.01$ ). Boxplots contain $50\\\\\\\\%$ of the data with median highlighted by central mark. HSS high shear stress condition (3.2 Pa), OSS oscillatory shear stress condition ( $\\\\\\\\pm 3.2$ Pa), LSS low shear stress condition (0.4 Pa). See Supplementary Fig. S1 for all boxplots of the gene expression data. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0270/b7875aa0d5ecb6d4244a6c6515f5efc368f50e2a403568eb88c22b5fe313e357.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,569,490,744]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and HSS), OSS seemed to stimulate the synthesis of more and thicker collagen fibers (Fig. 6b, d). The differences in HYP content, however, are small and not significant. Collagen fibers are especially suited to resist in vivo loading and slowly take over the load-bearing properties of the resorbing scaffold. However, this process can result in scar-like tissue if collagen production happens too fast. HSS stimulated relatively more collagen type I formation while $\\\\alpha$ -SMA-positive cells were predominantly detected at the tissue borders with LSS (Fig. 6c). Together, these observations are in line with the increased expression of growth markers at the gene level (Fig. 6a) and may have been further stimulated by the decreased levels of proteinases in the culture medium (Supplementary Fig. S2b). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,744,492,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We then focused on the neotissue organization in the appositional tissue layer which was in direct exposure to the shear stress and whose thickness was highest with HSS $(p = 0.0205$ compared to LSS, Fig. 6b, e). The collagen fibers were mainly oriented at an angle between $80^{\\\\circ}$ and $90^{\\\\circ}$ in all groups (i.e., parallel to the flow direction), and compared to LSS, consistently more aligned in the HSS condition, despite the limited differences in proteinase secretion (Supplementary Fig. S2b). In contrast, the peak in the OSS condition was much broader compared to LSS and HSS, indicating that the collagen is deposited with a substantially higher in-plane fiber dispersion when the flow is not unidirectionally applied. Based on these findings, we conclude that the collagen fiber dispersion in the superficial collagen layer is a direct result of flow-induced shear stress, rather than an indirect result of the secreted proteinases. On the other hand, the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,569,927,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"overall collagen fiber orientation is not necessarily mediated by shear stress alone, as the presence of cyclic strain has also contributed to this fiber orientation $^{14}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,609,929,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to tissue growth and remodeling by the mFBs, we aimed at scaffold degradation that is mainly induced by the macrophages. As the macrophages resided in the center of the scaffold and not at the surface, prohibiting the assessment of scaffold degradation by SEM, we examined the expression of genetic markers responsible for scaffold degradation. In the OSS group, NFKB1 (a protein complex involved in oxidative stress) was upregulated compared to LSS (Supplementary Fig. S3, $p = 0.0044$ ). LIPA (lysosomal lipase) followed a similar trend. On the other hand, NOX2 (ROS generating NADPH Oxidase 2 complex), which is involved in oxidative degradation, followed a decreasing, albeit non-significant, trend in the HSS condition. Although this could indicate enhanced oxidative and enzymatic degradative capacity of the macrophages with OSS, a previous study showed that the expression of these genes could not explain the differences in macrophage-driven scaffold mass loss, making it difficult to directly relate gene expression to scaffold degradation[24,34]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,875,584,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,888,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study aimed to elucidate how neotissue develops under the influence of the hemodynamic environment in regenerating AVGs via a combined in silico and in vitro approach (Fig. 1). With this approach, the hemodynamic environment could be \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,529,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[830,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n 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null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"C \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0404/056d7ddc2aec17fc7ecdb31b1e3b96ce94734bdf7f31f2c3fefc0ffe82004005.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[510,162,631,222]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"HSS \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1016/7086041cc7b8f9cce07ba04b4b4a557b74e64d294d5c60684572fc86fa0bded3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[640,162,761,222]\",\n 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\"[500,411,700,516]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0999/fccceb6d763a599a76e664ed8787c692f64acc27f2cc68607d841121bc95a7d6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[702,424,902,516]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 6 Changes to matrix growth, remodeling, and organization in response to shear stress. a Relative gene expression compared to the low shear stress condition (indicated by the circle at 1) for markers related to growth (i.e., collagenous matrix, proteoglycan, and elastic matrix formation), as well as markers related to remodeling. The dots and shaded areas indicate, respectively, the 50th and 25th-75th percentiles. See Supplementary Fig. S1 for all boxplots of the gene expression data. b Total hydroxyproline (left) and glycosaminoglycan (middle) content normalized to total construct mass, and quantification of the thickness of the appositional collagen layer on top of the scaffold from the confocal z-stacks in e (right, $^* p < 0.05$ ). Representative sections of each experimental group stained for (c) $\\\\\\\\alpha$ SMA (green), collagen I (red), and DAPI (blue) and (d) Picrosirius red (visualized under polarized light). e Confocal visualization of the collagen structure. f Overlay plot and g separate histograms quantifying the angular collagen distribution in the appositional matrix layer for each condition (directions of applied shear stress $(90^{\\\\\\\\circ})$ and stretch $(0^{\\\\\\\\circ})$ indicated by the arrows in c-e. Bars represent mean $\\\\\\\\pm$ standard deviation. HSS high shear stress condition $(3.2\\\\\\\\mathrm{Pa}, n = 4)$ , OSS oscillatory shear stress condition $(\\\\\\\\pm 3.2\\\\\\\\mathrm{Pa}, n = 5)$ , LSS low shear stress condition $(0.4\\\\\\\\mathrm{Pa}, n = 4$ or 5). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0372/07f49ea6063af9a9af4cb0eef64ddc12fd05a8b130f5964658286c2cc238af89.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[67,676,490,769]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"controlled in a systematic way and biological responses could be directly measured, allowing the identification of causal relationships between hemodynamic parameters and the venous remodeling process. Relevant hemodynamic parameters were selected according to currently existing theories on venous remodeling (i.e., OSS and $\\\\mathrm{HSS^{10}}$ ), while the exact magnitudes were derived from CFD and FSI simulations (Fig. 1a, b). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,769,492,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Using these in vitro dynamic co-cultures, we demonstrated that, compared to unidirectional shear stress (i.e., LSS and HSS), OSS activates both cell types to grow and remodel a tissue with a dense and disorganized structure (Fig. 1c). Furthermore, the secretion of NIH-related proteins was lower in the OSS and HSS conditions, indicating that the interaction between the different cell types and their mechanical environment resulted in a microenvironment that likely favored neotissue formation rather than tissue degradation. Here, it should be noted that other (complex) shear stress theories exist as well (e.g., spatial and/or temporal gradients in shear stress $^{10}$ ), and that the cellular composition and phenotypes may differ in patients requiring vascular access, which should be the subject of future investigation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,676,927,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Taken together, we identified oscillatory shear stress as a moderate, but progressive stimulator of cell proliferation and neotissue formation, even in the presence of cyclic strain. This is remarkable, because it was previously shown that laminar shear stress can have a stabilizing effect on strain-induced neotissue formation[14], making oscillatory shear stress a potential target to inhibit venous NIH and avoid excessive tissue formation. In the future, integration of these findings on cell mechano-response in the presence of complex hemodynamic situations into a computational framework of growth and remodeling can lead to the exciting possibility to predict the scaffold and venous (mal) adaptation to altered hemodynamics[35,36]. A thorough understanding of these mechanisms is essential to successfully translate in situ tissue engineering into a therapeutic approach as a solution to reduce vascular access dysfunction in patients with end-stage renal disease. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,907,571,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,921,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AVG geometry reconstruction. Realistic axillary artery to axillary vein loop AVG geometries were used as input for the CFD and FSI models. These geometries were \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[468,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,957,78,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[226,957,823,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[67,62,492,205]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"reconstructed using clinical data of a single patient and assumed constant-diameter vessels. For the CFD AVG model, vessel paths and AVG configuration were assumed to remain relatively constant after AVG creation. As such, these AVG characteristics were extracted from a 15-month postoperative CTA scan by means of vessel-centerline extraction. Since vessel diameters may have changed significantly in the period between AVG creation and the CTA scan, 2-weeks preoperative ultrasound diameter measurements were used to estimate arterial and venous diameters (6.6 and $7.7\\\\mathrm{mm}$ , respectively). Graft diameter was set to $6\\\\mathrm{mm}$ . For the FSI model a similar approach was taken, though for this model zero-pressure vessel diameters needed to be imposed. The zero-pressure venous diameter was set to $7.1\\\\mathrm{mm}$ , which was approximated using estimates of the average blood pressure at the time of ultrasound diameter measurements[15]. Zero-pressure graft diameter was set to $6\\\\mathrm{mm}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,218,490,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Simulations. The CFD equations were solved by using the OASIS<sup>37</sup> solver as implemented in the open-source finite element package FEniCS<sup>38</sup>. A mesh-independent solution was obtained at $3.1 \\\\cdot 10^{6}$ tetrahedral Taylor-Hood elements and a time step of $1 \\\\cdot 10^{-4}$ s. The FSI model was solved by using the Unicorn<sup>39</sup> solver that was also implemented in FEniCS. A mesh-independent solution was obtained at $2.5 \\\\cdot 10^{6}$ and $0.6 \\\\cdot 10^{6}$ linear tetrahedral elements in the fluid and solid domain, respectively. Blood was modeled as Newtonian fluid with a kinematic viscosity of $3.3 \\\\cdot 10^{-6} \\\\mathrm{~m}^2 \\\\mathrm{~s}^{-2}$ for the CFD simulations and $4.5 \\\\cdot 10^{-6} \\\\mathrm{~m}^2 \\\\mathrm{~s}^{-2}$ for the FSI simulations. From the CFD simulations, exposure to wall shear stress in the perianastomotic region was quantified using the time-averaged wall shear stress magnitude: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[196,343,489,370]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathrm {T A W S S} = \\\\frac {1}{T} \\\\int_ {0} ^ {T} | | \\\\vec {\\\\tau} (t, \\\\vec {x}) | | \\\\mathrm {d t} \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[67,375,489,401]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\vec{\\\\tau}(t, \\\\vec{x})$ represents the local WSS vector and $T$ the duration of the cardiac cycle. Exposure to oscillatory wall shear stress was assessed using the OSI: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[189,405,489,437]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathrm {O S I} = \\\\frac {1}{2} \\\\left(1 - \\\\frac {\\\\left| \\\\left| \\\\int_ {0} ^ {T} \\\\vec {\\\\tau} (t , \\\\vec {x}) \\\\mathrm {d t} \\\\right| \\\\right|}{\\\\int_ {0} ^ {T} \\\\left| \\\\left| \\\\vec {\\\\tau} (t , \\\\vec {x}) \\\\right| \\\\right| \\\\mathrm {d t}}\\\\right) \\\\tag {2}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[67,441,480,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which ranges between 0 (unidirectional WSS) and 0.5 (purely oscillatory WSS). From the FSI simulations, wall strain was computed over the inner and outer surface of the graft wall according to: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[236,480,489,512]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\varepsilon = \\\\sqrt {\\\\frac {A _ {\\\\mathrm {n}} - A _ {0}}{A _ {0}}} \\\\tag {3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[67,517,492,583]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"here, $A_0$ is the initial area of each surface element on the graft wall, whereas $A_{\\\\mathrm{n}}$ is the surface area of each element during the cardiac cycle. Finally, $\\\\varepsilon$ was averaged over the complete cardiac cycle. The $\\\\varepsilon$ strain metric is equivalent to engineering strain and combines both longitudinal and circumferential strain in a single scalar metric. For detailed information regarding the methodology of the simulations, the reader is referred to Quicken et al.[15,19]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,597,492,783]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scaffold preparation. Tubular scaffolds ( $\\\\phi 3\\\\mathrm{mm}$ , $2\\\\mathrm{cm}$ in length, $200\\\\mu \\\\mathrm{m}$ wall thickness) were electrospun from PCL-BU (SyMO-Chem, Eindhoven, The Netherlands) in a climate-controlled cabinet ( $25^{\\\\circ}\\\\mathrm{C}$ and $30\\\\%$ relative humidity; IME Technologies, Geldrop, The Netherlands). Briefly, $15\\\\%$ (w/w) PCL-BU was dissolved in $85\\\\%$ (w/w) $\\\\mathrm{CHCl}_3$ (Sigma, 372978) and delivered via a charged nozzle $(-1\\\\mathrm{kV})$ at a flow rate of $40\\\\mu \\\\mathrm{l}\\\\mathrm{min}^{-1}$ onto a positively charged $(16\\\\mathrm{kV})$ rotating cylindrical mandrel ( $\\\\phi 3\\\\mathrm{mm}$ , $500\\\\mathrm{rpm}$ ). The distance between the nozzle and the mandrel was kept constant at $16\\\\mathrm{cm}$ . The resulting scaffolds were removed from the mandrel, dried in vacuo overnight, and placed over silicone tubing ( $\\\\phi 2.8\\\\mathrm{mm}$ ). The scaffold-wrapped silicone tubing was mounted in the bioreactor, sterilized by UV exposure (30 min/side), wetted in sterile $\\\\mathrm{H}_2\\\\mathrm{O}$ , and incubated at $37^{\\\\circ}\\\\mathrm{C}$ in complete medium (1:1 advanced Dulbecco's Modified Eagle Medium (a-DMEM):Roswell Park Memorial Institute 1640 (RPMI-1640) (Gibco, 124910 and A10491) with $10\\\\%$ fetal bovine serum (FBS; Greiner, Alphen aan den Rijn, The Netherlands), $1\\\\%$ penicillin/streptomycin (P/S; Lonza, DE17-602E), $0.5\\\\%$ GlutaMax (Gibco, 35050), and $0.25\\\\mathrm{mgml}^{-1}$ AA2P (Sigma, A8960)) overnight to allow for protein adsorption. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,797,492,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Myo)fibroblast cell culture. Vascular cells were isolated from surgical leftover of human vena saphena magna and used in accordance to the Dutch guidelines for secondary-use materials. The cells were expanded conforming conventional protocols[40]. Due to their structural properties, these cells have earlier been characterized as myofibroblasts[40,41]. However, a subpopulation of these cells do not express $\\\\alpha$ -SMA, which is more characteristic for fibroblasts[41]. Therefore, we refer to these cells as mFBs. mFBs were cultured in a-DMEM containing $10\\\\%$ FBS, $1\\\\%$ P/S, and $1\\\\%$ GlutaMax in a standard culture incubator $(37^{\\\\circ}\\\\mathrm{C}, 5\\\\% \\\\mathrm{CO}_2)$ and passaged at $80\\\\%$ confluency. Culture medium was changed every 3-4 days. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,910,492,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"THP-1 cell culture. Human monocytic THP-1 cells (Sigma Aldrich, lot# 16K052) were cultured and expanded in suspension at a cell density of $(0.5 - 1.5)\\\\cdot 10^{6}$ cells $\\\\mathrm{ml}^{-1}$ culture medium (RPMI-1640 containing $10\\\\%$ FBS and $1\\\\%$ P/S) in a standard culture \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,62,927,86]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"incubator $(37^{\\\\circ}\\\\mathrm{C}, 5\\\\% \\\\mathrm{CO}_{2})$ . Culture medium was changed three times per week. The cells tested negative on routinely performed (monthly) mycoplasm tests. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,99,929,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell seeding. After cell expansion, the mFBs (passage 6) and THP-1 cells (passage 10 after thawing) were seeded in the pre-wetted scaffolds using fibrin as a cell carrier[42]. Prior to seeding, the THP-1 cells were primed for $15\\\\mathrm{min}$ in $50\\\\mathrm{ngml}^{-1}$ phorbol 12-myristate 13-acetate (Sigma, P8139)-enriched culture medium to stimulate macrophage differentiation. To co-seed the cells into the porous scaffold, cells $(15\\\\cdot 10^{6}\\\\mathrm{mFBscm}^{-3})$ and $30\\\\cdot 10^{6}$ THP-1 cells $\\\\mathrm{cm}^{-3}$ ) were added to a mixture of bovine fibrinogen $(10\\\\mathrm{mgml}^{-1}$ ; Sigma, F8630) and bovine thrombin $(10\\\\mathrm{IUml}^{-1}$ ; Sigma, T4648), and carefully pipetted in two steps onto two opposing sides of the scaffold. Directly after pipetting the cell suspension, the cell-seeded scaffold was manually rotated until the suspension was completely absorbed by the scaffold[21,22]. To complete fibrin polymerization, the cell-seeded constructs were transferred to a $15\\\\mathrm{ml}$ tube and kept in an incubator $(37^{\\\\circ}\\\\mathrm{C},5\\\\% \\\\mathrm{CO}_{2})$ for $30\\\\mathrm{min}$ , after which the tubes were filled with $8\\\\mathrm{ml}$ of complete medium. To allow for cell adhesion to the scaffold fibers, the constructs were statically cultured in these tubes for 3 days prior to exposing the constructs to the different hemodynamic loading conditions (Fig. 2d). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,289,929,485]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Shear stress and strain application. After 3 days of static culture, the constructs were mounted in the culture chambers of the bioreactor for the application of hemodynamic loading[21,22]. To determine the loading conditions that mimic the conditions in vivo, we first examined the expected hemodynamic loads at the vein-graft anastomosis, as computed from the CFD and FSI simulations[15,19]. The samples were allocated to the different experimental conditions in a non-blinded, random way. The medium reservoirs were filled with $50\\\\mathrm{ml}$ of complete medium, which was supplemented with $0.7\\\\mathrm{mgml}^{-1}$ X-gum (Sigma, G1253) to increase the medium viscosity toward the range of blood viscosity[26]. To correct for possible medium evaporation during culture, the culture medium was supplemented up to $50\\\\mathrm{ml}$ with sterile $\\\\mathrm{H}_2\\\\mathrm{O}$ every 4 days, after which $25\\\\mathrm{ml}$ of medium was replaced by fresh, X-gum-supplemented complete medium. After 14 days of dynamic culture, the tubular constructs were harvested, sectioned according to a cutting scheme (Supplementary Fig. S4), and stored at $4^{\\\\circ}\\\\mathrm{C}$ (after $15\\\\mathrm{min}$ fixing in $3.7\\\\%$ formaldehyde and $3\\\\times 5\\\\mathrm{min}$ washing in PBS) or $-30^{\\\\circ}\\\\mathrm{C}$ (after snap-freezing in liquid nitrogen) until further analysis. Supernatants from the culture medium after centrifugation $(300\\\\times g,5\\\\mathrm{min})$ at days 1, 4, 8, and 14 were stored at $-30^{\\\\circ}\\\\mathrm{C}$ until further analysis. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,500,929,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Xanthan gum sterilization and dissolving. In a sterile environment, X-gum was spread on a weighing paper in a large petri dish and UV-sterilized (10 min on two sides). After UV exposure, the X-gum was transferred to a pre-weighed $50\\\\mathrm{ml}$ tube, and weighed again to determine the X-gum mass in a sterile way. Then, $70\\\\%$ EtOH was added at a concentration of $1.4\\\\mu \\\\mathrm{l}\\\\mathrm{mg}^{-1}$ X-gum and the resulting suspension was transferred to 1:1 a-DMEM:RPMI-1640 at a concentration of $1.4\\\\mathrm{mg}\\\\mathrm{ml}^{-1}$ . The sterilized X-gum was dissolved on a magnetic hot plate stirrer (4 h at $40^{\\\\circ}\\\\mathrm{C}$ ), resulting in a viscous solution. To prepare the X-gum-supplemented complete medium, this viscous solution was diluted $2\\\\times$ with 1:1 a-DMEM:RPMI-1640 to which the rest of the supplements were added (10% FBS, 1% P/S, 0.25 mg ml $^{-1}$ AA2P). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,624,929,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viscosity measurements. To determine the shear stresses associated with the applied shear rates during the experiment, the viscous behavior of the supernatants (with and without X-gum) was quantified using a cone-plate rheometer $(\\\\phi 50\\\\mathrm{mm})$ at $37^{\\\\circ}\\\\mathrm{C}$ (ARES, Rheometric Scientific, 1 technical replicate/sample). The viscosity $\\\\eta$ was measured at shear rates $\\\\dot{\\\\gamma}$ varying from $10\\\\mathrm{s}^{-1}$ until $1500\\\\mathrm{s}^{-1}$ (6 measurements per decade). The resulting viscosity-shear rate curves were linearly interpolated to determine the viscosities at low shear rate $(\\\\dot{\\\\gamma}\\\\approx 100\\\\mathrm{s}^{-1})$ and high shear rate $(\\\\dot{\\\\gamma}\\\\approx 1200\\\\mathrm{s}^{-1})$ (Matlab, The Mathworks, Natick, MA). The shear stress was calculated via: $\\\\tau (\\\\dot{\\\\gamma}) = \\\\dot{\\\\gamma}\\\\cdot \\\\eta (\\\\dot{\\\\gamma})$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,737,929,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Biochemical assays. The snap-frozen samples were used for quantification of DNA, glycosaminoglycan (GAG), and HYP content (two technical replicates/ sample). After determination of the sample dry mass and surface (see \\\"Determination of total mass\\\"), samples were reduced to a fine powder using a microdismembrator (Sartorius) for sample digestion. Briefly, the samples were placed in cryovials containing 4 microbeads, frozen in liquid nitrogen, and disrupted at $3000~\\\\mathrm{rpm}$ for $60~s$ . To digest the sample, the powder was mixed with $500\\\\mu l$ digestion buffer $(100\\\\mathrm{mM}$ phosphate buffer $\\\\left(\\\\mathrm{pH} = 6.5\\\\right)$ , $5\\\\mathrm{mM}$ L-cysteine (C-1276), $5\\\\mathrm{mM}$ ethylenediamine tetraacetic acid (ED2SS), $140\\\\mu \\\\mathrm{g}\\\\mathrm{ml}^{-1}$ papain (P4762); all from Sigma), transferred to a fresh Eppendorf tube, and incubated overnight at $60^{\\\\circ}\\\\mathrm{C}$ . Prior to measurement of DNA, GAG, and HYP content, the samples were centrifuged at $12,000~\\\\mathrm{rpm}$ for $10\\\\mathrm{min}$ . From the supernatant, DNA was quantified using the Qubit dsDNA BR assay kit (Life Technologies, Q32853) according to the manufacturer's protocol. GAG was quantified using a modified dimethyl methylene blue (DMMB) $^{43}$ assay with Shark chondroitin sulfate (Sigma, C4348) as a standard. Briefly, $40\\\\mu l$ of the supernatant and standards were mixed with $150\\\\mu l$ DMMB solution in a 96-well plate. The absorbance was measured using a microplate reader $(540\\\\mathrm{nm}$ , Synergy HTX, Biotek). HYP, as a measure of collagen, was quantified with a Chloramin-T assay $^{44}$ with trans-4-hydroxyproline as a reference (Sigma, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,529,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[830,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,957,665,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[917,957,927,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[67,62,490,129]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"H5534). Before assaying, the samples were first hydrolyzed in $16\\\\mathrm{M}$ sodium hydroxide (Merck, B1438798). The absorbance was measured using a microplate reader $(550\\\\mathrm{nm}$ , Synergy HTX, Biotek). DNA, GAG, and HYP values were normalized to the sample dry mass. Normalized DNA was multiplied by the sample total mass to obtain DNA content per sample (see \\\"Determination of total mass\\\"). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,144,490,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Determination of total mass. To obtain the mass/surface, samples were weighed using a digital balance (XS105 dual-range analytical balance, Mettler Toledo, Switzerland) and photographed together with a ruler (one technical replicate/sample). The surfaces were measured from the photographs using ImageJ (v1.48, U.S. NIH, Bethesda, MD, USA). To estimate the increase in construct mass during culture, the mass/surface of the lyophilized samples at day 14 (see \\\"Biochemical assays\\\") was normalized to the initial mass/surface prior to seeding. To estimate the total sample mass at day 14, the mass/surface of the lyophilized samples was multiplied by the total surface of the samples $(15\\\\mathrm{mm}\\\\times 1.5\\\\pi \\\\mathrm{mm})$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,259,490,368]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scanning electron microscopy (SEM). Cell, tissue, and scaffold fiber morphology were assessed from SEM images (three predefined locations/sample). The formalin-fixed samples were placed in $0.25\\\\%$ glutaraldehyde $(1\\\\mathrm{h})$ , dehydrated in an ordered series of ethanol dilutions, and dried in vacuo overnight. After visualization of the cell and tissue morphology in low vacuum using a $10\\\\mathrm{kV}$ electron beam (Quanta 600F, FEI, Hillsboro, OR, USA), half of the samples were decellularized in $4.6\\\\%$ sodium hypochlorite $(15\\\\mathrm{min})$ , washed in $\\\\mathrm{H}_2\\\\mathrm{O}$ $(2\\\\times 5\\\\mathrm{min})$ , and dried in vacuo overnight to visualize the scaffold fiber morphology. Together with the non-decellularized samples, samples were gold-sputtered and visualized in high vacuum using a $10\\\\mathrm{kV}$ electron beam. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,384,490,570]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Immunohistochemistry. Cross-sections $(7\\\\mu \\\\mathrm{m})$ cryosections from formalin-fixed samples) were washed in PBS $(3\\\\times 5\\\\mathrm{min})$ , permeabilized in $0.5\\\\%$ Triton X-100 $(30\\\\mathrm{min})$ , and blocked for non-specific binding in $5\\\\%$ goat serum containing $1\\\\%$ BSA $(30\\\\mathrm{min})$ . The sections were then incubated with primary antihuman polyclonal antibodies against Ki67 (rabbit IgG, 1:200, Thermoscientific, RB-1510-P0), CD45 (mouse IgG1, 1:1000, Abcam, ab33533), vimentin (mouse IgM, 1:2000, Abcam, ab20346), $\\\\alpha$ SMA (rabbit IgG, 1:600, Abcam, ab5694), or collagen I (mouse IgG1, 1:200, Sigma, c2456), in $10\\\\times$ diluted block solution (overnight at $4^{\\\\circ}\\\\mathrm{C}$ ). After washing in PBS $(3\\\\times 5\\\\mathrm{min})$ , the sections were incubated with 1:500 secondary goat antibodies labeled with Alexa-488 conjugate (antimouse IgG1 (for CD45, Molecular Probes, A21121) or antirabbit IgG (for $\\\\alpha$ SMA, Molecular Probes, A11008)) or Alexa-647 conjugate (antimouse IgM (for vimentin, Jackson Immunoresearch, 115-605-075) or antimouse IgG1 (for collagen I and Ki67, Molecular Probes, A21240)), in $10\\\\times$ diluted block solution $(60\\\\mathrm{min})$ . Nuclei were stained with $4^{\\\\prime},6$ -diamidino-2-phenylindole (1:500, Sigma). The stained sections were mounted in mowiol (Sigma, 81381) and visualized with an inverted epifluorescent microscope (Zeiss Axiovert 200M, $\\\\times 20 / 0.5$ Plan-Neofluar lens, three sections/sample). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,586,490,675]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fluorescence stainings. Actin and collagen structures in formalin-fixed whole-mount samples were labeled with phalloidin-Atto 488 (1:200, Sigma) and CNA35-OG488 $(1\\\\mu \\\\mathrm{M}^{45})$ , respectively. Nuclei in the actin-stained samples were labeled with propidium iodide $(7\\\\mu \\\\mathrm{M}$ , Molecular Probes, P3566). The stained samples were kept in PBS and visualized with a confocal laser scanning microscope (Leica TCS SP5X with a $\\\\times 40 / 1.1$ HCX PL Apo CS lens). The collagen orientation in each sample was quantified from two $z$ -stacks $(\\\\approx 50\\\\mu \\\\mathrm{m})$ recorded at two predefined locations using in-house developed software[21]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,689,489,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Histological analysis. Overall matrix content and fibrillar collagen in cross-sections $(7\\\\mu \\\\mathrm{m}$ cryosections from formalin-fixed samples) were assessed from hematoxylin and eosin and Picrosiirus red stains, respectively. Images were acquired with a bright field microscope (Zeiss Axio Observer Z1 with a $\\\\times 20 / 0.8$ Plan-Apochromat lens, three sections/sample). Picrosiirus-stained sections were also imaged with polarized light to assess the birefringence of the collagen fibrils. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,771,490,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gene expression. The snap-frozen samples were disrupted in a microdismembrator (see \\\"Biochemical assays\\\") and lysed in RLT lysis buffer (5 min, on ice). To isolate the RNA, the lysates were further processed using the Qiagen RNeasy kit with an additional DNase treatment (30 min, Qiagen, 74106). RNA was eluted in $30\\\\mu \\\\mathrm{l}$ RNAse-free $\\\\mathrm{H}_2\\\\mathrm{O}$ and quantified with a spectrophotometer (NanoDrop, ND-1000, Isogen Life Science, The Netherlands). Total RNA was reverse-transcribed into cDNA in a thermal cycler (protocol: $65^{\\\\circ}\\\\mathrm{C}$ (5 min), on ice (2 min) while adding the enzyme mixture, $37^{\\\\circ}\\\\mathrm{C}$ (2 min), $25^{\\\\circ}\\\\mathrm{C}$ (1 min), $37^{\\\\circ}\\\\mathrm{C}$ (50 min), and $70^{\\\\circ}\\\\mathrm{C}$ (15 min)). The reaction solution consisted of $200\\\\mathrm{ng}$ RNA, $1\\\\mu \\\\mathrm{l}$ dNTPs (10 mM, Invitrogen), $1\\\\mu \\\\mathrm{l}$ random primers ( $50\\\\mathrm{ng}\\\\mu \\\\mathrm{l}^{-1}$ , Promega, C1181), $2\\\\mu \\\\mathrm{l}$ 0.1M DTT, $4\\\\mu \\\\mathrm{l}5\\\\times$ first strand buffer, and $1\\\\mu \\\\mathrm{l}$ M-MLV Reverse Transcriptase $(200\\\\mathrm{U}\\\\mu \\\\mathrm{l}^{-1}$ , Invitrogen, 28025-013), which was supplemented to $20\\\\mu \\\\mathrm{l}$ with RNAse-free $\\\\mathrm{H}_2\\\\mathrm{O}$ . qPCR was performed in a $10\\\\mu \\\\mathrm{l}$ reaction mix (two technical replicates/sample), containing $3\\\\mu \\\\mathrm{l}100\\\\times$ diluted cDNA, $500\\\\mathrm{nM}$ primer (forward and reversed, see Supplementary Table S1), and $5\\\\mu \\\\mathrm{l}$ SYBR Green Supermix \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,62,927,173]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Bio-Rad, 170-8886). Gene expression was normalized to GAPDH, identified as being most stable. $C_t$ values were acquired by exposing the reaction mixtures to the following thermal protocol: $95^{\\\\circ}\\\\mathrm{C}$ (3 min), 40 cycles of $95^{\\\\circ}\\\\mathrm{C}$ (20 s), $60^{\\\\circ}\\\\mathrm{C}$ (20 s), and $72^{\\\\circ}\\\\mathrm{C}$ (30 s), $95^{\\\\circ}\\\\mathrm{C}$ (1 min), and $65^{\\\\circ}\\\\mathrm{C}$ (1 min), concluded with a melting curve measurement. $C_t$ values were normalized for the housekeeping gene $(\\\\Delta C_t)$ and control $(\\\\Delta \\\\Delta C_t$ , LSS condition), and the $2^{-\\\\Delta \\\\Delta C_t}$ formula was applied to calculate relative fold gene expressions of the genes listed in Supplementary Table S2. Datapoints were excluded if the melting curve was off, if $>0.5 C_t$ difference between technical replicates, or if the blanco was off in comparison to the measured $C_t$ value. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,187,927,299]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ELISA. Intimal hyperplasia-related proteins (Supplementary Table S2) were quantified from the supernatants at day 14 using a Luminex-based multiplex immunoassay (Multiplex core facility of the laboratory for Translational Immunology, UMC Utrecht, the Netherlands, one technical replicate/sample). In short, the supernatants were consecutively incubated with antibody-conjugated MagPlex microspheres $(1\\\\mathrm{h})$ , biotinylated antibodies $(1\\\\mathrm{h})$ , and streptavidin-phycoerythrin $(10\\\\mathrm{min}$ , diluted in high performance ELISA buffer (Sanquin)). Fluorescence intensity was measured using a FLEXMAP 3D system and analyzed by five-parametric curve fitting using Bio-Plex Manager software (Bio-Rad, version 6.1.1). Protein concentrations were normalized to the average DNA content per condition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,310,927,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Statistics and reproducibility. To each loading condition in the culture experiment, $n = 5$ constructs from two separate experimental runs were assigned to allow for statistical analysis. No experimental-specific outcomes were observed. During the experiment, one sample from the HSS group dropped out due to experimental difficulties, resulting in $n = 4$ constructs for this group. Technical replicates were defined as repeated measurements of the same sample to assess the reproducibility of the analysis, and do not count to the total $n$ . All data are presented either as mean ± standard deviation or as boxplots using Matlab (Matlab R2017; The Mathworks, Natick, MA) or Prism (GraphPad, La Jolla, CA, USA). Statistical analysis was performed to test for significant differences between the different shear stress modes with respect to biomechanical loading, biochemical content, gene expression, and cytokine secretion using a two-sided non-parametric Kruskal-Wallis test with a Dunn's multiple comparison test (GraphPad, La Jolla, CA, USA). Shear stress data were obtained by multiplying the daily average of the shear rate $(\\\\bar{\\\\gamma})$ with the daily average of the viscosity $(\\\\bar{\\\\eta}(\\\\bar{\\\\gamma}))$ . The standard deviation for shear stress was estimated based on error propagation. Gene expression data were logarithmically transformed prior to statistical analysis. Statistical significance was assumed for $p < 0.05$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,523,927,546]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,561,621,574]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,574,910,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The source data underlying the graphs and charts presented in the main figures are available in the Supplementary Data file. The raw data are available from the corresponding author upon reasonable request. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,622,623,636]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Code availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,636,927,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All computational methods used in this paper to perform the CFD and FSI simulations were peer-reviewed and are extensively described in Quicken et al. [15,19]. The data and methods required to reproduce Fig. 2a-c from the simulation results can be obtained from a DOI-minting repository [46]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,696,816,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 24 July 2020; Accepted: 31 March 2021; Published online: 10 May 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,767,586,778]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,780,927,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Shiu, Y. T., Rotmans, J. I., Geelhoed, W. J., Pike, D. B. & Lee, T. Arteriovenous conduits for hemodialysis: how to better modulate the pathophysiological vascular response to optimize vascular access durability. Am. J. Physiol. Renal Physiol. 316, F794-F806 (2019). \\\",\\\"2. Lee, T. & Roy-Chaudhury, P. Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis. Adv. Chronic Kidney Dis. 16, 329-338 (2009). \\\",\\\"3. Haruguchi, H. & Teraoka, S. Intimal hyperplasia and hemodynamic factors in arterial bypass and arteriovenous grafts: a review. J. Artif. Organs 6, 227-235 (2003). \\\",\\\"4. Carroll, G. T., McGloughlin, T. M., O'Keefe, L. M., Callanan, A. & Walsh, M. T. Realistic temporal variations of shear stress modulate MMP-2 and MCP-1 expression in arteriovenous vascular access. Cell Mol. Bioeng. 2, 591-605 (2009). \\\"]\",\n \"page_idx\": \"9\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[468,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,957,87,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[226,957,823,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,63,490,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"5. Carroll, G. T. et al. Wall shear stresses remain elevated in mature arteriovenous fistulas: a case study. J. Biomech. Eng. 133, 1-9 (2011). \\\",\\\"6. Krishnamoorthy, M. K. et al. Hemodynamic wall shear stress profiles influence the magnitude and pattern of stenosis in a pig av fistula. *Kidney Int.* 74, 1410-1419 (2008). \\\",\\\"7. Ene-Iordache, B. & Remuzzi, A. Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: low and oscillating shear stress locates the sites of stenosis. Nephrol. Dial. Transplant. 27, 358-368 (2012). \\\",\\\"8. Rajabi-Jagahrgh, E. et al. Influence of temporal variation in wall shear stress on intima-media thickening in arteriovenous fistulae. Semin. Dial. 26, 511-519 (2013). \\\",\\\"9. Rajabi-Jagahrhgh, E. et al. New techniques for determining the longitudinal effects of local hemodynamics on the intima-media thickness in arteriovenous fistulae in an animal model. Semin. Dial. 27, 424-435 (2014). \\\",\\\"10. Browne, L. D. et al. The role of shear stress in arteriovenous fistula maturation and failure: a systematic review. PLoS ONE 10, 1-24 (2015). \\\",\\\"11. Peiffer, V., Sherwin, S. J. & Weinberg, P. D. Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? A systematic review. Cardiovasc. Res. 99, 242-250 (2013). \\\",\\\"12. Kirkton, R. D. et al. Bioengineered human acellular vessels recellularize and evolve into living blood vessels after human implantation. Sci. Transl. Med. 11, eaau6934 (2019). \\\",\\\"13. van Haaften, E. E., Bouten, C. V. C. & Kurniawan, N. A. Vascular mechanobiology: towards control of in situ regeneration. *Cells* 6, 19 (2017). \\\",\\\"14. van Haaften, E. E., Wissing, T. B., Kurniawan, N. A., Smits, A. I. P. M. & Bouten, C. V. C. Human in vitro model mimicking material-driven vascular regeneration reveals how cyclic stretch and shear stress differentially modulate inflammation and matrix deposition. Adv. Biosyst. 4, 1900249 (2020). \\\",\\\"15. Quicken, S. et al. Computational study on the haemodynamic and mechanical benefits of electrospun polyurethane dialysis grafts. Biomech. Model Mechanobiol. 19, 713-722 (2020). \\\",\\\"16. Decorato, I. et al. Numerical simulation of the fluid structure interactions in a compliant patient-specific arteriovenous fistula. Int. J. Num. Methods Biomed. Eng. 30, 143-159 (2014). \\\",\\\"17. Guess, W. P. et al. Fluid-structure interaction modelling and stabilisation of a patient-specific arteriovenous access fistula. ArXiv https://arxiv.org/abs/1704.07753 (2017). \\\",\\\"18. Montini-Ballarin, F., Abraham, G. A. & Caracciolo, P. C. Mechanical Behavior of Polyurethane-based Small-diameter Vascular Grafts, 451-477 (Woodhead Publishing, 2016). \\\",\\\"19. Quicken, S., Delhaas, T., Mees, B. M. E. & Huberts, W. Haemodynamic optimisation of a dialysis graft design using a global optimisation approach. Int. J. Numer. Method Biomed. Eng. 37, e3423 (2020). \\\",\\\"20. Malek, A. M., Alper, S. L. & Izumo, S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 282, 2035-2042 (1999). \\\",\\\"21. van Haaften, E. E. et al. Decoupling the effect of shear stress and stretch on tissue growth & remodeling in a vascular graft. Tissue Eng. Part C. 24, 418-429 (2018). \\\",\\\"22. Koch, S. E. et al. A multi-cue bioreactor to evaluate the inflammatory and regenerative capacity of biomaterials under flow and stretch. J. Vis. Exp. 166, e61824 (2020). \\\",\\\"23. Wisse, E. et al. Molecular recognition in poly(ε-caprolactone)-based thermoplastic elastomers. Biomacromolecules 7, 3385-3395 (2006). \\\",\\\"24. Wissing, T. B. et al. Hemodynamic loads distinctively impact the secretory profile of biomaterial-activated macrophages - implications for in situ vascular tissue engineering. Biomater. Sci. 8, 132-147 (2019). \\\",\\\"25. Butler, H. J. et al. Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 11, 664-687 (2016). \\\",\\\"26. van den Broek, C. N. et al. Medium with blood-analog mechanical properties for cardiovascular tissue culturing. *Biorheology* **45**, 651–661 (2008). \\\",\\\"27. Hata, R. & Senoo, H. L-ascorbic acid 2-phosphate stimulates collagen accumulation, cell proliferation, and formation of a three-dimensional tissue like substance by skin fibroblasts. J. Cell Physiol. 138, 8-16 (1989). \\\",\\\"28. Cheng, C. et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 113, 2744-2753 (2006). \\\",\\\"29. Cheng, C. et al. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J. Clin. Invest. 117, 616-626 (2007). \\\",\\\"30. Seneviratne, A. N. et al. Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques. J. Mol. Cell Cardiol. 89, 168-172 (2015). \\\",\\\"31. Cheng, C. et al. Large variations in absolute wall shear stress levels within one species and between species. Atherosclerosis 195, 225-235 (2007). \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[507,63,927,521]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"32. Vogel, C. & Marcotte, E. M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227-232 (2012). \\\",\\\"33. Yan, C. & Boyd, D. B. Regulation of matrix metalloproteinase gene expression. J. Cell Physiol. 211, 19-26 (2007). \\\",\\\"34. Wissing, T. B. et al. Macrophage-driven biomaterial degradation depends on scaffold microarchitecture. Front. Bioeng. Biotechnol. 7, 87 (2019). \\\",\\\"35. Ramachandra, A. B., Humphrey, J. D. & Marsden, A. L. Gradual loading ameliorates maladaptation in computational simulations of vein graft growth and remodelling. J. R. Soc. Interface 14, 20160995 (2017). \\\",\\\"36. Ramachandra, A. B., Sankaran, S., Humphrey, J. D. & Marsden, A. L. Computational simulation of the adaptive capacity of vein grafts in response to increased pressure. J. Biomech. Eng. 137, 31009 (2015). \\\",\\\"37. Mortensen, M. & Valen-Sendstad, K. Oasis: a high-level/high-performance open source Navier-Stokes solver. Comput. Phys. Commun. 188, 177-188 (2015). \\\",\\\"38. Logg, A., Mardal, K. & Wells, G. N. Automated Solution of Differential Equations by the Finite Element Method, Vol. 84 (Springer-Verlag, 2012). \\\",\\\"39. Hoffman, J. et al. *Unicorn: parallel adaptive finite element simulation of turbulent flow and fluid-structure interaction for deforming domains and complex geometry*. Comput. Fluid **80**, 310–319 (2013). \\\",\\\"40. Schnell, A. M. et al. Optimal cell source for cardiovascular tissue engineering: venous vs. aortic human myofibroblasts. Thorac. Cardiovasc. Surg. 49, 221-225 (2001). \\\",\\\"41. Mol, A. et al. Autologous human tissue-engineered heart valves: prospects for systemic application. Circulation 114, 152-158 (2006). \\\",\\\"42. Mol, A. et al. Fibrin as a cell carrier in cardiovascular tissue engineering applications. Biomaterials 26, 3113-3121 (2005). \\\",\\\"43. Farndale, R. W., Buttle, D. J. & Barrett, A. J. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim. Biophys. Acta 883, 173-177 (1986). \\\",\\\"44. Huszar, G., Maiocco, J. & Naftolin, F. Monitoring of collagen and collagen fragments in chromatography of protein mixtures. *Anal. Biochem.* **105**, 424–429 (1980). \\\",\\\"45. Boerboom, R. A. et al. High resolution imaging of collagen organisation and synthesis using a versatile collagen specific probe. J. Struct. Biol. 159, 392-399 (2007). \\\",\\\"46. van Haaften, E. E et al. Data underlying the publication: Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue, 4TU.ResearchData [Computed software] https://doi.org/10.4121/14292383.v1 (2021). \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[505,539,643,552]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,552,927,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors would like to thank Suzanne Koch and Tamar Wissing for their assistance in the in vitro experiments, Marina van Doeselaar and Marloes Janssen-van den Broek for their assistance in the sample analysis, and Anthal Smits for the fruitful discussions. This study is financially supported by ZonMw as part of the LSH 2Treat program (436001003) and the Dutch Kidney Foundation (14a2d507). N.A.K. acknowledges support from the European Research Council (851960). We gratefully acknowledge the Gravitation Program \\\"Materials Driven Regeneration\\\", funded by the Netherlands Organization for Scientific Research (024.003.013). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,657,653,668]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author contributions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,668,927,737]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C.V.C.B. and N.A.K. contributed equally. Author contributions according to the CRediT Taxonomy are as follows: conceptualization: all; formal analysis: E.E.v.H., C.V.C.B., and N.A.K.; investigation: E.E.v.H. and S.Q.; software: S.Q. and W.H.; funding acquisition: C.V.C.B.; supervision: N.A.K., C.V.C.B., and W.H.; visualization: E.E.v.H.; writing—original draft preparation: E.E.v.H.; writing—review and editing: all. All authors have approved the final article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,751,648,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Competing interests \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,765,927,799]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"N.A.K. is an Editorial Board Member for Communications Biology, but was not involved in the editorial review of, nor the decision to publish this article. Other authors declare no competing interests. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,814,665,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Additional information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,827,900,850]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s42003-021-02065-6. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,860,875,872]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Correspondence and requests for materials should be addressed to C.V.C.B. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,883,917,895]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reprints and permission information is available at http://www.nature.com/reprints \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,902,927,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,529,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02065-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[828,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,957,665,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY| (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": 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To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,209,179,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© The Author(s) 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n 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\"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMMUNICATIONS BIOLOGY | (2021)4:546 | https://doi.org/10.1038/s42003-021-02065-6 | www.nature.com/commsbio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1038/s42003-021-02065-6"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Materials Science and Engineering"},"sha256":{"kind":"string","value":"55ad70a3b799c61b61374b29de4843cfb8d6fd0d6733f70ad0ba98a0005ab962"},"title":{"kind":"string","value":"Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue"}}},{"rowIdx":146,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":""},"content_list":{"kind":"list like","value":[{"bbox":"[366,143,631,162]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supporting Information for ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[132,242,868,324]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fluorescent Molecular Cages with Sucrose and Cyclotriveratrylene Units for the Selective Recognition of Choline and Acetylcholine ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[159,357,836,376]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Łukasz Szyszka,* Marcin Górecki, Piotr Cmoch, and Sławomir Jarosz* ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[144,388,850,407]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[388,420,611,437]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"01-224 Warsaw, Poland","text_format":null,"text_level":null,"type":"text"},{"bbox":"[860,928,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[115,83,347,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table of Contents ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,134,880,151]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table S1. Comparison of ${}^{1}\\mathrm{H}$ and ${}^{13}\\mathrm{C}$ NMR signals of P-5a,P-5b,M-5a,and M-5b. S3 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,156,880,171]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure S1-S12. Fluorescence titration experiments.. .S5 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,177,880,192]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table S2. Fit parameters.. .S9 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,197,880,212]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure S13-S22. $^1\\mathsf{H}$ NMR titration experiments.. .S9 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,219,880,234]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure S23-S71. NMR spectra . S15 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,239,880,254]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure S72-S80. MS spectra . 64 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,260,880,275]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geometry of calculated structures. S73 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[860,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[77,107,894,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0416/eb7ccfbc56b3ed28561e3dcc0f27ddc4a966c5329dcb87833301328516d06662.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td></td><td colspan=\"4\">\\( ^1\\text{H} \\) and \\( ^{13}\\text{C} \\) NMR chemical shifts δ (ppm)</td></tr><tr><td>Glucose part</td><td>P-5a</td><td>P-5b</td><td>M-5a</td><td>M-5b</td></tr><tr><td>H-1/C-1</td><td>5.19/90.7</td><td>5.55/88.7</td><td>5.60/91.4</td><td>5.54/88.9</td></tr><tr><td>H-2/C-2</td><td>3.30/79.9</td><td>3.61/79.3</td><td>3.38/79.7</td><td>3.64/79.5</td></tr><tr><td>H-3/C-3</td><td>3.79/81.6</td><td>3.92/82.3</td><td>3.72/81.4</td><td>3.93/82.4</td></tr><tr><td>H-4/C-4</td><td>3.56/77.5</td><td>3.57/78.0</td><td>3.41/77.7</td><td>3.70/77.9</td></tr><tr><td>H-5/C-5</td><td>3.81/70.6</td><td>4.13/69.9</td><td>3.90/70.4</td><td>4.19/69.4</td></tr><tr><td>H-6a+H-6b/C-6</td><td>3.17+3.53/68.1</td><td>3.26+3.31/67.6</td><td>3.06+3.39/67.9</td><td>3.20+3.46/65.9</td></tr><tr><td>Fructose part</td><td></td><td></td><td></td><td></td></tr><tr><td>H-1'a+H-1'b/C-1'</td><td>3.45+3.65/69.9</td><td>3.58+3.71/74.8</td><td>3.66+3.72/69.1</td><td>3.43+3.80/74.8</td></tr><tr><td>C-2'</td><td>104.1</td><td>104.0</td><td>104.6</td><td>103.0</td></tr><tr><td>H-3'/C-3'</td><td>4.38/84.1</td><td>4.24/82.5</td><td>4.35/84.9</td><td>4.29/83.4</td></tr><tr><td>H-4'/C-4'</td><td>3.83/82.4</td><td>3.53/81.3</td><td>4.03/83.1</td><td>3.06/81.8</td></tr><tr><td>H-5'/C-5'</td><td>4.07/80.9</td><td>3.32/79.2</td><td>3.92/80.8</td><td>3.76/77.6</td></tr><tr><td>H-6'a+H-6'b/C-6'</td><td>3.36+3.54/73.0</td><td>2.84+3.37/70.9</td><td>3.46+3.49/73.1</td><td>2.25+2.95/72.7</td></tr><tr><td>Naphthalene linkers</td><td></td><td></td><td></td><td></td></tr><tr><td>H-7a+H-7b/C-7</td><td>4.15+4.45/73.1</td><td>4.23+4.78/73.0</td><td>4.04+4.64/73.4</td><td>4.23+4.94/72.8</td></tr><tr><td>H-7'a+H-7'b/C-7'</td><td>4.30+4.46/72.5</td><td>3.95+4.21/72.6</td><td>4.34/72.3</td><td>3.73+3.96/71.6</td></tr><tr><td>H-7\"a+H-7\"b/C-7\"</td><td>4.27+4.76/73.0</td><td>4.58+4.66/74.4</td><td>4.50+5.07/73.9</td><td>4.59+4.67/74.2</td></tr><tr><td>C-8</td><td>135.9</td><td>135.3</td><td>135.4</td><td>135.4</td></tr><tr><td>C-8'</td><td>136.9</td><td>136.1</td><td>136.3</td><td>136.5</td></tr><tr><td>C-8\"</td><td>135.8</td><td>136.5</td><td>135.9</td><td>136.6</td></tr><tr><td>H-9/C-9</td><td>7.47/126.1</td><td>7.62/127.0</td><td>7.36/126.7</td><td>7.78/128.5</td></tr><tr><td>H-9'/C-9'</td><td>7.51/124.5</td><td>7.47/126.0</td><td>7.40/124.4</td><td>7.16/123.1</td></tr><tr><td>H-9\"/C-9\"</td><td>7.64/126.2</td><td>7.49/125.5</td><td>7.83/127.4</td><td>7.62/125.1</td></tr><tr><td>C-10</td><td>132.78/132.0</td><td>132.6</td><td>nd</td><td>132.8</td></tr><tr><td>C-10'</td><td>132.6</td><td>132.4</td><td>nd</td><td>132.2</td></tr><tr><td>C-10\"</td><td>132.6</td><td>132.82/132.3</td><td>nd</td><td>132.8</td></tr><tr><td>H-11/C-11</td><td>7.51/127.8</td><td>7.65/127.8</td><td>7.30/127.8</td><td>7.67/128.0</td></tr><tr><td>H-11'/C-11'</td><td>7.46/126.1</td><td>7.55/127.6</td><td>7.44/127.2</td><td>7.18/126.4</td></tr><tr><td>H-11\"/C-11\"</td><td>7.65/128.1</td><td>7.23/125.3</td><td>7.76/128.4</td><td>7.49/128.8</td></tr><tr><td>H-12/C-12</td><td>7.16/125.4</td><td>7.27/125.3</td><td>7.21/125.9</td><td>7.14/127.2</td></tr><tr><td>H-12'/C-12'</td><td>7.11/125.6</td><td>7.32/125.8</td><td>7.17/126.6</td><td>7.12/128.0</td></tr><tr><td>H-12\"/C-12\"</td><td>7.35/124.8</td><td>6.87/125.4</td><td>7.38/125.5</td><td>7.32/123.7</td></tr><tr><td>C-13</td><td>134.2</td><td>135.1</td><td>134.3</td><td>134.2</td></tr><tr><td>C-13'</td><td>133.3</td><td>133.5</td><td>133.6</td><td>131.1</td></tr><tr><td>C-13\"</td><td>135.3</td><td>134.7</td><td>134.9</td><td>135.2</td></tr><tr><td>H-14/C-14</td><td>7.46/126.3</td><td>7.57/125.9</td><td>7.45/126.6</td><td>7.58/128.1</td></tr><tr><td>H-14'/C-14'</td><td>6.94/126.8</td><td>7.06/126.3</td><td>6.84/128.2</td><td>6.55/129.9</td></tr><tr><td>H-14\"/C-14\"</td><td>7.77/125.4</td><td>7.56/126.3</td><td>7.73/126.3</td><td>7.70/124.1</td></tr><tr><td>C-15</td><td>132.78/132.0</td><td>132.8</td><td>nd</td><td>132.8</td></tr><tr><td>C-15'</td><td>132.5</td><td>132.2</td><td>nd</td><td>131.1</td></tr><tr><td>C-15\"</td><td>132.6</td><td>132.82/132.3</td><td>nd</td><td>132.5</td></tr><tr><td>H-16/C-16</td><td>7.39/127.7</td><td>7.55/128.2</td><td>7.23/128.0</td><td>7.69/128.2</td></tr><tr><td>H-16'/C-16'</td><td>6.68/127.7</td><td>6.79/127.6</td><td>6.98/127.9</td><td>6.14/126.9</td></tr><tr><td>H-16\"/C-16\"</td><td>7.58/127.9</td><td>7.52/127.7</td><td>7.79/128.0</td><td>7.49/127.6</td></tr><tr><td>H-17/C-17</td><td>7.02/126.2</td><td>7.38/126.5</td><td>7.02/126.3</td><td>7.52/128.2</td></tr><tr><td>H-17'/C-17'</td><td>6.88/125.6</td><td>6.91/126.3</td><td>7.01/125.0</td><td>6.49/124.9</td></tr><tr><td>H-17\"/C-17\"</td><td>7.36/126.3</td><td>7.04/125.4</td><td>7.48/127.2</td><td>7.21/125.3</td></tr><tr><td>H-18a+H-18b/C-18</td><td>4.81+5.24/71.4</td><td>4.87+5.09/71.3</td><td>5.31+5.40/70.2</td><td>3.94+4.87/70.6</td></tr><tr><td>H-18'a+H-18'b/C-18'</td><td>5.15+5.26/72.6</td><td>5.35+5.46/72.3</td><td>4.40+5.20/76.2</td><td>5.00+5.35/77.0</td></tr><tr><td>H-18\"a+H-18\"b/C-18\"</td><td>5.15+5.36/72.7</td><td>4.94+5.27/73.9</td><td>4.97+5.21/71.3</td><td>5.45+5.64/69.4</td></tr><tr><td>CTV-ring A</td><td></td><td></td><td></td><td></td></tr><tr><td>C-19</td><td>146.1</td><td>147.3</td><td>145.8</td><td>147.1</td></tr><tr><td>C-20</td><td>148.5</td><td>148.4</td><td>148.6</td><td>147.6</td></tr><tr><td>H-21/C-21</td><td>6.64/113.0</td><td>6.70/113.5</td><td>6.99/113.8</td><td>6.54/111.8</td></tr><tr><td>C-22</td><td>132.7</td><td>132.8</td><td>133.2</td><td>130.9</td></tr><tr><td>H-23a+H-23b/C-23</td><td>3.51+4.70/36.4</td><td>3.55+4.77/36.3</td><td>3.61+4.79/36.2</td><td>3.57+4.74/36.6</td></tr><tr><td>C-24</td><td>131.6</td><td>131.6</td><td>131.9</td><td>131.4</td></tr><tr><td>H-25/C-25</td><td>6.86/116.3</td><td>6.88/116.4</td><td>7.09/116.7</td><td>6.42/112.4</td></tr><tr><td>H-26/C-26 (OCH3)</td><td>3.40/55.5</td><td>3.60/56.0</td><td>3.92/56.3</td><td>3.02/54.5</td></tr><tr><td>CTV-ring B</td><td></td><td></td><td></td><td></td></tr><tr><td>C-19'</td><td>145.9</td><td>147.6</td><td>146.8</td><td>146.9</td></tr><tr><td>C-20'</td><td>149.1</td><td>149.1</td><td>150.3</td><td>148.0</td></tr><tr><td>H-21'/C-21'</td><td>6.67/113.4</td><td>6.81/114.4</td><td>6.64/113.5</td><td>7.19/113.7</td></tr><tr><td>C-22'</td><td>133.7</td><td>133.6</td><td>134.7</td><td>133.0</td></tr><tr><td>H-23'a+H-23'b/C-23'</td><td>3.47+4.70/36.4</td><td>3.57+4.77/36.6</td><td>3.51+4.74/36.5</td><td>3.67+4.79/36.0</td></tr><tr><td>C-24'</td><td>131.7</td><td>132.5</td><td>132.1</td><td>132.4</td></tr><tr><td>H-25'/C-25'</td><td>6.95/118.6</td><td>7.09/118.5</td><td>7.12/121.9</td><td>7.13/113.8</td></tr><tr><td>H-26'/C-26' (OCH3)</td><td>3.55/55.9</td><td>3.44/56.2</td><td>3.22/55.5</td><td>4.03/56.4</td></tr><tr><td>CTV-ring C</td><td></td><td></td><td></td><td></td></tr><tr><td>C-19\"</td><td>147.0</td><td>145.3</td><td>147.3</td><td>144.4</td></tr><tr><td>C-20\"</td><td>148.8</td><td>149.7</td><td>148.0</td><td>151.1</td></tr><tr><td>H-21\"/C-21\"</td><td>6.61/113.4</td><td>6.86/113.9</td><td>6.93/115.0</td><td>6.33/112.9</td></tr><tr><td>C-22\"</td><td>133.3</td><td>134.0</td><td>131.8</td><td>135.6</td></tr><tr><td>H-23\"a+H-23\"b/C-23\"</td><td>3.48+4.68/36.2</td><td>3.59+4.77/36.5</td><td>3.51+4.74/36.4</td><td>3.37+4.71/36.2</td></tr><tr><td>C-24\"</td><td>132.0</td><td>132.3</td><td>132.4</td><td>131.6</td></tr><tr><td>H-25\"/C-25\"</td><td>6.99/117.6</td><td>7.07/120.0</td><td>6.76/113.3</td><td>7.34/124.1</td></tr><tr><td>H-26\"/C-26\" (OCH3)</td><td>3.21/55.5</td><td>3.73/56.3</td><td>3.48/55.7</td><td>3.19/55.4</td></tr></table>","table_caption":"[\"Table S1. Comparison of ${}^{1}\\\\mathrm{H}$ and ${}^{13}\\\\mathrm{C}$ NMR signals of P-5a, P-5b, M-5a, and M-5b. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[860,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[77,78,890,388]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[860,928,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[161,126,594,141]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fluorescence titration curves for acetylcholine iodide ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[154,173,524,374]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0931/69772aa599264cfe38afcac90eea103bfb54e6d7c1adc721cdcd1a4d83677784.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[531,177,875,376]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0140/83a61b49136a068d9e246e5eb6a3bde6dab89955c205b3ac9d235c630b18b241.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[152,411,522,611]","code_body":null,"code_caption":null,"image_caption":"[\"FigureS1. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage P-5a. \"]","image_footnote":"[]","img_path":"images/0016/1a887597f377f40079fccc688c6beb33a3aea40ed60d9145f0d19d9521c737e9.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[524,412,870,611]","code_body":null,"code_caption":null,"image_caption":"[\"FigureS2. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage M-5a. \"]","image_footnote":"[]","img_path":"images/0414/5999347999979ad29295bb306c5794272d61bd7ebf192d74a5bee45c37eb60a8.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[287,657,715,887]","code_body":null,"code_caption":null,"image_caption":"[\"FigureS3. Fluorescence titration of host P-5b with ACh in $\\\\mathrm{CH}_3\\\\mathrm{CN}$ excited at $280~\\\\mathrm{nm}$ . \"]","image_footnote":"[]","img_path":"images/0837/73a8ee8fadd68eb7c0ce1b1ee762d78e59342fd950d541a9736a20900a938d93.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[115,83,453,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fluorescence titration experiments ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[860,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[154,84,517,281]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0990/dd5eb05189bf69f978712bb51a51362d953e0743674334abe0820902ca2f5094.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[522,86,860,284]","code_body":null,"code_caption":null,"image_caption":"[\"FigureS4. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage P-5b. \"]","image_footnote":"[]","img_path":"images/0570/fc41c01606d7afc4409a584959794360380f544cfff7dbe7c7bd1563697bbb30.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[290,330,714,558]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S5. Fluorescence titration of host M-5b with ACh in $\\\\mathrm{CH}_3\\\\mathrm{CN}$ excited at $280~\\\\mathrm{nm}$ . \"]","image_footnote":"[]","img_path":"images/0864/7f70526c0b0fede270864ef2de14fef2a6a284d79dae03f8960cf13c32556635.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[154,623,515,822]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0016/075e2e4c59bb5bdcacc9e9a533ae30c1356e4991d922f769d71ddc787821ae49.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[522,624,860,822]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S6. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage M-5b. \"]","image_footnote":"[]","img_path":"images/0865/4b0844bc9f9ea8914be498031b6f56707e9a2ce5e0f531cbc89efdc07e00897d.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[860,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[159,127,519,326]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0316/97341d0dff524ff1ae3bbb747f7c392f1bb7b8cfb66fdabdd48d29701390dc48.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[522,127,867,326]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S7. Fluorescence intensity and molefraction as a function of guest/host ratio for cage P-5a. \"]","image_footnote":"[]","img_path":"images/0758/a3db01457fcb0e0b59f08cbfbdaf0dcc54c476a7fdc76b817d04096c39163296.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[154,378,524,577]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0756/613a9726c4a1b51d69e571d8aec1dc013752ad2e0b6c6038239025889b540ae7.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[527,376,872,577]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S8. Fluorescence intensity and molefraction as a function of guest/host ratio for cage M-5a. \"]","image_footnote":"[]","img_path":"images/0098/1af02b60933327fe5a4474142cd07e176c4b91134a2572b5b99c658be805d0bc.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[295,624,715,851]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S9. Fluorescence titration of host P-5b with Ch in $\\\\mathrm{CH}_3\\\\mathrm{CN}$ excited at $280~\\\\mathrm{nm}$ . \"]","image_footnote":"[]","img_path":"images/0943/4e26b655aa035490fe6afb2ff77736d4da717766a1630718b6dc607f10294f15.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[161,82,547,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fluorescence titration curves for choline iodide ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[860,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[154,85,524,284]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0917/92dd7199a481d23898bf5818ec4d9f4b650d666fe96df5b530c87e20726efb64.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[527,85,875,284]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S10. Fluorescence intensity and molefraction as a function of guest/host ratio for cage P-5b. \"]","image_footnote":"[]","img_path":"images/0410/bcfc3fdb6cd29e9debcad74173afec507920b22ceb01bfa59507abafc023fca2.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[285,332,712,558]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S11. Fluorescence titration of host M-5b with Ch in $\\\\mathrm{CH}_3\\\\mathrm{CN}$ excited at $280~\\\\mathrm{nm}$ . \"]","image_footnote":"[]","img_path":"images/0333/70558699593e73f058532e6f1059dd1d943bdef9525f25e2f843b3d249ad654a.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[154,606,515,807]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0294/ec01f2e4857a01a838f1bb51f224c18420464af5c7699bebcca200eb444bf677.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[522,606,867,806]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S12. Fluorescence intensity and molefraction as a function of guest/host ratio for cage M-5b. \"]","image_footnote":"[]","img_path":"images/0473/2eaf823f086b9b2c696abf45f28e4767fa59d6a316565744862e207d190f29bc.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[860,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[144,82,265,97]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fit parameters ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[136,129,892,262]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0488/90ee1e10e49f3408512cc605f6061e34ae4c76722184484692d993defef96c01.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td>Host</td><td>Guest</td><td>Ka(M-1)</td><td>RMS (Intensity a.u.)</td><td>Covariance</td></tr><tr><td rowspan=\"2\">P-5a</td><td>ACh</td><td>2.2 × 103± 1.6%</td><td>1.0 × 103</td><td>2.1 × 10-2</td></tr><tr><td>Ch</td><td>3.8 × 103± 0.9%</td><td>1.6 × 103</td><td>8.5 × 10-3</td></tr><tr><td rowspan=\"2\">M-5a</td><td>ACh</td><td>5.6 × 103± 1.7%</td><td>2.2 × 103</td><td>1.8 × 10-2</td></tr><tr><td>Ch</td><td>1.8 × 103± 1.4%</td><td>1.8 × 103</td><td>2.2 × 10-2</td></tr><tr><td rowspan=\"2\">P-5b</td><td>ACh</td><td>2.4 × 103± 3.5%</td><td>6.1 × 103</td><td>7.2 × 10-2</td></tr><tr><td>Ch</td><td>2.6 × 103± 3.8%</td><td>2.6 × 103</td><td>2.8 × 10-2</td></tr><tr><td rowspan=\"2\">M-5b</td><td>ACh</td><td>0.6 × 103± 0.9%</td><td>2.8 × 103</td><td>1.7 × 10-2</td></tr><tr><td>Ch</td><td>0.5 × 103± 1.1%</td><td>2.6 × 103</td><td>2.8 × 10-2</td></tr></table>","table_caption":"[\"Table S2. Fit parameters obtained from the fluorescence titrations. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[124,335,887,684]","code_body":null,"code_caption":null,"image_caption":"[\"$^{1}$ H NMR titration experiments \",\"Figure S13. ${}^{1}\\\\mathrm{H}$ NMR (400 MHz, $\\\\mathrm{CD}_3\\\\mathrm{CN} / \\\\mathrm{CDCl}_3 = 80:20$ ) spectra of M-5a after gradual addition of acetylcholine iodide in the same solvent. 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HRMS spectrum of compound M-5a. \"]","image_footnote":"[]","img_path":"images/0774/c349be6551309709389f5b6269a07c28de5204ed759c2818f1f6fdd902c3cb11.jpg","list_items":null,"page_idx":"65","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[894,897,915,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"65","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S66 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[126,144,879,823]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0218/c8b6ca745af1cee5642d8c7110b479ed681691b622b80105e00ed6a7ecfa3ded.jpg","list_items":null,"page_idx":"66","sub_type":null,"table_body":"<table><tr><td>Mass</td><td>Calc. Mass</td><td>mDa</td><td>PPM</td><td>DBE</td><td>Formula</td><td>i-FIT</td><td>i-FIT Norm</td><td>Fit Conf %</td><td>C</td><td>H</td><td>O</td><td>Na</td></tr><tr><td>1679.6836</td><td>1679.6858</td><td>-2.2</td><td>-1.3</td><td>57.5</td><td>C107 H100 O17 Na</td><td>97.7</td><td>n/a</td><td>n/a</td><td>107</td><td>100</td><td>17</td><td>1</td></tr><tr><td colspan=\"11\">z04_s1217 12 (0.259)</td><td colspan=\"2\">1: TOF MS ES+2.53e3</td></tr><tr><td rowspan=\"8\">100</td><td colspan=\"4\">[M+Na]+</td><td colspan=\"8\">1680.69</td></tr><tr><td colspan=\"4\">1679.69</td><td colspan=\"8\">1681.68</td></tr><tr><td colspan=\"4\">[ M+NH4]+</td><td colspan=\"8\">1682.68</td></tr><tr><td colspan=\"4\">1674.72</td><td colspan=\"8\">1683.68</td></tr><tr><td colspan=\"4\">1679.46</td><td colspan=\"8\">1685</td></tr><tr><td colspan=\"4\">1685</td><td colspan=\"8\">1690</td></tr><tr><td colspan=\"4\">1700</td><td colspan=\"8\">1705</td></tr><tr><td colspan=\"4\">1710</td><td colspan=\"8\">1715</td></tr></table>","table_caption":"[\"Elements Used: \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[366,838,629,860]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"66","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure S75. 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ESI-MS spectrum of adduct $[P - 5a + \\\\mathrm{Ch}]^{+}$ . \"]","image_footnote":"[]","img_path":"images/0788/a822bacf19c824cb7bec9ac3955e80861f3a614489a66238afcc204fdacce7cd.jpg","list_items":null,"page_idx":"68","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[894,897,915,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"68","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S69 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[116,117,873,800]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S78. ESI-MS spectrum of adduct $[P - 5a + ACh]^+$ . \"]","image_footnote":"[]","img_path":"images/0078/aba4b31aedaca62e1e7f0b1dfee17afc17f928f3de4c765a6f91a9ba7178dafe.jpg","list_items":null,"page_idx":"69","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[894,897,916,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"69","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S70 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[85,117,130,136]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"70","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KN3_Ch ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[86,136,209,147]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"70","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"z04_1s180 17 (0.364) Cm (17:27-(4:14+35:42)) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[818,134,863,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"70","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1:TOF MS ES+ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[841,146,863,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"70","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.05e4 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[86,146,863,818]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S79. ESI-MS spectrum of adduct $[M - 5a + Ch]^{+}$ . \"]","image_footnote":"[]","img_path":"images/0881/8fda6523444f32dedb387502a50458b96c961a982334ddf60297a654c42c655f.jpg","list_items":null,"page_idx":"70","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[892,897,915,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"70","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S71 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[105,114,884,815]","code_body":null,"code_caption":null,"image_caption":"[\"Figure S80. ESI-MS spectrum of adduct $[M - 5a + ACh]^+$ . \"]","image_footnote":"[]","img_path":"images/0464/678e558287f69025ca115027eb421a069a224499812441ce65b6670a08017445.jpg","list_items":null,"page_idx":"71","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[892,897,916,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"71","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S72 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[115,83,445,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"72","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geometry of calculated structures 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,195,485,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0099/9e206501eae78bdcbbfcd7f9ae627e66104293070d07ef0ab4922b5873bbd644.jpg","list_items":null,"page_idx":"72","sub_type":null,"table_body":"<table><tr><td>C</td><td>7.04048300</td><td>2.16352500</td><td>0.03090500</td></tr><tr><td>C</td><td>7.39308900</td><td>1.65453100</td><td>-1.36290000</td></tr><tr><td>C</td><td>6.15137000</td><td>1.04199700</td><td>-2.03362000</td></tr><tr><td>C</td><td>4.70910400</td><td>2.52736100</td><td>-0.81529100</td></tr><tr><td>C</td><td>5.88632200</td><td>3.15908300</td><td>-0.04844500</td></tr><tr><td>O</td><td>5.14509900</td><td>2.03469400</td><td>-2.08835300</td></tr><tr><td>O</td><td>8.23163000</td><td>2.74531400</td><td>0.55846900</td></tr><tr><td>O</td><td>8.43143400</td><td>0.68181500</td><td>-1.29949700</td></tr><tr><td>O</td><td>5.76710000</td><td>-0.09268500</td><td>-1.27973100</td></tr><tr><td>O</td><td>5.52997300</td><td>3.51344000</td><td>1.28554900</td></tr><tr><td>C</td><td>3.59479100</td><td>3.52440700</td><td>-1.12896300</td></tr><tr><td>O</td><td>3.04611100</td><td>3.96104700</td><td>0.11556800</td></tr><tr><td>C</td><td>5.78723300</td><td>-3.21146000</td><td>-0.47286000</td></tr><tr><td>C</td><td>7.13560800</td><td>-2.82310900</td><td>-1.06694500</td></tr><tr><td>C</td><td>5.42737000</td><td>-1.34221700</td><td>-1.89827700</td></tr><tr><td>C</td><td>6.69760500</td><td>-2.11835900</td><td>-2.35525100</td></tr><tr><td>O</td><td>4.90001800</td><td>-2.12649200</td><td>-0.83860900</td></tr><tr><td>O</td><td>7.69496700</td><td>-1.36726700</td><td>-3.00401900</td></tr><tr><td>C</td><td>4.38803900</td><td>-1.21957600</td><td>-3.03351500</td></tr><tr><td>C</td><td>5.72144800</td><td>-3.45721300</td><td>1.02269700</td></tr><tr><td>O</td><td>3.37239700</td><td>-0.254443300</td><td>-2.86726100</td></tr><tr><td>H</td><td>7.71678400</td><td>2.50380400</td><td>-1.98078800</td></tr><tr><td>H</td><td>6.38495900</td><td>-2.89239500</td><td>-3.06824900</td></tr><tr><td>H</td><td>7.64124500</td><td>-2.10057000</td><td>-0.41267500</td></tr><tr><td>H</td><td>5.44250100</td><td>-4.13044600</td><td>-0.96944500</td></tr><tr><td>H</td><td>6.72932200</td><td>1.31028400</td><td>0.64925800</td></tr><tr><td>H</td><td>6.23206700</td><td>4.04788700</td><td>-0.60103500</td></tr><tr><td>H</td><td>4.29579100</td><td>1.70708400</td><td>-0.21597800</td></tr><tr><td>H</td><td>3.99499700</td><td>4.38130200</td><td>-1.69133600</td></tr><tr><td>H</td><td>2.83073200</td><td>3.03592700</td><td>-1.74565100</td></tr><tr><td>H</td><td>3.97809400</td><td>-2.22910400</td><td>-3.18777100</td></tr><tr><td>H</td><td>4.66352700</td><td>-3.50728800</td><td>1.31666400</td></tr><tr><td>H</td><td>4.90559400</td><td>-0.92962500</td><td>-3.95451600</td></tr><tr><td>C</td><td>-3.91871600</td><td>-4.22891900</td><td>1.07533900</td></tr><tr><td>C</td><td>-4.24732300</td><td>-3.31916200</td><td>2.08119500</td></tr><tr><td>C</td><td>-4.74506300</td><td>-4.30039100</td><td>-0.06495900</td></tr><tr><td>C</td><td>-5.36360800</td><td>-2.46839500</td><td>1.99093700</td></tr><tr><td>H</td><td>-3.62937800</td><td>-3.26423800</td><td>2.97038700</td></tr><tr><td>C</td><td>-5.86599600</td><td>-3.48308500</td><td>-0.14066100</td></tr><tr><td>C</td><td>-6.19771800</td><td>-2.55626300</td><td>0.86226700</td></tr><tr><td>H</td><td>-6.51555400</td><td>-3.58276000</td><td>-1.00598700</td></tr><tr><td>C</td><td>-2.93528500</td><td>1.13594000</td><td>3.72625400</td></tr><tr><td>C</td><td>-3.60205000</td><td>2.32731800</td><td>3.36573000</td></tr><tr><td>C</td><td>-3.61897300</td><td>-0.07222200</td><td>3.62803600</td></tr><tr><td>C</td><td>-4.88042900</td><td>2.23454600</td><td>2.81708500</td></tr><tr><td>C</td><td>-4.92811100</td><td>-0.16774500</td><td>3.12797800</td></tr><tr><td>H</td><td>-3.10086600</td><td>-0.96407800</td><td>3.97056600</td></tr><tr><td>C</td><td>-5.54983300</td><td>1.00862300</td><td>2.67200300</td></tr><tr><td>H</td><td>-5.39399900</td><td>3.14048700</td><td>2.51561900</td></tr><tr><td>C</td><td>-6.49849900</td><td>1.81162900</td><td>-1.71158100</td></tr><tr><td>C</td><td>-6.87819400</td><td>0.59694300</td><td>-2.32822800</td></tr><tr><td>C</td><td>-6.53004600</td><td>1.89873800</td><td>-0.32563100</td></tr><tr><td>C</td><td>-7.18659700</td><td>-0.49533400</td><td>-1.52112800</td></tr><tr><td>C</td><td>-6.87856000</td><td>0.81174100</td><td>0.49627200</td></tr><tr><td>H</td><td>-6.28044700</td><td>2.85868100</td><td>0.11780300</td></tr><tr><td>C</td><td>-7.17278600</td><td>-0.41695400</td><td>-0.11614900</td></tr><tr><td>O</td><td>-6.92835600</td><td>0.59662200</td><td>-3.69387500</td></tr><tr><td>O</td><td>-2.94794100</td><td>3.50327900</td><td>3.60478400</td></tr><tr><td>C</td><td>-7.35670600</td><td>-0.59186100</td><td>-4.35330400</td></tr><tr><td>H</td><td>-7.34630400</td><td>-0.36000700</td><td>-5.41920600</td></tr><tr><td>H</td><td>-6.67641300</td><td>-1.42931200</td><td>-4.15640600</td></tr><tr><td>H</td><td>-8.37247400</td><td>-0.87142300</td><td>-4.04914000</td></tr><tr><td>C</td><td>-3.57219200</td><td>4.71924800</td><td>3.20152600</td></tr><tr><td>H</td><td>-3.75084500</td><td>4.73712900</td><td>2.11982100</td></tr><tr><td>H</td><td>-4.52002000</td><td>4.87617500</td><td>3.73015900</td></tr><tr><td>H</td><td>-2.87314700</td><td>5.51318400</td><td>3.46805700</td></tr><tr><td>C</td><td>-5.62458900</td><td>-1.52806000</td><td>3.16474400</td></tr><tr><td>H</td><td>-5.29029600</td><td>-2.03887000</td><td>4.07489800</td></tr><tr><td>H</td><td>-6.70021700</td><td>-1.38238800</td><td>3.29137700</td></tr><tr><td>C</td><td>-6.91916500</td><td>1.03571200</td><td>2.00665600</td></tr><tr><td>H</td><td>-7.36665100</td><td>2.01945900</td><td>2.18848300</td></tr><tr><td>H</td><td>-7.59071000</td><td>0.31441900</td><td>2.47754300</td></tr><tr><td>H</td><td>-7.46399600</td><td>-1.43645000</td><td>-1.98242100</td></tr><tr><td>C</td><td>-7.44697200</td><td>-1.70258000</td><td>0.65703000</td></tr><tr><td>H</td><td>-8.17342600</td><td>-2.29611800</td><td>0.09055700</td></tr><tr><td>H</td><td>-7.92378000</td><td>-1.48543900</td><td>1.61531100</td></tr><tr><td>H</td><td>6.35759800</td><td>0.78008800</td><td>-3.07191800</td></tr><tr><td>H</td><td>4.67478000</td><td>3.98218300</td><td>1.22328100</td></tr><tr><td>H</td><td>9.09858900</td><td>1.01390700</td><td>-0.67391100</td></tr><tr><td>H</td><td>8.08963200</td><td>-0.74649600</td><td>-2.35320900</td></tr><tr><td>H</td><td>8.04976200</td><td>2.98128600</td><td>1.48271600</td></tr><tr><td>O</td><td>-2.85708800</td><td>-5.08452700</td><td>1.11457900</td></tr><tr><td>C</td><td>-1.99695400</td><td>-5.03240400</td><td>2.24872000</td></tr><tr><td>H</td><td>-1.53224700</td><td>-4.04458000</td><td>2.35486100</td></tr><tr><td>H</td><td>-2.53444300</td><td>-5.28125100</td><td>3.17203500</td></tr><tr><td>H</td><td>-1.22269800</td><td>-5.77975400</td><td>2.06864100</td></tr><tr><td>O</td><td>6.40144200</td><td>-2.43619800</td><td>1.73430800</td></tr><tr><td>H</td><td>6.17509900</td><td>-4.43805600</td><td>1.23680900</td></tr><tr><td>O</td><td>-6.21349100</td><td>2.93729400</td><td>-2.45149000</td></tr><tr><td>O</td><td>-1.66539800</td><td>1.11615200</td><td>4.25930500</td></tr><tr><td>C</td><td>-0.66778500</td><td>1.92290100</td><td>3.61979200</td></tr><tr><td>H</td><td>-0.59496200</td><td>2.88821600</td><td>4.13264500</td></tr><tr><td>H</td><td>-0.97008300</td><td>2.13412200</td><td>2.58652700</td></tr><tr><td>O</td><td>7.93010200</td><td>-3.97890100</td><td>-1.27194100</td></tr><tr><td>H</td><td>8.75219300</td><td>-3.68481400</td><td>-1.69768600</td></tr><tr><td>C</td><td>1.97535100</td><td>4.90032200</td><td>-0.00080400</td></tr><tr><td>H</td><td>2.28806800</td><td>5.75900200</td><td>-0.61169400</td></tr><tr><td>H</td><td>1.81705900</td><td>5.26091800</td><td>1.02167700</td></tr><tr><td>C</td><td>0.69146500</td><td>4.30565200</td><td>-0.55131900</td></tr><tr><td>C</td><td>-0.17740000</td><td>5.08306200</td><td>-1.28909700</td></tr><tr><td>C</td><td>0.34388000</td><td>2.95529100</td><td>-0.26839800</td></tr><tr><td>C</td><td>-1.41320400</td><td>4.56665200</td><td>-1.76549600</td></tr><tr><td>H</td><td>0.07569800</td><td>6.11664600</td><td>-1.51802500</td></tr><tr><td>C</td><td>-0.83290100</td><td>2.41575700</td><td>-0.73773400</td></tr><tr><td>H</td><td>1.02802400</td><td>2.34849400</td><td>0.31666000</td></tr><tr><td>C</td><td>-2.32711200</td><td>5.35410300</td><td>-2.51699300</td></tr><tr><td>C</td><td>-1.74379000</td><td>3.19776800</td><td>-1.50123500</td></tr><tr><td>H</td><td>-1.07783300</td><td>1.37706400</td><td>-0.53057200</td></tr><tr><td>C</td><td>-3.49646700</td><td>4.80922200</td><td>-2.99652200</td></tr><tr><td>H</td><td>-2.08388500</td><td>6.39485400</td><td>-2.71655600</td></tr><tr><td>C</td><td>-2.95075500</td><td>2.66449200</td><td>-2.02753500</td></tr><tr><td>C</td><td>-3.82013800</td><td>3.44311000</td><td>-2.76913900</td></tr><tr><td>H</td><td>-4.18077600</td><td>5.42298800</td><td>-3.57739600</td></tr><tr><td>H</td><td>-3.17610800</td><td>1.61484400</td><td>-1.85056000</td></tr><tr><td>C</td><td>2.50701500</td><td>-0.38592400</td><td>-1.72752200</td></tr><tr><td>H</td><td>2.05328900</td><td>0.60415000</td><td>-1.62661000</td></tr><tr><td>H</td><td>3.09250900</td><td>-0.58638700</td><td>-0.82612000</td></tr><tr><td>C</td><td>1.40888900</td><td>-1.41854600</td><td>-1.87891700</td></tr><tr><td>C</td><td>0.21130000</td><td>-1.07749200</td><td>-2.47792200</td></tr><tr><td>C</td><td>1.56768000</td><td>-2.73157000</td><td>-1.35241600</td></tr><tr><td>C</td><td>-0.87563700</td><td>-1.98899000</td><td>-2.53996400</td></tr><tr><td>H</td><td>0.07253600</td><td>-0.07514500</td><td>-2.87855500</td></tr><tr><td>C</td><td>0.53885000</td><td>-3.64391400</td><td>-1.40339700</td></tr><tr><td>H</td><td>2.51234200</td><td>-2.99460700</td><td>-0.88630300</td></tr><tr><td>C</td><td>-2.13529500</td><td>-1.63648900</td><td>-3.09487300</td></tr><tr><td>C</td><td>-0.71648600</td><td>-3.29664000</td><td>-1.97398400</td></tr><tr><td>H</td><td>0.66462100</td><td>-4.63799400</td><td>-0.98074800</td></tr><tr><td>C</td><td>-3.19368400</td><td>-2.51671000</td><td>-3.05265600</td></tr><tr><td>H</td><td>-2.26039700</td><td>-0.64778600</td><td>-3.52988900</td></tr><tr><td>C</td><td>-1.82460000</td><td>-4.18128700</td><td>-1.96023000</td></tr><tr><td>C</td><td>-3.05202300</td><td>-3.80362700</td><td>-2.46887200</td></tr><tr><td>H</td><td>-4.15874900</td><td>-2.22106000</td><td>-3.45669300</td></tr><tr><td>H</td><td>-1.71160000</td><td>-5.15522900</td><td>-1.49255200</td></tr><tr><td>C</td><td>6.10148700</td><td>-2.43140000</td><td>3.13521400</td></tr><tr><td>H</td><td>6.89726500</td><td>-1.83392500</td><td>3.59088800</td></tr><tr><td>H</td><td>6.16689000</td><td>-3.45035300</td><td>3.54351200</td></tr><tr><td>C</td><td>4.74497900</td><td>-1.82073300</td><td>3.42546900</td></tr><tr><td>C</td><td>4.53009200</td><td>-0.48654700</td><td>3.13633900</td></tr><tr><td>C</td><td>3.66845100</td><td>-2.59347500</td><td>3.93401700</td></tr><tr><td>C</td><td>3.26199500</td><td>0.11604200</td><td>3.31515500</td></tr><tr><td>H</td><td>5.34508300</td><td>0.12071900</td><td>2.74803000</td></tr><tr><td>C</td><td>2.41928200</td><td>-2.03745800</td><td>4.12193500</td></tr><tr><td>H</td><td>3.83488200</td><td>-3.64154800</td><td>4.17226300</td></tr><tr><td>C</td><td>3.03102700</td><td>1.48511200</td><td>3.00458800</td></tr><tr><td>C</td><td>2.17250800</td><td>-0.67499900</td><td>3.80654300</td></tr><tr><td>H</td><td>1.60211400</td><td>-2.64543800</td><td>4.50275600</td></tr><tr><td>C</td><td>1.77997400</td><td>2.02967200</td><td>3.15287400</td></tr><tr><td>H</td><td>3.85628800</td><td>2.08616900</td><td>2.63124200</td></tr><tr><td>C</td><td>0.88466200</td><td>-0.07852400</td><td>3.93442600</td></tr><tr><td>C</td><td>0.68079000</td><td>1.24226800</td><td>3.60333500</td></tr><tr><td>H</td><td>1.61501500</td><td>3.07676300</td><td>2.90976900</td></tr><tr><td>H</td><td>0.05263500</td><td>-0.68293200</td><td>4.28270700</td></tr><tr><td>C</td><td>-5.08237300</td><td>2.86100900</td><td>-3.36173500</td></tr><tr><td>H</td><td>-5.38510600</td><td>3.43452300</td><td>-4.24231900</td></tr><tr><td>H</td><td>-4.92797500</td><td>1.82501900</td><td>-3.66697000</td></tr><tr><td>O</td><td>-4.44770300</td><td>-5.23859400</td><td>-1.03376600</td></tr><tr><td>C</td><td>-4.24212400</td><td>-4.73543700</td><td>-2.36916800</td></tr><tr><td>H</td><td>-4.09311600</td><td>-5.63889200</td><td>-2.96847200</td></tr><tr><td>H</td><td>-5.14748200</td><td>-4.23773200</td><td>-2.73685000</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"72","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S73 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,487,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"73","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"73","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S74 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,487,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"74","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,819,307,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"74","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,848,371,862]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"74","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5336189 a.u. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"74","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S75 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,164,487,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0677/a8fe657d57ef49b701a0e9592636231c817df15bbe003d1f9afee79615c71102.jpg","list_items":null,"page_idx":"75","sub_type":null,"table_body":"<table><tr><td>C</td><td>-6.57531800</td><td>-2.47382400</td><td>-0.12229800</td></tr><tr><td>C</td><td>-7.20312100</td><td>-1.92903900</td><td>-1.39453600</td></tr><tr><td>C</td><td>-6.28117300</td><td>-0.87372100</td><td>-2.02995600</td></tr><tr><td>C</td><td>-4.34046600</td><td>-2.01955400</td><td>-1.16166700</td></tr><tr><td>C</td><td>-5.20835700</td><td>-3.06896200</td><td>-0.43508500</td></tr><tr><td>O</td><td>-5.02548300</td><td>-1.47830400</td><td>-2.30487900</td></tr><tr><td>O</td><td>-7.48712800</td><td>-3.44142900</td><td>0.39667000</td></tr><tr><td>O</td><td>-8.48104800</td><td>-1.36226500</td><td>-1.12405100</td></tr><tr><td>O</td><td>-6.15239100</td><td>0.22317400</td><td>-1.15447500</td></tr><tr><td>O</td><td>-4.64187800</td><td>-3.47641600</td><td>0.80228200</td></tr><tr><td>C</td><td>-3.04690900</td><td>-2.61804200</td><td>-1.71547700</td></tr><tr><td>O</td><td>-2.29699200</td><td>-3.10713300</td><td>-0.60188300</td></tr><tr><td>C</td><td>-6.97461500</td><td>2.84635600</td><td>0.27404700</td></tr><tr><td>C</td><td>-8.21068900</td><td>2.12200000</td><td>-0.25535600</td></tr><tr><td>C</td><td>-6.31873100</td><td>1.58936900</td><td>-1.61865300</td></tr><tr><td>C</td><td>-7.83355600</td><td>1.92176100</td><td>-1.73031800</td></tr><tr><td>O</td><td>-5.87696600</td><td>2.39970600</td><td>-0.56019700</td></tr><tr><td>O</td><td>-8.64237000</td><td>1.02461500</td><td>-2.45081000</td></tr><tr><td>C</td><td>-5.48329000</td><td>1.92358500</td><td>-2.88205500</td></tr><tr><td>C</td><td>-6.62774400</td><td>2.66676300</td><td>1.74087000</td></tr><tr><td>O</td><td>-4.19768300</td><td>2.45299900</td><td>-2.62465100</td></tr><tr><td>H</td><td>-7.31012500</td><td>-2.74750500</td><td>-2.12031000</td></tr><tr><td>H</td><td>-7.92711000</td><td>2.89303000</td><td>-2.23111300</td></tr><tr><td>H</td><td>-8.32232800</td><td>1.14387000</td><td>0.22837600</td></tr><tr><td>H</td><td>-7.11480700</td><td>3.92355800</td><td>0.10592200</td></tr><tr><td>H</td><td>-6.44520000</td><td>-1.65208500</td><td>0.59488400</td></tr><tr><td>H</td><td>-5.34834300</td><td>-3.93408100</td><td>-1.10518600</td></tr><tr><td>H</td><td>-4.09833900</td><td>-1.21821600</td><td>-0.45221100</td></tr><tr><td>H</td><td>-3.28308800</td><td>-3.43998500</td><td>-2.40680100</td></tr><tr><td>H</td><td>-2.48184500</td><td>-1.85554600</td><td>-2.26585900</td></tr><tr><td>H</td><td>-6.00603500</td><td>2.71230300</td><td>-3.43058400</td></tr><tr><td>H</td><td>-5.68513000</td><td>3.19641400</td><td>1.93641100</td></tr><tr><td>H</td><td>-5.42118000</td><td>1.04638000</td><td>-3.54001900</td></tr><tr><td>C</td><td>3.58460100</td><td>3.46648200</td><td>2.48785000</td></tr><tr><td>C</td><td>4.03641000</td><td>2.31871600</td><td>3.14065900</td></tr><tr><td>C</td><td>4.38391700</td><td>4.01711700</td><td>1.46490200</td></tr><tr><td>C</td><td>5.25025300</td><td>1.69181100</td><td>2.80641600</td></tr><tr><td>H</td><td>3.43759400</td><td>1.88917100</td><td>3.93578400</td></tr><tr><td>C</td><td>5.60154300</td><td>3.42097800</td><td>1.16177700</td></tr><tr><td>C</td><td>6.05660500</td><td>2.25736700</td><td>1.80398300</td></tr><tr><td>H</td><td>6.22697000</td><td>3.88876100</td><td>0.40637100</td></tr><tr><td>C</td><td>3.15713700</td><td>-2.42855800</td><td>2.98176800</td></tr><tr><td>C</td><td>3.88716000</td><td>-3.30718200</td><td>2.15202200</td></tr><tr><td>C</td><td>3.76080500</td><td>-1.24954900</td><td>3.40541600</td></tr><tr><td>C</td><td>5.15916300</td><td>-2.92311200</td><td>1.72882700</td></tr><tr><td>C</td><td>5.05372700</td><td>-0.87006200</td><td>3.01049200</td></tr><tr><td>H</td><td>3.18790600</td><td>-0.61607800</td><td>4.07710700</td></tr><tr><td>C</td><td>5.75358700</td><td>-1.71417600</td><td>2.13001900</td></tr><tr><td>H</td><td>5.72676500</td><td>-3.58801600</td><td>1.08749600</td></tr><tr><td>C</td><td>6.97048600</td><td>-0.77280900</td><td>-2.19094100</td></tr><tr><td>C</td><td>7.19045000</td><td>0.61947700</td><td>-2.28896500</td></tr><tr><td>C</td><td>6.96342900</td><td>-1.36613400</td><td>-0.93517100</td></tr><tr><td>C</td><td>7.33453600</td><td>1.35746100</td><td>-1.11598400</td></tr><tr><td>C</td><td>7.13222500</td><td>-0.63355900</td><td>0.25304000</td></tr><tr><td>H</td><td>6.83108600</td><td>-2.44374900</td><td>-0.89651600</td></tr><tr><td>C</td><td>7.29349500</td><td>0.75850500</td><td>0.15634300</td></tr><tr><td>O</td><td>7.26540000</td><td>1.13820300</td><td>-3.55073300</td></tr><tr><td>O</td><td>3.29327400</td><td>-4.49928800</td><td>1.84366700</td></tr><tr><td>C</td><td>7.48444400</td><td>2.53951400</td><td>-3.69197500</td></tr><tr><td>H</td><td>7.50830400</td><td>2.72922800</td><td>-4.76593900</td></tr><tr><td>H</td><td>6.67262400</td><td>3.11965500</td><td>-3.23640700</td></tr><tr><td>H</td><td>8.44018100</td><td>2.84055100</td><td>-3.24658900</td></tr><tr><td>C</td><td>3.96012600</td><td>-5.37204700</td><td>0.93568300</td></tr><tr><td>H</td><td>4.11831200</td><td>-4.89084400</td><td>-0.03699200</td></tr><tr><td>H</td><td>4.92347600</td><td>-5.70834500</td><td>1.33761000</td></tr><tr><td>H</td><td>3.30028600</td><td>-6.23218100</td><td>0.81319800</td></tr><tr><td>C</td><td>5.62440700</td><td>0.42856300</td><td>3.57651100</td></tr><tr><td>H</td><td>5.24844500</td><td>0.53724400</td><td>4.60014700</td></tr><tr><td>H</td><td>6.71015500</td><td>0.35069900</td><td>3.66899600</td></tr><tr><td>C</td><td>7.13809500</td><td>-1.39754600</td><td>1.57548200</td></tr><tr><td>H</td><td>7.66036300</td><td>-2.34680900</td><td>1.41014900</td></tr><tr><td>H</td><td>7.73199100</td><td>-0.85994400</td><td>2.31810900</td></tr><tr><td>H</td><td>7.50177900</td><td>2.42686300</td><td>-1.17721600</td></tr><tr><td>C</td><td>7.40049200</td><td>1.68184300</td><td>1.36539100</td></tr><tr><td>H</td><td>8.05709600</td><td>2.51811900</td><td>1.09992300</td></tr><tr><td>H</td><td>7.89013600</td><td>1.17295500</td><td>2.19833600</td></tr><tr><td>H</td><td>-6.67314900</td><td>-0.56892100</td><td>-3.00188900</td></tr><tr><td>H</td><td>-3.68856600</td><td>-3.61192800</td><td>0.63947700</td></tr><tr><td>H</td><td>-8.91992000</td><td>-1.94440600</td><td>-0.47895200</td></tr><tr><td>H</td><td>-8.73750300</td><td>0.20216000</td><td>-1.92272400</td></tr><tr><td>H</td><td>-7.13014900</td><td>-3.73718500</td><td>1.25009700</td></tr><tr><td>O</td><td>2.42356900</td><td>4.12170800</td><td>2.77670200</td></tr><tr><td>C</td><td>1.58421000</td><td>3.58109400</td><td>3.79263800</td></tr><tr><td>H</td><td>1.24861900</td><td>2.56795600</td><td>3.53885200</td></tr><tr><td>H</td><td>2.09166600</td><td>3.56169200</td><td>4.76488200</td></tr><tr><td>H</td><td>0.72085800</td><td>4.24579800</td><td>3.84896300</td></tr><tr><td>O</td><td>-6.52149200</td><td>1.29132500</td><td>2.06696900</td></tr><tr><td>H</td><td>-7.41261300</td><td>3.15428000</td><td>2.34183900</td></tr><tr><td>O</td><td>6.86909600</td><td>-1.56495000</td><td>-3.31441300</td></tr><tr><td>O</td><td>1.90084900</td><td>-2.71508500</td><td>3.46212600</td></tr><tr><td>C</td><td>0.90668100</td><td>-3.16362600</td><td>2.50868600</td></tr><tr><td>H</td><td>0.84845900</td><td>-4.25517500</td><td>2.53992800</td></tr><tr><td>H</td><td>1.21940100</td><td>-2.86854200</td><td>1.50253100</td></tr><tr><td>O</td><td>-9.36068200</td><td>2.92864600</td><td>-0.05139600</td></tr><tr><td>H</td><td>-10.11382700</td><td>2.44790500</td><td>-0.43223200</td></tr><tr><td>C</td><td>-1.20169600</td><td>-3.96076500</td><td>-0.92737400</td></tr><tr><td>H</td><td>-1.52991800</td><td>-4.75172500</td><td>-1.61681300</td></tr><tr><td>H</td><td>-0.93953300</td><td>-4.44043400</td><td>0.02239800</td></tr><tr><td>C</td><td>0.00992100</td><td>-3.24088700</td><td>-1.49103700</td></tr><tr><td>C</td><td>0.93919500</td><td>-3.93990500</td><td>-2.23578500</td></tr><tr><td>C</td><td>0.24184900</td><td>-1.86947200</td><td>-1.19983200</td></tr><tr><td>C</td><td>2.12999700</td><td>-3.32266000</td><td>-2.70117700</td></tr><tr><td>H</td><td>0.77330800</td><td>-4.99038800</td><td>-2.46817700</td></tr><tr><td>C</td><td>1.37232800</td><td>-1.23300100</td><td>-1.66288700</td></tr><tr><td>H</td><td>-0.48966000</td><td>-1.32571300</td><td>-0.61040700</td></tr><tr><td>C</td><td>3.11604800</td><td>-4.03114100</td><td>-3.44349100</td></tr><tr><td>C</td><td>2.34764200</td><td>-1.93447000</td><td>-2.42176600</td></tr><tr><td>H</td><td>1.53283700</td><td>-0.17975900</td><td>-1.44728200</td></tr><tr><td>C</td><td>4.25091500</td><td>-3.39581100</td><td>-3.89085900</td></tr><tr><td>H</td><td>2.95562000</td><td>-5.08515800</td><td>-3.65702100</td></tr><tr><td>C</td><td>3.52334200</td><td>-1.30751300</td><td>-2.91642200</td></tr><tr><td>C</td><td>4.46555100</td><td>-2.01105000</td><td>-3.64083400</td></tr><tr><td>H</td><td>4.99436900</td><td>-3.95008200</td><td>-4.45875700</td></tr><tr><td>H</td><td>3.66918500</td><td>-0.24770000</td><td>-2.71853500</td></tr><tr><td>C</td><td>-3.23000200</td><td>1.51827300</td><td>-2.13627600</td></tr><tr><td>H</td><td>-2.98509800</td><td>0.78329700</td><td>-2.91691000</td></tr><tr><td>H</td><td>-3.63797700</td><td>0.97583200</td><td>-1.27564700</td></tr><tr><td>C</td><td>-2.00729200</td><td>2.29391100</td><td>-1.71657100</td></tr><tr><td>C</td><td>-0.79268000</td><td>2.14132600</td><td>-2.34964700</td></tr><tr><td>C</td><td>-2.11756400</td><td>3.20911200</td><td>-0.63017300</td></tr><tr><td>C</td><td>0.35690100</td><td>2.86889100</td><td>-1.93035700</td></tr><tr><td>H</td><td>-0.69701500</td><td>1.45145500</td><td>-3.18552800</td></tr><tr><td>C</td><td>-1.02770500</td><td>3.92432600</td><td>-0.19639100</td></tr><tr><td>H</td><td>-3.08447600</td><td>3.33005900</td><td>-0.15047700</td></tr><tr><td>C</td><td>1.62041000</td><td>2.73188600</td><td>-2.56449100</td></tr><tr><td>C</td><td>0.24105200</td><td>3.77507700</td><td>-0.82637400</td></tr><tr><td>H</td><td>-1.11977100</td><td>4.61731300</td><td>0.63659200</td></tr><tr><td>C</td><td>2.71366700</td><td>3.44587300</td><td>-2.12170000</td></tr><tr><td>H</td><td>1.71683100</td><td>2.04771600</td><td>-3.40412000</td></tr><tr><td>C</td><td>1.38495900</td><td>4.49482400</td><td>-0.39893000</td></tr><tr><td>C</td><td>2.60699300</td><td>4.34109300</td><td>-1.02530700</td></tr><tr><td>H</td><td>3.67505600</td><td>3.32178400</td><td>-2.61466800</td></tr><tr><td>H</td><td>1.29799900</td><td>5.16121400</td><td>0.45404600</td></tr><tr><td>C</td><td>-5.93850300</td><td>1.01752400</td><td>3.35057500</td></tr><tr><td>H</td><td>-6.58862400</td><td>0.29251400</td><td>3.85261100</td></tr><tr><td>H</td><td>-5.92876500</td><td>1.93134900</td><td>3.95906600</td></tr><tr><td>C</td><td>-4.54349600</td><td>0.44585600</td><td>3.21264400</td></tr><tr><td>C</td><td>-4.29837500</td><td>-0.88463900</td><td>3.48130500</td></tr><tr><td>C</td><td>-3.46715700</td><td>1.26659200</td><td>2.76391800</td></tr><tr><td>C</td><td>-3.00766600</td><td>-1.45641200</td><td>3.30579600</td></tr><tr><td>H</td><td>-5.10732100</td><td>-1.52670300</td><td>3.82355500</td></tr><tr><td>C</td><td>-2.20848900</td><td>0.74832200</td><td>2.57752200</td></tr><tr><td>H</td><td>-3.64464100</td><td>2.32046300</td><td>2.56930600</td></tr><tr><td>C</td><td>-2.74295200</td><td>-2.82828100</td><td>3.55642900</td></tr><tr><td>C</td><td>-1.94004600</td><td>-0.62651500</td><td>2.83243900</td></tr><tr><td>H</td><td>-1.40143600</td><td>1.38497200</td><td>2.22343800</td></tr><tr><td>C</td><td>-1.49124500</td><td>-3.35775400</td><td>3.32646400</td></tr><tr><td>H</td><td>-3.54798000</td><td>-3.46098600</td><td>3.92110500</td></tr><tr><td>C</td><td>-0.66497200</td><td>-1.20414900</td><td>2.60870900</td></tr><tr><td>C</td><td>-0.43362600</td><td>-2.54900400</td><td>2.83344900</td></tr><tr><td>H</td><td>-1.30597300</td><td>-4.41277300</td><td>3.51296100</td></tr><tr><td>H</td><td>0.13647600</td><td>-0.57171400</td><td>2.23247700</td></tr><tr><td>C</td><td>5.71079100</td><td>-1.33656400</td><td>-4.16223100</td></tr><tr><td>H</td><td>6.00019100</td><td>-1.75914100</td><td>-5.12834000</td></tr><tr><td>H</td><td>5.55478700</td><td>-0.26289700</td><td>-4.28637000</td></tr><tr><td>O</td><td>3.96897800</td><td>5.18487500</td><td>0.85523000</td></tr><tr><td>C</td><td>3.81498400</td><td>5.13891900</td><td>-0.57414200</td></tr><tr><td>H</td><td>3.71546000</td><td>6.18997500</td><td>-0.86453700</td></tr><tr><td>H</td><td>4.72383600</td><td>4.75068500</td><td>-1.04854300</td></tr></table>","table_caption":"[\"Symbolic Z-matrix: \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,110,369,124]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"75","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conformation #2 (Pop. = 20.28%) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"75","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S76 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,489,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"76","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"76","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S77 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,485,760]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"77","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,777,307,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"77","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,804,371,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"77","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5324641 a.u. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"77","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S78 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[115,110,157,123]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"78","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"M-5a ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,137,369,152]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"78","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conformation #1 (Pop. = 81.87%) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,191,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0236/62f969cb93085ea7ed557e9bd066c3e294640fe5da3ace564c7dde3d6e76aa7e.jpg","list_items":null,"page_idx":"78","sub_type":null,"table_body":"<table><tr><td>C</td><td>-5.80016800</td><td>-0.71927100</td><td>3.10539100</td></tr><tr><td>C</td><td>-6.86809800</td><td>-1.52981300</td><td>2.38272100</td></tr><tr><td>C</td><td>-6.42566900</td><td>-1.82120200</td><td>0.94043400</td></tr><tr><td>C</td><td>-4.11168000</td><td>-1.81589900</td><td>1.59341900</td></tr><tr><td>C</td><td>-4.46098100</td><td>-1.45032300</td><td>3.04999700</td></tr><tr><td>O</td><td>-5.19618600</td><td>-2.51798400</td><td>0.96911900</td></tr><tr><td>O</td><td>-6.26107600</td><td>-0.53720000</td><td>4.44345000</td></tr><tr><td>O</td><td>-6.34247200</td><td>-0.58743500</td><td>0.25625900</td></tr><tr><td>C</td><td>-2.92890400</td><td>-2.77726700</td><td>1.49683700</td></tr><tr><td>O</td><td>-1.79427300</td><td>-2.16753000</td><td>2.11023900</td></tr><tr><td>C</td><td>-7.42087800</td><td>1.81154100</td><td>-1.50694600</td></tr><tr><td>C</td><td>-8.57397700</td><td>1.17992300</td><td>-0.73347800</td></tr><tr><td>C</td><td>-6.84792800</td><td>-0.44765300</td><td>-1.08363900</td></tr><tr><td>O</td><td>-6.38044700</td><td>0.80581400</td><td>-1.53225000</td></tr><tr><td>C</td><td>-6.33043800</td><td>-1.52750200</td><td>-2.03393300</td></tr><tr><td>O</td><td>-4.91984300</td><td>-1.56355600</td><td>-1.98220700</td></tr><tr><td>H</td><td>-6.98820900</td><td>-2.49541900</td><td>2.89382600</td></tr><tr><td>H</td><td>-8.42902500</td><td>1.32204800</td><td>0.34537500</td></tr><tr><td>H</td><td>-7.75614300</td><td>1.99295300</td><td>-2.53843800</td></tr><tr><td>H</td><td>-5.69366800</td><td>0.25353300</td><td>2.60619300</td></tr><tr><td>H</td><td>-4.55445800</td><td>-2.38203900</td><td>3.63268600</td></tr><tr><td>H</td><td>-3.88748900</td><td>-0.89682700</td><td>1.03841400</td></tr><tr><td>H</td><td>-3.18253400</td><td>-3.71608800</td><td>2.01207000</td></tr><tr><td>H</td><td>-2.72080100</td><td>-3.00695500</td><td>0.44362500</td></tr><tr><td>H</td><td>-6.68570300</td><td>-1.27423000</td><td>-3.04435400</td></tr><tr><td>H</td><td>-6.75682500</td><td>-2.50833600</td><td>-1.77054600</td></tr><tr><td>C</td><td>4.97649600</td><td>-3.41454300</td><td>-1.45188500</td></tr><tr><td>C</td><td>5.13722200</td><td>-2.40565100</td><td>-2.39325900</td></tr><tr><td>C</td><td>5.80674100</td><td>-3.42348100</td><td>-0.30960300</td></tr><tr><td>C</td><td>6.05895200</td><td>-1.35711800</td><td>-2.23292400</td></tr><tr><td>H</td><td>4.51273900</td><td>-2.45381500</td><td>-3.28084300</td></tr><tr><td>C</td><td>6.70790300</td><td>-2.37558900</td><td>-0.13078000</td></tr><tr><td>C</td><td>6.83550900</td><td>-1.32877600</td><td>-1.06197600</td></tr><tr><td>H</td><td>7.34762200</td><td>-2.36837200</td><td>0.74465500</td></tr><tr><td>C</td><td>2.77679100</td><td>1.45275400</td><td>-3.60871000</td></tr><tr><td>C</td><td>3.00315900</td><td>2.66765000</td><td>-2.91907200</td></tr><tr><td>C</td><td>3.82976500</td><td>0.55629800</td><td>-3.74590300</td></tr><tr><td>C</td><td>4.27747300</td><td>2.94405900</td><td>-2.43997500</td></tr><tr><td>C</td><td>5.10670500</td><td>0.80627100</td><td>-3.20457100</td></tr><tr><td>H</td><td>3.66600500</td><td>-0.37742600</td><td>-4.27161000</td></tr><tr><td>C</td><td>5.34056800</td><td>2.02564300</td><td>-2.55498900</td></tr><tr><td>H</td><td>4.46345700</td><td>3.89963800</td><td>-1.96071800</td></tr><tr><td>C</td><td>6.22350900</td><td>2.95537800</td><td>1.81699900</td></tr><tr><td>C</td><td>6.62532300</td><td>1.71405000</td><td>2.35644400</td></tr><tr><td>C</td><td>6.27760300</td><td>3.13111800</td><td>0.43444200</td></tr><tr><td>C</td><td>7.12829200</td><td>0.74447500</td><td>1.49579900</td></tr><tr><td>C</td><td>6.74699200</td><td>2.13191100</td><td>-0.43629100</td></tr><tr><td>H</td><td>5.96382500</td><td>4.07759900</td><td>0.00911400</td></tr><tr><td>C</td><td>7.21491100</td><td>0.92280200</td><td>0.10598100</td></tr><tr><td>O</td><td>6.65234100</td><td>1.43635600</td><td>3.70450300</td></tr><tr><td>O</td><td>1.92062500</td><td>3.49430900</td><td>-2.79587900</td></tr><tr><td>C</td><td>1.90294700</td><td>4.46718900</td><td>-1.74229200</td></tr><tr><td>H</td><td>2.54295500</td><td>4.12489600</td><td>-0.91905500</td></tr><tr><td>H</td><td>2.30593700</td><td>5.42075000</td><td>-2.10602900</td></tr><tr><td>C</td><td>6.14576200</td><td>-0.30220400</td><td>-3.33355800</td></tr><tr><td>H</td><td>5.98975500</td><td>-0.80549300</td><td>-4.29471300</td></tr><tr><td>H</td><td>7.15345600</td><td>0.11639400</td><td>-3.37901500</td></tr><tr><td>C</td><td>6.67948200</td><td>2.41626800</td><td>-1.93316700</td></tr><tr><td>H</td><td>6.82532900</td><td>3.49195700</td><td>-2.08524200</td></tr><tr><td>H</td><td>7.50320400</td><td>1.92744400</td><td>-2.45780200</td></tr><tr><td>H</td><td>7.46905700</td><td>-0.18298200</td><td>1.94752900</td></tr><tr><td>C</td><td>7.81448100</td><td>-0.20890900</td><td>-0.72702600</td></tr><tr><td>H</td><td>8.64209200</td><td>-0.64241400</td><td>-0.15386700</td></tr><tr><td>H</td><td>8.26412200</td><td>0.19161000</td><td>-1.63826600</td></tr><tr><td>H</td><td>-7.12895600</td><td>-2.49920500</td><td>0.45555200</td></tr><tr><td>H</td><td>-5.60396800</td><td>0.01867200</td><td>4.89375200</td></tr><tr><td>O</td><td>4.07414200</td><td>-4.42097200</td><td>-1.70642000</td></tr><tr><td>O</td><td>-6.57034600</td><td>2.99877400</td><td>0.41062400</td></tr><tr><td>O</td><td>-9.80567500</td><td>1.73618100</td><td>-1.16340200</td></tr><tr><td>H</td><td>-10.50716400</td><td>1.29965800</td><td>-0.65286500</td></tr><tr><td>C</td><td>3.06497700</td><td>-4.67528800</td><td>-0.69399800</td></tr><tr><td>H</td><td>3.19208100</td><td>-5.70885100</td><td>-0.35859000</td></tr><tr><td>H</td><td>3.23319000</td><td>-4.01880200</td><td>0.16218100</td></tr><tr><td>C</td><td>5.46290800</td><td>1.66122700</td><td>4.50362300</td></tr><tr><td>H</td><td>5.28361200</td><td>2.73309600</td><td>4.60398700</td></tr><tr><td>H</td><td>5.74620800</td><td>1.25905000</td><td>5.48001100</td></tr><tr><td>O</td><td>5.66776100</td><td>-4.48900000</td><td>0.53492500</td></tr><tr><td>O</td><td>5.82103900</td><td>3.91672600</td><td>2.70323500</td></tr><tr><td>O</td><td>1.51175700</td><td>1.25994400</td><td>-4.08571100</td></tr><tr><td>C</td><td>1.25496300</td><td>0.07205800</td><td>-4.82888400</td></tr><tr><td>H</td><td>1.41063000</td><td>-0.82594100</td><td>-4.21891000</td></tr><tr><td>H</td><td>0.20665200</td><td>0.12806800</td><td>-5.12594500</td></tr><tr><td>H</td><td>1.88647000</td><td>0.01700500</td><td>-5.72416900</td></tr><tr><td>C</td><td>6.45173600</td><td>-4.51142700</td><td>1.72466500</td></tr><tr><td>H</td><td>6.23640400</td><td>-3.64456300</td><td>2.36098700</td></tr><tr><td>H</td><td>6.17081900</td><td>-5.42635000</td><td>2.24830700</td></tr><tr><td>H</td><td>7.52407000</td><td>-4.53753600</td><td>1.49642500</td></tr><tr><td>C</td><td>5.41858000</td><td>5.18432600</td><td>2.18951900</td></tr><tr><td>H</td><td>4.54955400</td><td>5.09011500</td><td>1.52744300</td></tr><tr><td>H</td><td>5.14908700</td><td>5.78439600</td><td>3.05967300</td></tr><tr><td>H</td><td>6.23774400</td><td>5.67255500</td><td>1.64839400</td></tr><tr><td>C</td><td>-6.87247500</td><td>3.12158200</td><td>-0.97090000</td></tr><tr><td>H</td><td>-7.62408700</td><td>3.91081400</td><td>-1.13139900</td></tr><tr><td>H</td><td>-5.97588600</td><td>3.38742000</td><td>-1.54635100</td></tr><tr><td>C</td><td>-0.67801000</td><td>-3.04780200</td><td>2.19136500</td></tr><tr><td>H</td><td>-0.91391000</td><td>-3.89156700</td><td>2.85821300</td></tr><tr><td>H</td><td>-0.47975300</td><td>-3.47206200</td><td>1.19456500</td></tr><tr><td>C</td><td>-5.70817100</td><td>4.01731500</td><td>0.90547000</td></tr><tr><td>H</td><td>-5.72619200</td><td>3.89200800</td><td>1.99460100</td></tr><tr><td>H</td><td>-6.11276600</td><td>5.01617200</td><td>0.68212700</td></tr><tr><td>C</td><td>0.54732700</td><td>-2.31805500</td><td>2.68872200</td></tr><tr><td>C</td><td>0.67718200</td><td>-0.94849100</td><td>2.59861700</td></tr><tr><td>C</td><td>1.61709500</td><td>-3.08559100</td><td>3.23067800</td></tr><tr><td>C</td><td>1.85609900</td><td>-0.29019900</td><td>3.04705200</td></tr><tr><td>H</td><td>-0.13221600</td><td>-0.35434700</td><td>2.18502500</td></tr><tr><td>C</td><td>2.77291100</td><td>-2.48099300</td><td>3.66512200</td></tr><tr><td>H</td><td>1.51054000</td><td>-4.16523900</td><td>3.30609200</td></tr><tr><td>C</td><td>2.00974300</td><td>1.11994500</td><td>2.97625700</td></tr><tr><td>C</td><td>2.92905100</td><td>-1.06846600</td><td>3.59238600</td></tr><tr><td>H</td><td>3.57987900</td><td>-3.07809800</td><td>4.08280100</td></tr><tr><td>C</td><td>3.16032500</td><td>1.72770700</td><td>3.42860800</td></tr><tr><td>H</td><td>1.20249000</td><td>1.71603800</td><td>2.55761200</td></tr><tr><td>C</td><td>4.09654700</td><td>-0.40851900</td><td>4.05507400</td></tr><tr><td>C</td><td>4.22279900</td><td>0.96658300</td><td>3.98597000</td></tr><tr><td>H</td><td>3.26479400</td><td>2.80757500</td><td>3.36781100</td></tr><tr><td>H</td><td>4.90043300</td><td>-1.00663400</td><td>4.47994300</td></tr><tr><td>C</td><td>-4.28465700</td><td>3.90213100</td><td>0.38917500</td></tr><tr><td>C</td><td>-3.51924300</td><td>5.02410400</td><td>0.14860100</td></tr><tr><td>C</td><td>-3.72195800</td><td>2.61230000</td><td>0.17319400</td></tr><tr><td>C</td><td>-2.17471600</td><td>4.91981300</td><td>-0.30388900</td></tr><tr><td>H</td><td>-3.94239200</td><td>6.01583300</td><td>0.29882300</td></tr><tr><td>C</td><td>-2.43017600</td><td>2.47630600</td><td>-0.27491900</td></tr><tr><td>H</td><td>-4.34518100</td><td>1.73761400</td><td>0.32886100</td></tr><tr><td>C</td><td>-1.36297800</td><td>6.05599200</td><td>-0.56521700</td></tr><tr><td>C</td><td>-1.61992500</td><td>3.61784300</td><td>-0.52880000</td></tr><tr><td>H</td><td>-2.01098700</td><td>1.48753400</td><td>-0.44728600</td></tr><tr><td>C</td><td>-0.07358700</td><td>5.91262400</td><td>-1.03202200</td></tr><tr><td>H</td><td>-1.77776500</td><td>7.04770500</td><td>-0.40173000</td></tr><tr><td>C</td><td>-0.29154800</td><td>3.50690200</td><td>-1.00743200</td></tr><tr><td>C</td><td>0.47793600</td><td>4.62562300</td><td>-1.26105200</td></tr><tr><td>H</td><td>0.52967500</td><td>6.79403800</td><td>-1.23590100</td></tr><tr><td>H</td><td>0.11653200</td><td>2.51744900</td><td>-1.19528900</td></tr><tr><td>C</td><td>-2.89198100</td><td>-2.65250300</td><td>-2.59831900</td></tr><tr><td>C</td><td>-2.35128400</td><td>-3.91836800</td><td>-2.51697400</td></tr><tr><td>C</td><td>-2.06353200</td><td>-1.52432000</td><td>-2.33412000</td></tr><tr><td>C</td><td>-0.99315400</td><td>-4.12345400</td><td>-2.14818500</td></tr><tr><td>H</td><td>-2.97256900</td><td>-4.78958400</td><td>-2.71362300</td></tr><tr><td>C</td><td>-0.74855700</td><td>-1.68630500</td><td>-1.96573100</td></tr><tr><td>H</td><td>-2.49191900</td><td>-0.52891500</td><td>-2.40426200</td></tr><tr><td>C</td><td>-0.42832200</td><td>-5.42036100</td><td>-2.02434700</td></tr><tr><td>C</td><td>-0.17660100</td><td>-2.98540000</td><td>-1.84462200</td></tr><tr><td>H</td><td>-0.12899800</td><td>-0.81865500</td><td>-1.75187500</td></tr><tr><td>C</td><td>0.86763000</td><td>-5.58487500</td><td>-1.58747700</td></tr><tr><td>H</td><td>-1.04142000</td><td>-6.28599900</td><td>-2.26287800</td></tr><tr><td>C</td><td>1.15298800</td><td>-3.19320600</td><td>-1.39388000</td></tr><tr><td>C</td><td>1.67445100</td><td>-4.46663000</td><td>-1.24758800</td></tr><tr><td>H</td><td>1.28039000</td><td>-6.58513800</td><td>-1.48114500</td></tr><tr><td>H</td><td>1.75653100</td><td>-2.32586400</td><td>-1.13463900</td></tr><tr><td>C</td><td>-4.34878100</td><td>-2.45247100</td><td>-2.93951300</td></tr><tr><td>H</td><td>-4.46728900</td><td>-2.02816200</td><td>-3.95089300</td></tr><tr><td>H</td><td>-4.87201900</td><td>-3.41999900</td><td>-2.92820900</td></tr><tr><td>O</td><td>-9.10964400</td><td>-1.19065300</td><td>-0.23259600</td></tr><tr><td>H</td><td>-8.90801500</td><td>-0.96507100</td><td>0.70129100</td></tr><tr><td>O</td><td>-3.48780400</td><td>-0.58997600</td><td>3.63014300</td></tr><tr><td>H</td><td>-2.62452300</td><td>-1.01918600</td><td>3.47352000</td></tr><tr><td>O</td><td>-8.11441200</td><td>-0.83949600</td><td>2.35533600</td></tr><tr><td>H</td><td>-8.28207700</td><td>-0.50854300</td><td>3.25430400</td></tr><tr><td>C</td><td>-8.39747400</td><td>-0.30670500</td><td>-1.06733400</td></tr><tr><td>H</td><td>-8.77223400</td><td>-0.47382600</td><td>-2.08459400</td></tr></table>","table_caption":"[\"Symbolic Z-matrix: \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"78","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S79 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,489,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"79","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"79","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S80 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,485,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"80","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,804,307,820]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"80","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,832,371,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"80","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5398342 a.u. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"80","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S81 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,164,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0958/98f1b995356575bd1b530e3424b3300b5ccfaa2c689183ebf78047c45649a07e.jpg","list_items":null,"page_idx":"81","sub_type":null,"table_body":"<table><tr><td>C</td><td>-5.79521100</td><td>-0.67942100</td><td>3.06253500</td></tr><tr><td>C</td><td>-6.84753000</td><td>-1.48341600</td><td>2.31054600</td></tr><tr><td>C</td><td>-6.39366400</td><td>-1.73257600</td><td>0.86277600</td></tr><tr><td>C</td><td>-4.08482100</td><td>-1.72349800</td><td>1.54199700</td></tr><tr><td>C</td><td>-4.44988200</td><td>-1.39699700</td><td>3.00392500</td></tr><tr><td>O</td><td>-5.15695700</td><td>-2.41790600</td><td>0.88694800</td></tr><tr><td>O</td><td>-6.27423400</td><td>-0.53391600</td><td>4.39918600</td></tr><tr><td>O</td><td>-6.31213400</td><td>-0.48570600</td><td>0.20493300</td></tr><tr><td>C</td><td>-2.89576500</td><td>-2.67547100</td><td>1.43504200</td></tr><tr><td>O</td><td>-1.77080400</td><td>-2.08148300</td><td>2.08135500</td></tr><tr><td>C</td><td>-7.36411200</td><td>2.00044900</td><td>-1.36809700</td></tr><tr><td>C</td><td>-8.52265700</td><td>1.34182300</td><td>-0.62239500</td></tr><tr><td>C</td><td>-6.84710400</td><td>-0.29604600</td><td>-1.11807000</td></tr><tr><td>O</td><td>-6.36942000</td><td>0.96132700</td><td>-1.54016600</td></tr><tr><td>C</td><td>-6.38751500</td><td>-1.35919700</td><td>-2.11477800</td></tr><tr><td>O</td><td>-4.97855600</td><td>-1.45851900</td><td>-2.10517600</td></tr><tr><td>H</td><td>-6.95788900</td><td>-2.46413200</td><td>2.79441300</td></tr><tr><td>H</td><td>-8.36327500</td><td>1.40487100</td><td>0.46146000</td></tr><tr><td>H</td><td>-7.72193800</td><td>2.30150100</td><td>-2.36283100</td></tr><tr><td>H</td><td>-5.69295000</td><td>0.30619800</td><td>2.58863200</td></tr><tr><td>H</td><td>-4.54074500</td><td>-2.34325900</td><td>3.56320500</td></tr><tr><td>H</td><td>-3.86107400</td><td>-0.78795700</td><td>1.01477200</td></tr><tr><td>H</td><td>-3.15393900</td><td>-3.62939100</td><td>1.91959200</td></tr><tr><td>H</td><td>-2.67117300</td><td>-2.87570300</td><td>0.37964800</td></tr><tr><td>H</td><td>-6.75884100</td><td>-1.06015900</td><td>-3.10698900</td></tr><tr><td>H</td><td>-6.84919000</td><td>-2.32938600</td><td>-1.87133900</td></tr><tr><td>C</td><td>4.75469700</td><td>-3.55627000</td><td>-1.41835500</td></tr><tr><td>C</td><td>4.94268000</td><td>-2.56876800</td><td>-2.37680100</td></tr><tr><td>C</td><td>5.59714300</td><td>-3.57976200</td><td>-0.28580900</td></tr><tr><td>C</td><td>5.90420100</td><td>-1.55427600</td><td>-2.24321500</td></tr><tr><td>H</td><td>4.30787000</td><td>-2.60794200</td><td>-3.25742700</td></tr><tr><td>C</td><td>6.54383500</td><td>-2.56656500</td><td>-0.13682000</td></tr><tr><td>C</td><td>6.70139600</td><td>-1.54043300</td><td>-1.08607000</td></tr><tr><td>H</td><td>7.19668200</td><td>-2.57356900</td><td>0.72891300</td></tr><tr><td>C</td><td>2.71902600</td><td>1.41178600</td><td>-3.48157900</td></tr><tr><td>C</td><td>3.05239300</td><td>2.64943100</td><td>-2.89676600</td></tr><tr><td>C</td><td>3.70866100</td><td>0.45138800</td><td>-3.63871200</td></tr><tr><td>C</td><td>4.36969300</td><td>2.87208200</td><td>-2.50059000</td></tr><tr><td>C</td><td>5.02777100</td><td>0.64628500</td><td>-3.19662800</td></tr><tr><td>H</td><td>3.42149000</td><td>-0.49013100</td><td>-4.09842500</td></tr><tr><td>C</td><td>5.36201300</td><td>1.88200300</td><td>-2.61530500</td></tr><tr><td>H</td><td>4.63730800</td><td>3.83703300</td><td>-2.08159300</td></tr><tr><td>C</td><td>6.39319500</td><td>2.85500400</td><td>1.69214100</td></tr><tr><td>C</td><td>6.72368300</td><td>1.60289800</td><td>2.25465900</td></tr><tr><td>C</td><td>6.43646300</td><td>2.99606300</td><td>0.30552600</td></tr><tr><td>C</td><td>7.14796700</td><td>0.58320600</td><td>1.41041800</td></tr><tr><td>C</td><td>6.82656000</td><td>1.94868800</td><td>-0.54796900</td></tr><tr><td>H</td><td>6.17567000</td><td>3.95052200</td><td>-0.13720500</td></tr><tr><td>C</td><td>7.22293900</td><td>0.72361600</td><td>0.01527800</td></tr><tr><td>O</td><td>6.75274300</td><td>1.36001700</td><td>3.60938600</td></tr><tr><td>O</td><td>2.04141500</td><td>3.56185900</td><td>-2.77272700</td></tr><tr><td>C</td><td>2.05447600</td><td>4.48697400</td><td>-1.67687600</td></tr><tr><td>H</td><td>2.74958100</td><td>4.13118100</td><td>-0.90604500</td></tr><tr><td>H</td><td>2.41376200</td><td>5.46339400</td><td>-2.02448000</td></tr><tr><td>C</td><td>6.00427600</td><td>-0.51419900</td><td>-3.35434400</td></tr><tr><td>H</td><td>5.78440000</td><td>-1.01411400</td><td>-4.30455000</td></tr><tr><td>H</td><td>7.02886600</td><td>-0.14706800</td><td>-3.44338300</td></tr><tr><td>C</td><td>6.74409700</td><td>2.20291400</td><td>-2.05036000</td></tr><tr><td>H</td><td>6.95358600</td><td>3.26264900</td><td>-2.23420400</td></tr><tr><td>H</td><td>7.51868100</td><td>1.64744400</td><td>-2.58296800</td></tr><tr><td>H</td><td>7.43520900</td><td>-0.35412300</td><td>1.87859700</td></tr><tr><td>C</td><td>7.74065100</td><td>-0.46274600</td><td>-0.79641400</td></tr><tr><td>H</td><td>8.55543200</td><td>-0.92413700</td><td>-0.22663400</td></tr><tr><td>H</td><td>8.19335700</td><td>-0.11222100</td><td>-1.72669800</td></tr><tr><td>H</td><td>-7.08658900</td><td>-2.40661900</td><td>0.35739200</td></tr><tr><td>H</td><td>-5.63403000</td><td>0.02590800</td><td>4.86839700</td></tr><tr><td>O</td><td>3.81122200</td><td>-4.52824700</td><td>-1.65794900</td></tr><tr><td>O</td><td>-6.38256400</td><td>2.93312000</td><td>0.62455200</td></tr><tr><td>O</td><td>-9.74469400</td><td>1.95868400</td><td>-0.99650500</td></tr><tr><td>H</td><td>-10.45059200</td><td>1.51154000</td><td>-0.50154100</td></tr><tr><td>C</td><td>2.81320400</td><td>-4.76202100</td><td>-0.63788600</td></tr><tr><td>H</td><td>2.93100500</td><td>-5.79031400</td><td>-0.28226800</td></tr><tr><td>H</td><td>2.99307000</td><td>-4.09523200</td><td>0.20963900</td></tr><tr><td>C</td><td>5.57214100</td><td>1.64632700</td><td>4.40376400</td></tr><tr><td>H</td><td>5.42556500</td><td>2.72607200</td><td>4.46798300</td></tr><tr><td>H</td><td>5.84495900</td><td>1.26808900</td><td>5.39246300</td></tr><tr><td>O</td><td>5.42675400</td><td>-4.62468800</td><td>0.57842700</td></tr><tr><td>O</td><td>6.06479900</td><td>3.85783900</td><td>2.56230800</td></tr><tr><td>O</td><td>1.41990100</td><td>1.10463200</td><td>-3.82800600</td></tr><tr><td>C</td><td>0.90996600</td><td>1.78889700</td><td>-4.98142100</td></tr><tr><td>H</td><td>1.51983200</td><td>1.56296600</td><td>-5.86499000</td></tr><tr><td>H</td><td>-0.10386800</td><td>1.41323600</td><td>-5.13439400</td></tr><tr><td>H</td><td>0.88142600</td><td>2.87025000</td><td>-4.81929500</td></tr><tr><td>C</td><td>6.22438100</td><td>-4.65928900</td><td>1.75886800</td></tr><tr><td>H</td><td>6.05327100</td><td>-3.77341300</td><td>2.38224100</td></tr><tr><td>H</td><td>5.91240500</td><td>-5.55257700</td><td>2.30189500</td></tr><tr><td>H</td><td>7.29166600</td><td>-4.73428300</td><td>1.51812700</td></tr><tr><td>C</td><td>5.73803200</td><td>5.13813000</td><td>2.02658000</td></tr><tr><td>H</td><td>4.85409200</td><td>5.08732700</td><td>1.37964100</td></tr><tr><td>H</td><td>5.52242900</td><td>5.77289900</td><td>2.88706200</td></tr><tr><td>H</td><td>6.57866800</td><td>5.55970700</td><td>1.46281900</td></tr><tr><td>C</td><td>-6.74474000</td><td>3.22456700</td><td>-0.71667100</td></tr><tr><td>H</td><td>-7.47532600</td><td>4.04874500</td><td>-0.74822300</td></tr><tr><td>H</td><td>-5.86759200</td><td>3.52859000</td><td>-1.30275100</td></tr><tr><td>C</td><td>-0.66094900</td><td>-2.97134200</td><td>2.16302500</td></tr><tr><td>H</td><td>-0.90934300</td><td>-3.81967500</td><td>2.81916800</td></tr><tr><td>H</td><td>-0.45916900</td><td>-3.38761300</td><td>1.16354500</td></tr><tr><td>C</td><td>-5.46547600</td><td>3.85901600</td><td>1.19411600</td></tr><tr><td>H</td><td>-5.43487000</td><td>3.60024900</td><td>2.25922200</td></tr><tr><td>H</td><td>-5.84880700</td><td>4.88809200</td><td>1.11754100</td></tr><tr><td>C</td><td>0.56591100</td><td>-2.25614200</td><td>2.67663700</td></tr><tr><td>C</td><td>0.74294500</td><td>-0.89729200</td><td>2.52208400</td></tr><tr><td>C</td><td>1.59052000</td><td>-3.02688700</td><td>3.29482900</td></tr><tr><td>C</td><td>1.92866700</td><td>-0.25418300</td><td>2.97313300</td></tr><tr><td>H</td><td>-0.03293000</td><td>-0.30095900</td><td>2.05109600</td></tr><tr><td>C</td><td>2.75146800</td><td>-2.43689200</td><td>3.73624400</td></tr><tr><td>H</td><td>1.44547700</td><td>-4.09703300</td><td>3.42255000</td></tr><tr><td>C</td><td>2.13422700</td><td>1.14408500</td><td>2.82929500</td></tr><tr><td>C</td><td>2.95760500</td><td>-1.03671300</td><td>3.59266700</td></tr><tr><td>H</td><td>3.52420300</td><td>-3.03606600</td><td>4.21168500</td></tr><tr><td>C</td><td>3.29388800</td><td>1.73616400</td><td>3.27879900</td></tr><tr><td>H</td><td>1.36085800</td><td>1.74262000</td><td>2.35400900</td></tr><tr><td>C</td><td>4.13545700</td><td>-0.39201500</td><td>4.05074900</td></tr><tr><td>C</td><td>4.31407100</td><td>0.97105800</td><td>3.90612900</td></tr><tr><td>H</td><td>3.43885000</td><td>2.80669900</td><td>3.16098300</td></tr><tr><td>H</td><td>4.90648000</td><td>-0.99262700</td><td>4.52960300</td></tr><tr><td>C</td><td>-4.07082400</td><td>3.77665200</td><td>0.59622400</td></tr><tr><td>C</td><td>-3.25210300</td><td>4.88630100</td><td>0.55069500</td></tr><tr><td>C</td><td>-3.59025700</td><td>2.53313400</td><td>0.09862100</td></tr><tr><td>C</td><td>-1.93430200</td><td>4.81180700</td><td>0.02259000</td></tr><tr><td>H</td><td>-3.61194000</td><td>5.84589900</td><td>0.91828800</td></tr><tr><td>C</td><td>-2.32793900</td><td>2.43183800</td><td>-0.43687100</td></tr><tr><td>H</td><td>-4.25454300</td><td>1.67517100</td><td>0.10915500</td></tr><tr><td>C</td><td>-1.06806300</td><td>5.93700500</td><td>-0.03868000</td></tr><tr><td>C</td><td>-1.46487900</td><td>3.56056500</td><td>-0.49415000</td></tr><tr><td>H</td><td>-1.97550000</td><td>1.48171000</td><td>-0.83205000</td></tr><tr><td>C</td><td>0.19067400</td><td>5.83165500</td><td>-0.58887000</td></tr><tr><td>H</td><td>-1.41792000</td><td>6.89179600</td><td>0.34650000</td></tr><tr><td>C</td><td>-0.16589900</td><td>3.48719500</td><td>-1.05746500</td></tr><tr><td>C</td><td>0.65557300</td><td>4.59532700</td><td>-1.10997600</td></tr><tr><td>H</td><td>0.83573500</td><td>6.70596200</td><td>-0.63562900</td></tr><tr><td>H</td><td>0.17303100</td><td>2.54496700</td><td>-1.47856300</td></tr><tr><td>C</td><td>-3.03554100</td><td>-2.66335100</td><td>-2.78778400</td></tr><tr><td>C</td><td>-2.62484000</td><td>-3.90287900</td><td>-2.34532600</td></tr><tr><td>C</td><td>-2.07145600</td><td>-1.62482300</td><td>-2.93381500</td></tr><tr><td>C</td><td>-1.26959900</td><td>-4.15534700</td><td>-1.99677700</td></tr><tr><td>H</td><td>-3.34854800</td><td>-4.70743300</td><td>-2.23264700</td></tr><tr><td>C</td><td>-0.75012500</td><td>-1.83354500</td><td>-2.61305500</td></tr><tr><td>H</td><td>-2.39490500</td><td>-0.65323100</td><td>-3.29810100</td></tr><tr><td>C</td><td>-0.83966700</td><td>-5.41194100</td><td>-1.49640700</td></tr><tr><td>C</td><td>-0.31160800</td><td>-3.09533500</td><td>-2.11508600</td></tr><tr><td>H</td><td>-0.02433800</td><td>-1.03228400</td><td>-2.73421800</td></tr><tr><td>C</td><td>0.46583100</td><td>-5.60139200</td><td>-1.09918800</td></tr><tr><td>H</td><td>-1.56031600</td><td>-6.22236600</td><td>-1.41894500</td></tr><tr><td>C</td><td>1.02476800</td><td>-3.32752400</td><td>-1.69836800</td></tr><tr><td>C</td><td>1.41597800</td><td>-4.54966700</td><td>-1.17963700</td></tr><tr><td>H</td><td>0.77768600</td><td>-6.56634800</td><td>-0.70705400</td></tr><tr><td>H</td><td>1.74176500</td><td>-2.51285600</td><td>-1.77018200</td></tr><tr><td>C</td><td>-4.49131500</td><td>-2.39233800</td><td>-3.07229100</td></tr><tr><td>H</td><td>-4.63028300</td><td>-1.97842500</td><td>-4.08428800</td></tr><tr><td>H</td><td>-5.06489900</td><td>-3.32905500</td><td>-3.01618300</td></tr><tr><td>O</td><td>-9.10767600</td><td>-1.04819000</td><td>-0.27776000</td></tr><tr><td>H</td><td>-8.90103000</td><td>-0.87859500</td><td>0.66689100</td></tr><tr><td>O</td><td>-3.48864200</td><td>-0.54314200</td><td>3.61239400</td></tr><tr><td>H</td><td>-2.62021200</td><td>-0.95947400</td><td>3.44850500</td></tr><tr><td>O</td><td>-8.10206500</td><td>-0.80792600</td><td>2.30169700</td></tr><tr><td>H</td><td>-8.26248000</td><td>-0.48581100</td><td>3.20544400</td></tr><tr><td>C</td><td>-8.39055900</td><td>-0.12229200</td><td>-1.06045500</td></tr><tr><td>H</td><td>-8.78435700</td><td>-0.20862900</td><td>-2.08070000</td></tr></table>","table_caption":"[\"Symbolic Z-matrix: \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,110,369,124]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"81","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conformation #2 (Pop. = 12.04%) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"81","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S82 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,489,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"82","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"82","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S83 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,485,760]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"83","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,776,307,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"83","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,803,369,816]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"83","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5380266 a.u. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"83","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S84 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[115,110,156,122]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"84","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"P-5b ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,137,369,152]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"84","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conformation #1 (Pop. = 75.32%) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,191,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0637/8d967e44b96163d515a262d5f8e5ec282cae11cc3383201fd16cf4bc39cc5b6e.jpg","list_items":null,"page_idx":"84","sub_type":null,"table_body":"<table><tr><td>C</td><td>-5.74916800</td><td>4.67505000</td><td>-1.18282900</td></tr><tr><td>C</td><td>-5.74829200</td><td>4.39628600</td><td>0.31511100</td></tr><tr><td>C</td><td>-4.69552300</td><td>3.33385500</td><td>0.65252800</td></tr><tr><td>C</td><td>-3.34115300</td><td>3.98482800</td><td>-1.22653300</td></tr><tr><td>C</td><td>-4.34621300</td><td>5.07931300</td><td>-1.63043600</td></tr><tr><td>O</td><td>-3.42680700</td><td>3.74490600</td><td>0.19491800</td></tr><tr><td>O</td><td>-6.70400100</td><td>5.70577700</td><td>-1.41050700</td></tr><tr><td>O</td><td>-7.01343000</td><td>3.94676800</td><td>0.78279500</td></tr><tr><td>O</td><td>-5.12283000</td><td>2.11066700</td><td>0.06935000</td></tr><tr><td>O</td><td>-4.39509700</td><td>5.24859900</td><td>-3.04762700</td></tr><tr><td>C</td><td>-1.89380300</td><td>4.32524900</td><td>-1.53925600</td></tr><tr><td>O</td><td>-1.58506900</td><td>5.60583700</td><td>-1.00634000</td></tr><tr><td>C</td><td>-5.86001400</td><td>-1.21335500</td><td>0.51959700</td></tr><tr><td>C</td><td>-5.86225500</td><td>-0.85441600</td><td>2.02426400</td></tr><tr><td>C</td><td>-4.78213100</td><td>0.88561900</td><td>0.72722600</td></tr><tr><td>C</td><td>-5.65849500</td><td>0.67123400</td><td>1.99890800</td></tr><tr><td>O</td><td>-5.17436100</td><td>-0.13518000</td><td>-0.16817100</td></tr><tr><td>O</td><td>-6.94016600</td><td>1.25703500</td><td>1.85334400</td></tr><tr><td>O</td><td>-4.88065700</td><td>-1.54667800</td><td>2.77432100</td></tr><tr><td>C</td><td>-3.24948800</td><td>0.83058800</td><td>0.91966000</td></tr><tr><td>O</td><td>-2.78650900</td><td>-0.45646600</td><td>1.33694500</td></tr><tr><td>O</td><td>-7.99860900</td><td>-2.44097500</td><td>0.43561100</td></tr><tr><td>H</td><td>-5.46158800</td><td>5.31865200</td><td>0.84010600</td></tr><tr><td>H</td><td>-5.15693600</td><td>1.01970000</td><td>2.91270900</td></tr><tr><td>H</td><td>-6.82491600</td><td>-1.08808900</td><td>2.48377200</td></tr><tr><td>H</td><td>-5.28116900</td><td>-2.12671500</td><td>0.37028500</td></tr><tr><td>H</td><td>-6.04268600</td><td>3.76105200</td><td>-1.71990900</td></tr><tr><td>H</td><td>-4.07267900</td><td>6.01887400</td><td>-1.13722700</td></tr><tr><td>H</td><td>-3.59120900</td><td>3.06240500</td><td>-1.76683300</td></tr><tr><td>H</td><td>-1.24627800</td><td>3.55028000</td><td>-1.10806000</td></tr><tr><td>H</td><td>-1.75043200</td><td>4.32004000</td><td>-2.63052200</td></tr><tr><td>H</td><td>-2.92372400</td><td>1.55160200</td><td>1.67436300</td></tr><tr><td>H</td><td>-2.78811700</td><td>1.10436300</td><td>-0.03181100</td></tr><tr><td>C</td><td>5.20040600</td><td>2.55837300</td><td>3.91397700</td></tr><tr><td>H</td><td>6.24063200</td><td>2.43710600</td><td>3.59389700</td></tr><tr><td>H</td><td>5.20443600</td><td>3.22032200</td><td>4.78472400</td></tr><tr><td>C</td><td>1.57382400</td><td>-4.04251200</td><td>-3.96615800</td></tr><tr><td>H</td><td>1.94918100</td><td>-3.02659600</td><td>-4.13548700</td></tr><tr><td>H</td><td>0.66816200</td><td>-4.19826300</td><td>-4.55408500</td></tr><tr><td>O</td><td>4.66603300</td><td>1.32988000</td><td>4.43296600</td></tr><tr><td>O</td><td>1.18949000</td><td>-4.22802300</td><td>-2.60537900</td></tr><tr><td>C</td><td>2.14565300</td><td>-4.08416800</td><td>-1.64076700</td></tr><tr><td>C</td><td>3.48563100</td><td>-3.79115400</td><td>-1.88601100</td></tr><tr><td>C</td><td>1.72469000</td><td>-4.24830100</td><td>-0.30392400</td></tr><tr><td>C</td><td>4.41818400</td><td>-3.62506100</td><td>-0.84619400</td></tr><tr><td>H</td><td>3.82609400</td><td>-3.67237800</td><td>-2.90818200</td></tr><tr><td>C</td><td>2.65515300</td><td>-4.12425700</td><td>0.71947600</td></tr><tr><td>C</td><td>4.00367000</td><td>-3.80372400</td><td>0.48464800</td></tr><tr><td>H</td><td>2.29938900</td><td>-4.27303700</td><td>1.73542800</td></tr><tr><td>C</td><td>5.68876300</td><td>0.28298000</td><td>-2.74794000</td></tr><tr><td>C</td><td>6.31958600</td><td>1.06948200</td><td>-1.76699600</td></tr><tr><td>C</td><td>5.59050100</td><td>-1.09014300</td><td>-2.54180100</td></tr><tr><td>C</td><td>6.74902800</td><td>0.46138900</td><td>-0.59110400</td></tr><tr><td>C</td><td>6.02693400</td><td>-1.71149300</td><td>-1.36237500</td></tr><tr><td>H</td><td>5.12938300</td><td>-1.67885400</td><td>-3.32938600</td></tr><tr><td>C</td><td>6.58431900</td><td>-0.91040700</td><td>-0.34648100</td></tr><tr><td>H</td><td>7.22372800</td><td>1.09395100</td><td>0.15381500</td></tr><tr><td>C</td><td>4.78200600</td><td>0.17867800</td><td>3.69421900</td></tr><tr><td>C</td><td>3.85297000</td><td>-0.84421600</td><td>3.99686500</td></tr><tr><td>C</td><td>5.76499600</td><td>-0.07056400</td><td>2.74443400</td></tr><tr><td>C</td><td>3.95544200</td><td>-2.06354200</td><td>3.33412100</td></tr><tr><td>C</td><td>5.86517300</td><td>-1.29898000</td><td>2.06270500</td></tr><tr><td>H</td><td>6.49539700</td><td>0.69923800</td><td>2.52305200</td></tr><tr><td>C</td><td>4.94131200</td><td>-2.31140500</td><td>2.35927300</td></tr><tr><td>O</td><td>2.92271700</td><td>-0.54550000</td><td>4.95061500</td></tr><tr><td>O</td><td>6.47601900</td><td>2.43458100</td><td>-1.90476800</td></tr><tr><td>O</td><td>0.39628200</td><td>-4.44351400</td><td>0.00409500</td></tr><tr><td>C</td><td>1.95701900</td><td>-1.54055200</td><td>5.27433300</td></tr><tr><td>H</td><td>2.42995600</td><td>-2.44148600</td><td>5.68454800</td></tr><tr><td>H</td><td>1.31213600</td><td>-1.09369100</td><td>6.03268400</td></tr><tr><td>H</td><td>1.35503000</td><td>-1.81469700</td><td>4.39916100</td></tr><tr><td>C</td><td>7.40557700</td><td>2.83376400</td><td>-2.92480800</td></tr><tr><td>H</td><td>8.40717600</td><td>2.44540400</td><td>-2.70383600</td></tr><tr><td>H</td><td>7.08611500</td><td>2.48456500</td><td>-3.91140100</td></tr><tr><td>H</td><td>7.42576300</td><td>3.92524000</td><td>-2.90829600</td></tr><tr><td>C</td><td>5.83529500</td><td>-3.22187900</td><td>-1.24006000</td></tr><tr><td>H</td><td>6.05878600</td><td>-3.66926300</td><td>-2.21504600</td></tr><tr><td>H</td><td>6.56404500</td><td>-3.64387000</td><td>-0.54515600</td></tr><tr><td>C</td><td>6.97983300</td><td>-1.43967400</td><td>1.02733200</td></tr><tr><td>H</td><td>7.84572300</td><td>-0.86734500</td><td>1.37893600</td></tr><tr><td>H</td><td>7.31486000</td><td>-2.47708100</td><td>0.96316300</td></tr><tr><td>H</td><td>3.25606300</td><td>-2.85660500</td><td>3.57341700</td></tr><tr><td>C</td><td>4.93610700</td><td>-3.68197100</td><td>1.68748700</td></tr><tr><td>H</td><td>4.61603700</td><td>-4.41921100</td><td>2.43285100</td></tr><tr><td>H</td><td>5.95193400</td><td>-3.97019600</td><td>1.40705800</td></tr><tr><td>H</td><td>2.33459100</td><td>-4.77120600</td><td>-4.27048600</td></tr><tr><td>H</td><td>-4.59283100</td><td>3.23415300</td><td>1.73738600</td></tr><tr><td>H</td><td>-3.72796400</td><td>5.90753700</td><td>-3.29497800</td></tr><tr><td>H</td><td>-7.69159200</td><td>4.46424700</td><td>0.31523900</td></tr><tr><td>H</td><td>-6.88107200</td><td>2.08232600</td><td>1.32953900</td></tr><tr><td>H</td><td>-4.01120200</td><td>-1.31300000</td><td>2.38527000</td></tr><tr><td>H</td><td>-6.67651600</td><td>5.89772500</td><td>-2.36316200</td></tr><tr><td>C</td><td>4.09343500</td><td>1.75550100</td><td>-3.76259100</td></tr><tr><td>H</td><td>4.42103400</td><td>2.58432800</td><td>-3.12980500</td></tr><tr><td>H</td><td>3.92297300</td><td>2.12825700</td><td>-4.77540800</td></tr><tr><td>O</td><td>5.19503900</td><td>0.81423500</td><td>-3.92149800</td></tr><tr><td>C</td><td>-0.20147700</td><td>5.93348900</td><td>-1.05095200</td></tr><tr><td>H</td><td>0.20861300</td><td>5.75690000</td><td>-2.05665300</td></tr><tr><td>H</td><td>-0.16484100</td><td>7.01418700</td><td>-0.86816100</td></tr><tr><td>C</td><td>-2.19009500</td><td>-1.26360500</td><td>0.30089000</td></tr><tr><td>H</td><td>-2.91782500</td><td>-1.45354600</td><td>-0.49532800</td></tr><tr><td>H</td><td>-1.96640800</td><td>-2.21459400</td><td>0.79537700</td></tr><tr><td>C</td><td>0.63519300</td><td>5.21014800</td><td>-0.00877100</td></tr><tr><td>C</td><td>1.96296400</td><td>4.91981900</td><td>-0.24518100</td></tr><tr><td>C</td><td>0.06515800</td><td>4.88316700</td><td>1.25347300</td></tr><tr><td>C</td><td>2.78088600</td><td>4.32424300</td><td>0.75447400</td></tr><tr><td>H</td><td>2.40969200</td><td>5.15461800</td><td>-1.20969200</td></tr><tr><td>C</td><td>0.82232700</td><td>4.29058700</td><td>2.23620900</td></tr><tr><td>H</td><td>-0.98721000</td><td>5.09113000</td><td>1.41852400</td></tr><tr><td>C</td><td>4.15602400</td><td>4.03510700</td><td>0.54469900</td></tr><tr><td>C</td><td>2.19922000</td><td>3.99973100</td><td>2.02423100</td></tr><tr><td>H</td><td>0.37596600</td><td>4.03887800</td><td>3.19532600</td></tr><tr><td>C</td><td>4.91843900</td><td>3.46650400</td><td>1.54282600</td></tr><tr><td>H</td><td>4.60583400</td><td>4.26093000</td><td>-0.41876600</td></tr><tr><td>C</td><td>3.01274600</td><td>3.41041300</td><td>3.02519700</td></tr><tr><td>C</td><td>4.35262600</td><td>3.14928200</td><td>2.80518700</td></tr><tr><td>H</td><td>5.96999400</td><td>3.25929600</td><td>1.36229500</td></tr><tr><td>H</td><td>2.56516600</td><td>3.16419100</td><td>3.98547000</td></tr><tr><td>C</td><td>-0.92940500</td><td>-0.64887000</td><td>-0.26873400</td></tr><tr><td>C</td><td>-0.68571200</td><td>-0.67028000</td><td>-1.62720700</td></tr><tr><td>C</td><td>0.02481600</td><td>-0.05067100</td><td>0.60097400</td></tr><tr><td>C</td><td>0.49828500</td><td>-0.10564400</td><td>-2.17558600</td></tr><tr><td>H</td><td>-1.40882300</td><td>-1.12333100</td><td>-2.30230800</td></tr><tr><td>C</td><td>1.16892900</td><td>0.52538800</td><td>0.10187800</td></tr><tr><td>H</td><td>-0.17258300</td><td>-0.03738700</td><td>1.66887600</td></tr><tr><td>C</td><td>0.77625300</td><td>-0.11816000</td><td>-3.57059700</td></tr><tr><td>C</td><td>1.43646800</td><td>0.52300100</td><td>-1.29558800</td></tr><tr><td>H</td><td>1.88624100</td><td>0.99047000</td><td>0.77305600</td></tr><tr><td>C</td><td>1.91974900</td><td>0.46683900</td><td>-4.06753000</td></tr><tr><td>H</td><td>0.06529800</td><td>-0.59144700</td><td>-4.24343300</td></tr><tr><td>C</td><td>2.59371700</td><td>1.13403100</td><td>-1.84519200</td></tr><tr><td>C</td><td>2.84526000</td><td>1.11563000</td><td>-3.20427600</td></tr><tr><td>H</td><td>2.11585600</td><td>0.45072200</td><td>-5.13699400</td></tr><tr><td>H</td><td>3.28751000</td><td>1.62969500</td><td>-1.17058800</td></tr><tr><td>C</td><td>-0.17703600</td><td>-5.73382200</td><td>-0.33427500</td></tr><tr><td>H</td><td>-0.01384000</td><td>-6.41989900</td><td>0.50599800</td></tr><tr><td>H</td><td>0.32063700</td><td>-6.13639400</td><td>-1.22039600</td></tr><tr><td>C</td><td>-6.57714800</td><td>-4.35227000</td><td>-0.16319000</td></tr><tr><td>C</td><td>-5.68705200</td><td>-4.36534700</td><td>-1.21759600</td></tr><tr><td>C</td><td>-6.16831900</td><td>-4.87327000</td><td>1.09652300</td></tr><tr><td>C</td><td>-4.34897300</td><td>-4.81305500</td><td>-1.05076600</td></tr><tr><td>H</td><td>-5.98812100</td><td>-3.97607200</td><td>-2.18821300</td></tr><tr><td>C</td><td>-4.88780800</td><td>-5.33606800</td><td>1.28770200</td></tr><tr><td>H</td><td>-6.87734600</td><td>-4.87844700</td><td>1.92053200</td></tr><tr><td>C</td><td>-3.39011000</td><td>-4.74186400</td><td>-2.09829600</td></tr><tr><td>C</td><td>-3.93192100</td><td>-5.28779100</td><td>0.23468400</td></tr><tr><td>H</td><td>-4.58026400</td><td>-5.71794100</td><td>2.25816900</td></tr><tr><td>C</td><td>-2.07432900</td><td>-5.06964300</td><td>-1.86974800</td></tr><tr><td>H</td><td>-3.70839600</td><td>-4.39524600</td><td>-3.07854900</td></tr><tr><td>C</td><td>-2.56978400</td><td>-5.64211000</td><td>0.42799400</td></tr><tr><td>C</td><td>-1.64492800</td><td>-5.51510600</td><td>-0.58885700</td></tr><tr><td>H</td><td>-1.33887200</td><td>-4.97451300</td><td>-2.66261400</td></tr><tr><td>H</td><td>-2.25362800</td><td>-5.98490700</td><td>1.41113200</td></tr><tr><td>C</td><td>-7.25227400</td><td>-1.35696800</td><td>-0.11353700</td></tr><tr><td>H</td><td>-7.14561200</td><td>-1.46539200</td><td>-1.20175800</td></tr><tr><td>H</td><td>-7.82184000</td><td>-0.44498700</td><td>0.08782100</td></tr><tr><td>C</td><td>-7.92538200</td><td>-3.67904500</td><td>-0.28676200</td></tr><tr><td>H</td><td>-8.71382600</td><td>-4.29875500</td><td>0.15256300</td></tr><tr><td>H</td><td>-8.17112900</td><td>-3.50874600</td><td>-1.34454500</td></tr></table>","table_caption":"[\"Symbolic Z-matrix: \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"84","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S85 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,487,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"85","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"85","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S86 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,485,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"86","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,804,307,820]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"86","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,832,366,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"86","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5350289 a.u ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"86","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S87 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,164,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0061/ac509ece88ff0440a5740ba323dbb66e33bbb29bc05f042e0f31fa252314f477.jpg","list_items":null,"page_idx":"87","sub_type":null,"table_body":"<table><tr><td>C</td><td>-5.87160200</td><td>4.53565500</td><td>-1.29345700</td></tr><tr><td>C</td><td>-5.91307200</td><td>4.25748200</td><td>0.20403600</td></tr><tr><td>C</td><td>-4.84564000</td><td>3.22310900</td><td>0.57976200</td></tr><tr><td>C</td><td>-3.44959500</td><td>3.90043000</td><td>-1.26335500</td></tr><tr><td>C</td><td>-4.46490600</td><td>4.97316900</td><td>-1.69770400</td></tr><tr><td>O</td><td>-3.57412100</td><td>3.65814800</td><td>0.15450100</td></tr><tr><td>O</td><td>-6.84275700</td><td>5.54288000</td><td>-1.55358600</td></tr><tr><td>O</td><td>-7.18021800</td><td>3.77535700</td><td>0.63116900</td></tr><tr><td>O</td><td>-5.22776200</td><td>1.98317300</td><td>0.00074500</td></tr><tr><td>O</td><td>-4.47594200</td><td>5.14054800</td><td>-3.11598400</td></tr><tr><td>C</td><td>-1.99855500</td><td>4.26716300</td><td>-1.52646700</td></tr><tr><td>O</td><td>-1.71727900</td><td>5.53116800</td><td>-0.94083600</td></tr><tr><td>C</td><td>-5.86437700</td><td>-1.35765200</td><td>0.53958900</td></tr><tr><td>C</td><td>-5.87709400</td><td>-0.95475400</td><td>2.03357500</td></tr><tr><td>C</td><td>-4.85999000</td><td>0.77994500</td><td>0.68369100</td></tr><tr><td>C</td><td>-5.72550600</td><td>0.57535400</td><td>1.96284800</td></tr><tr><td>O</td><td>-5.23804800</td><td>-0.26811200</td><td>-0.18598500</td></tr><tr><td>O</td><td>-7.02601200</td><td>1.11464800</td><td>1.80017100</td></tr><tr><td>O</td><td>-4.87273500</td><td>-1.59130800</td><td>2.80236400</td></tr><tr><td>C</td><td>-3.32526000</td><td>0.76273500</td><td>0.87049000</td></tr><tr><td>O</td><td>-2.82888300</td><td>-0.51075500</td><td>1.29008900</td></tr><tr><td>O</td><td>-7.94158800</td><td>-2.68457700</td><td>0.52639600</td></tr><tr><td>H</td><td>-5.66703100</td><td>5.18768600</td><td>0.73603600</td></tr><tr><td>H</td><td>-5.23632500</td><td>0.96757200</td><td>2.86542000</td></tr><tr><td>H</td><td>-6.83102900</td><td>-1.20660100</td><td>2.50145900</td></tr><tr><td>H</td><td>-5.24236300</td><td>-2.24575200</td><td>0.41391200</td></tr><tr><td>H</td><td>-6.12512000</td><td>3.61450900</td><td>-1.83892000</td></tr><tr><td>H</td><td>-4.22791100</td><td>5.91893200</td><td>-1.19707000</td></tr><tr><td>H</td><td>-3.66417800</td><td>2.97414200</td><td>-1.81257300</td></tr><tr><td>H</td><td>-1.35547200</td><td>3.48440800</td><td>-1.10367200</td></tr><tr><td>H</td><td>-1.82538600</td><td>4.29965700</td><td>-2.61286100</td></tr><tr><td>H</td><td>-3.01400500</td><td>1.49639700</td><td>1.61918200</td></tr><tr><td>H</td><td>-2.87537500</td><td>1.04287100</td><td>-0.08448500</td></tr><tr><td>C</td><td>4.43786300</td><td>2.23803800</td><td>4.60332000</td></tr><tr><td>H</td><td>4.90263300</td><td>3.03179400</td><td>5.19892400</td></tr><tr><td>H</td><td>3.72155500</td><td>1.71168700</td><td>5.23712300</td></tr><tr><td>C</td><td>1.45926300</td><td>-3.80385100</td><td>-4.03985000</td></tr><tr><td>H</td><td>1.81335200</td><td>-2.78245500</td><td>-4.22151900</td></tr><tr><td>H</td><td>0.51821700</td><td>-3.96152500</td><td>-4.56876200</td></tr><tr><td>O</td><td>5.55274800</td><td>1.38440500</td><td>4.28400500</td></tr><tr><td>O</td><td>1.16712700</td><td>-4.00898700</td><td>-2.65904000</td></tr><tr><td>C</td><td>2.18356700</td><td>-3.86927400</td><td>-1.75861200</td></tr><tr><td>C</td><td>3.50163000</td><td>-3.55986200</td><td>-2.08769000</td></tr><tr><td>C</td><td>1.85432600</td><td>-4.06101700</td><td>-0.40017100</td></tr><tr><td>C</td><td>4.50171300</td><td>-3.41248900</td><td>-1.11019600</td></tr><tr><td>H</td><td>3.77267000</td><td>-3.42058300</td><td>-3.12785500</td></tr><tr><td>C</td><td>2.84946900</td><td>-3.94670800</td><td>0.56190300</td></tr><tr><td>C</td><td>4.17837200</td><td>-3.61654500</td><td>0.24268000</td></tr><tr><td>H</td><td>2.56493500</td><td>-4.11954400</td><td>1.59649900</td></tr><tr><td>C</td><td>5.62522000</td><td>0.56290300</td><td>-2.92906300</td></tr><tr><td>C</td><td>6.33124700</td><td>1.30777700</td><td>-1.96657900</td></tr><tr><td>C</td><td>5.54333100</td><td>-0.81816300</td><td>-2.77833100</td></tr><tr><td>C</td><td>6.86289600</td><td>0.64885700</td><td>-0.86247700</td></tr><tr><td>C</td><td>6.07983500</td><td>-1.49017800</td><td>-1.66968900</td></tr><tr><td>H</td><td>5.01614100</td><td>-1.37228100</td><td>-3.54939100</td></tr><tr><td>C</td><td>6.72669400</td><td>-0.73492800</td><td>-0.67291500</td></tr><tr><td>H</td><td>7.39150000</td><td>1.25023300</td><td>-0.12802900</td></tr><tr><td>C</td><td>5.36029200</td><td>0.22345400</td><td>3.56635600</td></tr><tr><td>C</td><td>4.42367300</td><td>-0.77677100</td><td>3.90716300</td></tr><tr><td>C</td><td>6.24345400</td><td>-0.01950500</td><td>2.52049000</td></tr><tr><td>C</td><td>4.40518700</td><td>-1.95546100</td><td>3.15887600</td></tr><tr><td>C</td><td>6.23968300</td><td>-1.20547300</td><td>1.77135500</td></tr><tr><td>H</td><td>6.97401500</td><td>0.75515600</td><td>2.30510000</td></tr><tr><td>C</td><td>5.29233500</td><td>-2.19252500</td><td>2.09416600</td></tr><tr><td>O</td><td>3.61924500</td><td>-0.53518800</td><td>4.98590000</td></tr><tr><td>O</td><td>6.46555700</td><td>2.67901400</td><td>-2.05162600</td></tr><tr><td>O</td><td>0.54999400</td><td>-4.29181500</td><td>-0.01937300</td></tr><tr><td>C</td><td>2.64963500</td><td>-1.51759600</td><td>5.34220700</td></tr><tr><td>H</td><td>3.12600500</td><td>-2.46378100</td><td>5.62557800</td></tr><tr><td>H</td><td>2.11615300</td><td>-1.10881400</td><td>6.20139700</td></tr><tr><td>H</td><td>1.94260800</td><td>-1.69641200</td><td>4.52348100</td></tr><tr><td>C</td><td>7.31359200</td><td>3.13607000</td><td>-3.11701000</td></tr><tr><td>H</td><td>8.33295800</td><td>2.75259400</td><td>-2.98722900</td></tr><tr><td>H</td><td>6.92671800</td><td>2.82709500</td><td>-4.09283500</td></tr><tr><td>H</td><td>7.32344400</td><td>4.22599300</td><td>-3.05236800</td></tr><tr><td>C</td><td>5.88904200</td><td>-3.00319400</td><td>-1.59321100</td></tr><tr><td>H</td><td>6.03509500</td><td>-3.41396200</td><td>-2.59846800</td></tr><tr><td>H</td><td>6.66348100</td><td>-3.45615000</td><td>-0.97112100</td></tr><tr><td>C</td><td>7.24749400</td><td>-1.32680200</td><td>0.63185200</td></tr><tr><td>H</td><td>8.15390000</td><td>-0.78234300</td><td>0.91901800</td></tr><tr><td>H</td><td>7.55397800</td><td>-2.36594600</td><td>0.49490400</td></tr><tr><td>H</td><td>3.70189300</td><td>-2.73659600</td><td>3.42476700</td></tr><tr><td>C</td><td>5.19551300</td><td>-3.53822400</td><td>1.37890800</td></tr><tr><td>H</td><td>4.91461700</td><td>-4.29042200</td><td>2.12500800</td></tr><tr><td>H</td><td>6.18185900</td><td>-3.83900000</td><td>1.01726200</td></tr><tr><td>H</td><td>2.20488900</td><td>-4.52146500</td><td>-4.40242000</td></tr><tr><td>H</td><td>-4.77038600</td><td>3.13668600</td><td>1.66801600</td></tr><tr><td>H</td><td>-3.82196700</td><td>5.81864600</td><td>-3.34565300</td></tr><tr><td>H</td><td>-7.85658400</td><td>4.28423500</td><td>0.15188600</td></tr><tr><td>H</td><td>-6.99373000</td><td>1.91714300</td><td>1.24038500</td></tr><tr><td>H</td><td>-4.01339200</td><td>-1.36282000</td><td>2.38874900</td></tr><tr><td>H</td><td>-6.78624500</td><td>5.73697300</td><td>-2.50457000</td></tr><tr><td>C</td><td>3.94624200</td><td>2.06236200</td><td>-3.74502500</td></tr><tr><td>H</td><td>4.29530500</td><td>2.83342500</td><td>-3.05332300</td></tr><tr><td>H</td><td>3.73028400</td><td>2.52470500</td><td>-4.71131400</td></tr><tr><td>O</td><td>5.04365400</td><td>1.14882100</td><td>-4.03457400</td></tr><tr><td>C</td><td>-0.32983300</td><td>5.82646000</td><td>-0.83362500</td></tr><tr><td>H</td><td>0.17893100</td><td>5.66821700</td><td>-1.79646200</td></tr><tr><td>H</td><td>-0.28945900</td><td>6.90070100</td><td>-0.61686500</td></tr><tr><td>C</td><td>-2.20384200</td><td>-1.29747200</td><td>0.25429600</td></tr><tr><td>H</td><td>-2.92180300</td><td>-1.50341600</td><td>-0.54681600</td></tr><tr><td>H</td><td>-1.95586400</td><td>-2.24364100</td><td>0.74589800</td></tr><tr><td>C</td><td>0.37863500</td><td>5.05307300</td><td>0.26763000</td></tr><tr><td>C</td><td>1.73272700</td><td>4.79337600</td><td>0.19046400</td></tr><tr><td>C</td><td>-0.34355500</td><td>4.64069800</td><td>1.42052500</td></tr><tr><td>C</td><td>2.42342500</td><td>4.14232700</td><td>1.24835700</td></tr><tr><td>H</td><td>2.29690400</td><td>5.09588500</td><td>-0.69013100</td></tr><tr><td>C</td><td>0.29063300</td><td>3.98704600</td><td>2.45206900</td></tr><tr><td>H</td><td>-1.41158200</td><td>4.82764000</td><td>1.46009800</td></tr><tr><td>C</td><td>3.82302000</td><td>3.88498900</td><td>1.20855800</td></tr><tr><td>C</td><td>1.68650300</td><td>3.72401800</td><td>2.40330300</td></tr><tr><td>H</td><td>-0.27258300</td><td>3.66676800</td><td>3.32559700</td></tr><tr><td>C</td><td>4.46048600</td><td>3.26586500</td><td>2.26014300</td></tr><tr><td>H</td><td>4.39022600</td><td>4.19320300</td><td>0.33314600</td></tr><tr><td>C</td><td>2.37176400</td><td>3.05983000</td><td>3.45572900</td></tr><tr><td>C</td><td>3.73373500</td><td>2.84115800</td><td>3.40677600</td></tr><tr><td>H</td><td>5.53128500</td><td>3.09129700</td><td>2.22031900</td></tr><tr><td>H</td><td>1.80034800</td><td>2.73484800</td><td>4.32317800</td></tr><tr><td>C</td><td>-0.95936500</td><td>-0.64098600</td><td>-0.30303700</td></tr><tr><td>C</td><td>-0.73553900</td><td>-0.58797400</td><td>-1.66397100</td></tr><tr><td>C</td><td>-0.00216900</td><td>-0.07148900</td><td>0.58264700</td></tr><tr><td>C</td><td>0.42783500</td><td>0.02967200</td><td>-2.19921700</td></tr><tr><td>H</td><td>-1.46084000</td><td>-1.01792100</td><td>-2.35167700</td></tr><tr><td>C</td><td>1.12446600</td><td>0.54945300</td><td>0.09799300</td></tr><tr><td>H</td><td>-0.18343700</td><td>-0.11625800</td><td>1.65264900</td></tr><tr><td>C</td><td>0.68017100</td><td>0.10065200</td><td>-3.59736700</td></tr><tr><td>C</td><td>1.36861800</td><td>0.62856600</td><td>-1.30154500</td></tr><tr><td>H</td><td>1.84396900</td><td>0.99117300</td><td>0.78208000</td></tr><tr><td>C</td><td>1.80010100</td><td>0.73970000</td><td>-4.08038500</td></tr><tr><td>H</td><td>-0.03296700</td><td>-0.35028300</td><td>-4.28315700</td></tr><tr><td>C</td><td>2.50289200</td><td>1.29480300</td><td>-1.83598300</td></tr><tr><td>C</td><td>2.72717000</td><td>1.36038200</td><td>-3.19808300</td></tr><tr><td>H</td><td>1.97634800</td><td>0.78888300</td><td>-5.15227700</td></tr><tr><td>H</td><td>3.19958400</td><td>1.76594500</td><td>-1.14660700</td></tr><tr><td>C</td><td>0.02232400</td><td>-5.61824400</td><td>-0.28748600</td></tr><tr><td>H</td><td>0.23867200</td><td>-6.26096100</td><td>0.57475000</td></tr><tr><td>H</td><td>0.51520800</td><td>-6.03655000</td><td>-1.16962800</td></tr><tr><td>C</td><td>-6.43498300</td><td>-4.54588100</td><td>-0.02185500</td></tr><tr><td>C</td><td>-5.56806900</td><td>-4.56371100</td><td>-1.09521000</td></tr><tr><td>C</td><td>-5.97345500</td><td>-4.98756000</td><td>1.24996900</td></tr><tr><td>C</td><td>-4.20593200</td><td>-4.93644100</td><td>-0.93992200</td></tr><tr><td>H</td><td>-5.90900900</td><td>-4.23575000</td><td>-2.07525800</td></tr><tr><td>C</td><td>-4.66720200</td><td>-5.37645400</td><td>1.43168900</td></tr><tr><td>H</td><td>-6.66354000</td><td>-4.98999100</td><td>2.08987300</td></tr><tr><td>C</td><td>-3.27575400</td><td>-4.86925400</td><td>-2.01295700</td></tr><tr><td>C</td><td>-3.73724100</td><td>-5.32840400</td><td>0.35561700</td></tr><tr><td>H</td><td>-4.32012700</td><td>-5.69709300</td><td>2.41094100</td></tr><tr><td>C</td><td>-1.94057300</td><td>-5.12050100</td><td>-1.80160000</td></tr><tr><td>H</td><td>-3.63307000</td><td>-4.58759100</td><td>-3.00054300</td></tr><tr><td>C</td><td>-2.35455900</td><td>-5.60391600</td><td>0.53231200</td></tr><tr><td>C</td><td>-1.46012600</td><td>-5.47972200</td><td>-0.51199100</td></tr><tr><td>H</td><td>-1.22903400</td><td>-5.03028300</td><td>-2.61631600</td></tr><tr><td>H</td><td>-1.99993400</td><td>-5.88382700</td><td>1.52224200</td></tr><tr><td>C</td><td>-7.25253100</td><td>-1.59027900</td><td>-0.07513800</td></tr><tr><td>H</td><td>-7.15079900</td><td>-1.73775100</td><td>-1.15917500</td></tr><tr><td>H</td><td>-7.86253900</td><td>-0.69833300</td><td>0.09569900</td></tr><tr><td>C</td><td>-7.81795800</td><td>-3.94714300</td><td>-0.14493400</td></tr><tr><td>H</td><td>-8.56549000</td><td>-4.58613100</td><td>0.33629900</td></tr><tr><td>H</td><td>-8.09167800</td><td>-3.83523600</td><td>-1.20363800</td></tr></table>","table_caption":"[\"Symbolic Z-matrix: \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,110,369,124]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"87","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conformation #2 (Pop. = 21.14%) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"87","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S88 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,487,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"88","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"88","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S89 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,485,760]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"89","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,791,307,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"89","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,818,366,833]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"89","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5338306 a.u 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,191,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0942/368e97f340003c449278029e5f2b649d1eab0588e45269842ee1c39b1f0bf235.jpg","list_items":null,"page_idx":"90","sub_type":null,"table_body":"<table><tr><td>C</td><td>7.28986400</td><td>-2.78527500</td><td>-2.16707300</td></tr><tr><td>C</td><td>6.36770200</td><td>-1.69230000</td><td>-2.72740900</td></tr><tr><td>C</td><td>6.46688500</td><td>-0.44477000</td><td>-1.84339600</td></tr><tr><td>C</td><td>6.92881700</td><td>-3.07787100</td><td>-0.69188400</td></tr><tr><td>O</td><td>6.06553100</td><td>-0.75992500</td><td>-0.51859300</td></tr><tr><td>O</td><td>8.62321500</td><td>-2.30392400</td><td>-2.31966000</td></tr><tr><td>O</td><td>5.03220200</td><td>-2.20045200</td><td>-2.72957200</td></tr><tr><td>O</td><td>5.58923900</td><td>0.51314600</td><td>-2.40594300</td></tr><tr><td>O</td><td>5.72002400</td><td>-3.82818900</td><td>-0.63322000</td></tr><tr><td>C</td><td>5.55318600</td><td>2.35399000</td><td>-0.69546400</td></tr><tr><td>O</td><td>4.15557800</td><td>2.22111700</td><td>-2.61994700</td></tr><tr><td>O</td><td>6.85089900</td><td>1.96081700</td><td>-0.30245800</td></tr><tr><td>O</td><td>5.86480400</td><td>4.81885700</td><td>-0.84082400</td></tr><tr><td>H</td><td>6.68391800</td><td>-1.42963400</td><td>-3.74574500</td></tr><tr><td>H</td><td>4.92399600</td><td>2.59234500</td><td>0.17089100</td></tr><tr><td>H</td><td>7.13452600</td><td>-3.70927400</td><td>-2.73981800</td></tr><tr><td>H</td><td>7.70891100</td><td>-3.71360000</td><td>-0.25402200</td></tr><tr><td>O</td><td>-0.86786500</td><td>-3.53945600</td><td>2.16725300</td></tr><tr><td>C</td><td>-6.36437400</td><td>2.74559900</td><td>1.01693800</td></tr><tr><td>C</td><td>-7.01704100</td><td>1.53558600</td><td>0.81524800</td></tr><tr><td>C</td><td>-6.81396300</td><td>0.41539000</td><td>1.63837800</td></tr><tr><td>H</td><td>-7.72599400</td><td>1.47898400</td><td>-0.00700000</td></tr><tr><td>C</td><td>-5.27151800</td><td>1.77029400</td><td>2.93141200</td></tr><tr><td>C</td><td>-5.90615200</td><td>0.53565000</td><td>2.70609900</td></tr><tr><td>H</td><td>-4.60052300</td><td>1.85639300</td><td>3.77868100</td></tr><tr><td>C</td><td>-6.87843000</td><td>-2.28916600</td><td>-2.11979800</td></tr><tr><td>C</td><td>-5.97436700</td><td>-3.33504100</td><td>-1.83057200</td></tr><tr><td>C</td><td>-7.36709700</td><td>-1.51532200</td><td>-1.06664300</td></tr><tr><td>C</td><td>-5.64313300</td><td>-3.57876100</td><td>-0.50157800</td></tr><tr><td>C</td><td>-7.01735100</td><td>-1.75638500</td><td>0.27323400</td></tr><tr><td>H</td><td>-8.06682100</td><td>-0.71514300</td><td>-1.27985000</td></tr><tr><td>C</td><td>-6.15056300</td><td>-2.82270700</td><td>0.56625500</td></tr><tr><td>H</td><td>-4.97561700</td><td>-4.41399700</td><td>-0.30850200</td></tr><tr><td>C</td><td>-1.99011900</td><td>-2.81357200</td><td>2.50749700</td></tr><tr><td>C</td><td>-1.90507900</td><td>-1.65428700</td><td>3.29884400</td></tr><tr><td>C</td><td>-3.24381600</td><td>-3.27385300</td><td>2.12045900</td></tr><tr><td>C</td><td>-3.07650900</td><td>-0.98401000</td><td>3.64151000</td></tr><tr><td>C</td><td>-4.42991000</td><td>-2.60720200</td><td>2.46304500</td></tr><tr><td>H</td><td>-3.28284000</td><td>-4.18916900</td><td>1.53623100</td></tr><tr><td>C</td><td>-4.34416400</td><td>-1.42714000</td><td>3.22907700</td></tr><tr><td>C</td><td>-7.62012100</td><td>-0.84604400</td><td>1.33808300</td></tr><tr><td>H</td><td>-8.61046300</td><td>-0.53148400</td><td>0.98976600</td></tr><tr><td>H</td><td>-7.79762600</td><td>-1.40749200</td><td>2.25838200</td></tr><tr><td>C</td><td>-5.74308700</td><td>-3.21606800</td><td>1.98250300</td></tr><tr><td>H</td><td>-5.63228700</td><td>-4.30588000</td><td>2.00724500</td></tr><tr><td>H</td><td>-6.54771400</td><td>-2.98589600</td><td>2.68424100</td></tr><tr><td>H</td><td>-2.98488200</td><td>-0.09527900</td><td>4.25999300</td></tr><tr><td>C</td><td>-5.56163600</td><td>-0.60944700</td><td>3.65570200</td></tr><tr><td>H</td><td>-5.35002800</td><td>-0.17974800</td><td>4.64089200</td></tr><tr><td>H</td><td>-6.42639100</td><td>-1.26172300</td><td>3.79642400</td></tr><tr><td>H</td><td>7.48588100</td><td>-0.04487100</td><td>-1.85035000</td></tr><tr><td>H</td><td>5.11569300</td><td>-3.37682900</td><td>-1.25974100</td></tr><tr><td>H</td><td>9.23012000</td><td>-3.02807700</td><td>-2.09723500</td></tr><tr><td>H</td><td>4.41686100</td><td>-1.46871300</td><td>-2.48804600</td></tr><tr><td>H</td><td>6.82266900</td><td>1.17604400</td><td>0.27929200</td></tr><tr><td>H</td><td>6.69449100</td><td>4.73653100</td><td>-0.34265200</td></tr><tr><td>C</td><td>-0.06427200</td><td>-2.94621100</td><td>1.13461100</td></tr><tr><td>H</td><td>-0.63473900</td><td>-2.86164400</td><td>0.20186300</td></tr><tr><td>H</td><td>0.30087400</td><td>-1.95975500</td><td>1.43596100</td></tr><tr><td>H</td><td>0.78231700</td><td>-3.61908000</td><td>0.98340600</td></tr><tr><td>O</td><td>-7.23344900</td><td>-2.11931400</td><td>-3.43032000</td></tr><tr><td>C</td><td>-8.17755200</td><td>-1.09910300</td><td>-3.75029900</td></tr><tr><td>H</td><td>-7.80097800</td><td>-0.10573800</td><td>-3.47936600</td></tr><tr><td>H</td><td>-8.31584200</td><td>-1.15294600</td><td>-4.83091100</td></tr><tr><td>H</td><td>-9.13679000</td><td>-1.27473000</td><td>-3.24925800</td></tr><tr><td>O</td><td>-0.68805000</td><td>-1.14789600</td><td>3.70366700</td></tr><tr><td>O</td><td>-5.49068800</td><td>-4.21857400</td><td>-2.76796300</td></tr><tr><td>C</td><td>-5.48441200</td><td>2.87966700</td><td>2.11061800</td></tr><tr><td>O</td><td>-4.92020300</td><td>4.10540200</td><td>2.29516800</td></tr><tr><td>C</td><td>-3.99653100</td><td>4.26463600</td><td>3.36763000</td></tr><tr><td>H</td><td>-3.13672900</td><td>3.59253500</td><td>3.25844800</td></tr><tr><td>H</td><td>-3.65653800</td><td>5.29997500</td><td>3.31457300</td></tr><tr><td>H</td><td>-4.47394200</td><td>4.08802700</td><td>4.33934600</td></tr><tr><td>C</td><td>5.70227700</td><td>3.61064500</td><td>-1.55921100</td></tr><tr><td>H</td><td>6.56437900</td><td>3.43565100</td><td>-2.21993000</td></tr><tr><td>C</td><td>6.81763300</td><td>-1.79152100</td><td>0.15665100</td></tr><tr><td>H</td><td>6.18940400</td><td>-2.04106200</td><td>1.01389800</td></tr><tr><td>C</td><td>8.15509700</td><td>-1.24509600</td><td>0.67581400</td></tr><tr><td>H</td><td>8.82266000</td><td>-0.99579700</td><td>-0.15243900</td></tr><tr><td>H</td><td>8.64627300</td><td>-2.01902500</td><td>1.28211600</td></tr><tr><td>O</td><td>8.00329100</td><td>-0.04481800</td><td>1.43559800</td></tr><tr><td>C</td><td>4.76192600</td><td>1.38627500</td><td>-1.63371500</td></tr><tr><td>C</td><td>3.62599000</td><td>0.60581100</td><td>-0.93941900</td></tr><tr><td>H</td><td>4.00357600</td><td>0.08864300</td><td>-0.05971000</td></tr><tr><td>H</td><td>2.86746700</td><td>1.33456800</td><td>-0.63765200</td></tr><tr><td>C</td><td>4.43280400</td><td>3.61790400</td><td>-2.41244400</td></tr><tr><td>H</td><td>4.61790100</td><td>4.05651100</td><td>-3.39949100</td></tr><tr><td>O</td><td>3.04742500</td><td>-0.40478600</td><td>-1.76517900</td></tr><tr><td>C</td><td>3.23250100</td><td>4.35520900</td><td>-1.82534300</td></tr><tr><td>H</td><td>2.37213200</td><td>4.21603300</td><td>-2.49626100</td></tr><tr><td>H</td><td>3.46798100</td><td>5.42907300</td><td>-1.79108400</td></tr><tr><td>O</td><td>2.93989800</td><td>3.87392800</td><td>-0.52125300</td></tr><tr><td>O</td><td>-6.63113200</td><td>3.83095400</td><td>0.20523600</td></tr><tr><td>C</td><td>-5.97428900</td><td>3.81580300</td><td>-1.08926300</td></tr><tr><td>H</td><td>-6.10154300</td><td>2.82819300</td><td>-1.54759900</td></tr><tr><td>H</td><td>-6.52711500</td><td>4.54981900</td><td>-1.68144200</td></tr><tr><td>C</td><td>-4.85218600</td><td>-3.72609900</td><td>-3.97542100</td></tr><tr><td>H</td><td>-5.58795800</td><td>-3.20484900</td><td>-4.59038300</td></tr><tr><td>H</td><td>-4.55074200</td><td>-4.64422000</td><td>-4.48523000</td></tr><tr><td>C</td><td>0.05321900</td><td>-1.96349900</td><td>4.63157500</td></tr><tr><td>H</td><td>-0.23709700</td><td>-1.67169000</td><td>5.65181400</td></tr><tr><td>H</td><td>-0.20823300</td><td>-3.01657900</td><td>4.49866700</td></tr><tr><td>C</td><td>7.72611200</td><td>-0.19731400</td><td>2.83871200</td></tr><tr><td>H</td><td>8.14238700</td><td>0.70525100</td><td>3.29981000</td></tr><tr><td>H</td><td>8.27559900</td><td>-1.06224700</td><td>3.23153300</td></tr><tr><td>C</td><td>2.17152000</td><td>0.05833100</td><td>-2.81229600</td></tr><tr><td>H</td><td>1.83833600</td><td>1.07602800</td><td>-2.59465700</td></tr><tr><td>H</td><td>2.74121400</td><td>0.09952300</td><td>-3.75019100</td></tr><tr><td>C</td><td>1.94494400</td><td>4.61965400</td><td>0.17636900</td></tr><tr><td>H</td><td>2.10910700</td><td>4.38135700</td><td>1.23417300</td></tr><tr><td>H</td><td>2.11638700</td><td>5.69812600</td><td>0.04916200</td></tr><tr><td>C</td><td>6.25224300</td><td>-0.31205600</td><td>3.16501000</td></tr><tr><td>C</td><td>5.73069100</td><td>-1.43675300</td><td>3.77062400</td></tr><tr><td>C</td><td>5.37944400</td><td>0.76335800</td><td>2.83604300</td></tr><tr><td>C</td><td>4.33882200</td><td>-1.55805700</td><td>4.03581400</td></tr><tr><td>H</td><td>6.38557500</td><td>-2.26308500</td><td>4.04037400</td></tr><tr><td>C</td><td>4.02731000</td><td>0.67663300</td><td>3.07149200</td></tr><tr><td>H</td><td>5.79607900</td><td>1.66150900</td><td>2.38715800</td></tr><tr><td>C</td><td>3.77645800</td><td>-2.71748900</td><td>4.63405500</td></tr><tr><td>C</td><td>3.46249200</td><td>-0.48988400</td><td>3.65949500</td></tr><tr><td>H</td><td>3.37032200</td><td>1.50170100</td><td>2.80726500</td></tr><tr><td>C</td><td>2.41707900</td><td>-2.82532100</td><td>4.81919400</td></tr><tr><td>H</td><td>4.43492700</td><td>-3.53208000</td><td>4.92536500</td></tr><tr><td>C</td><td>2.06490500</td><td>-0.63084700</td><td>3.86931100</td></tr><tr><td>C</td><td>1.53857600</td><td>-1.78001800</td><td>4.42354000</td></tr><tr><td>H</td><td>2.00264500</td><td>-3.72919800</td><td>5.25937500</td></tr><tr><td>H</td><td>1.40335000</td><td>0.17328800</td><td>3.56122800</td></tr><tr><td>C</td><td>0.97962300</td><td>-0.85913200</td><td>-2.94653500</td></tr><tr><td>C</td><td>-0.28207100</td><td>-0.32225400</td><td>-3.09811700</td></tr><tr><td>C</td><td>1.13847300</td><td>-2.27355400</td><td>-2.97144900</td></tr><tr><td>C</td><td>-1.42297100</td><td>-1.14551600</td><td>-3.29474200</td></tr><tr><td>H</td><td>-0.41976200</td><td>0.75655500</td><td>-3.07392900</td></tr><tr><td>C</td><td>0.05230700</td><td>-3.10096300</td><td>-3.14324000</td></tr><tr><td>H</td><td>2.13117200</td><td>-2.69842400</td><td>-2.85307200</td></tr><tr><td>C</td><td>-2.72283400</td><td>-0.60529300</td><td>-3.48575800</td></tr><tr><td>C</td><td>-1.25686800</td><td>-2.56812500</td><td>-3.31597800</td></tr><tr><td>H</td><td>0.18462500</td><td>-4.18009900</td><td>-3.16080700</td></tr><tr><td>C</td><td>-3.80301500</td><td>-1.43071300</td><td>-3.69987400</td></tr><tr><td>H</td><td>-2.85005500</td><td>0.47452200</td><td>-3.47348600</td></tr><tr><td>C</td><td>-2.39582900</td><td>-3.38921000</td><td>-3.52816600</td></tr><tr><td>C</td><td>-3.65123500</td><td>-2.84448600</td><td>-3.72512100</td></tr><tr><td>H</td><td>-4.78867000</td><td>-1.00599500</td><td>-3.86724200</td></tr><tr><td>H</td><td>-2.26327500</td><td>-4.46922000</td><td>-3.55164600</td></tr><tr><td>C</td><td>0.51976300</td><td>4.26558700</td><td>-0.20250100</td></tr><tr><td>C</td><td>-0.43438500</td><td>5.24474900</td><td>-0.38976500</td></tr><tr><td>C</td><td>0.13240200</td><td>2.89894600</td><td>-0.28384900</td></tr><tr><td>C</td><td>-1.79839900</td><td>4.91672100</td><td>-0.62374100</td></tr><tr><td>H</td><td>-0.15454800</td><td>6.29504400</td><td>-0.33321800</td></tr><tr><td>C</td><td>-1.17203700</td><td>2.54549500</td><td>-0.53669300</td></tr><tr><td>H</td><td>0.88015000</td><td>2.12795800</td><td>-0.12787300</td></tr><tr><td>C</td><td>-2.80898100</td><td>5.90773100</td><td>-0.76309300</td></tr><tr><td>C</td><td>-2.17711900</td><td>3.53789900</td><td>-0.70069800</td></tr><tr><td>H</td><td>-1.45528300</td><td>1.49729500</td><td>-0.59072000</td></tr><tr><td>C</td><td>-4.12675100</td><td>5.55004100</td><td>-0.93237300</td></tr><tr><td>H</td><td>-2.52575400</td><td>6.95662800</td><td>-0.71868200</td></tr><tr><td>C</td><td>-3.54265100</td><td>3.20561000</td><td>-0.90326900</td></tr><tr><td>C</td><td>-4.51361500</td><td>4.18296400</td><td>-0.99585300</td></tr><tr><td>H</td><td>-4.89078000</td><td>6.31919100</td><td>-1.01651300</td></tr><tr><td>H</td><td>-3.81989200</td><td>2.15521300</td><td>-0.96051200</td></tr></table>","table_caption":"[\"Symbolic 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","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,485,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"92","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,804,307,820]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"92","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,832,371,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"92","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4064.5224152 a.u. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[850,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"92","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S93 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,831,393,844]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"100","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C 4.556981 3.352204 3.997564 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,845,393,858]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"100","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"H 3.700189 3.435756 3.314244 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,859,393,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"100","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"H 4.215435 3.518216 5.020905 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,873,393,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"100","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"H 5.300361 4.116602 3.734161 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,888,393,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"100","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C -6.326548 3.222274 0.067170 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[840,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"100","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S101 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,394,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"H -6.994203 3.966981 0.532924 \",\"H -5.636410 3.759001 -0.596531 \",\"C -0.964299 -4.241161 1.485265 \",\"H -1.569203 -4.824672 2.200074 \",\"H -0.817363 -4.851190 0.584944 \",\"C -4.660255 3.238461 1.776415 \",\"H -4.323514 2.569076 2.577594 \",\"H -5.128765 4.114827 2.255470 \",\"C 0.347724 -3.810810 2.061279 \",\"C 0.390872 -2.921277 3.155640 \",\"C 1.557496 -4.260161 1.509937 \",\"C 1.615269 -2.392550 3.636481 \",\"H -0.530365 -2.608921 3.645012 \",\"C 2.785125 -3.825113 2.008808 \",\"H 1.533394 -4.958712 0.675106 \",\"C 1.673555 -1.371928 4.624179 \",\"C 2.855849 -2.850480 3.052719 \",\"H 3.709995 -4.194268 1.571579 \",\"C 2.886755 -0.801473 4.998441 \",\"H 0.743912 -1.009157 5.057745 \",\"C 4.070573 -2.283583 3.499249 \",\"C 4.098100 -1.251028 4.451502 \",\"H 2.898838 0.000519 5.734489 \",\"H 5.004119 -2.637954 3.068069 \",\"C -3.450777 3.682199 0.968442 \",\"C -2.604202 4.645664 1.488239 \",\"C -3.136467 3.080272 -0.275309 \",\"C -1.411960 5.024903 0.821590 \",\"H -2.834743 5.112195 2.444911 \",\"C -2.009675 3.467558 -0.976625 \",\"H -3.797119 2.314727 -0.672610 \",\"C -0.490544 5.957295 1.372620 \",\"C -1.111564 4.436039 -0.451731\",\"H -1.794859 3.027268 -1.948393 \",\"C 0.673405 6.278105 0.708802 \",\"H -0.711617 6.403517 2.339365 \",\"C 0.078825 4.819923 -1.128409 \",\"C 0.967922 5.709530 -0.556830 \",\"H 1.373318 6.982253 1.155235 \",\"H 0.291838 4.402927 -2.108725 \",\"C -3.476018 -2.235159 -3.597706 \",\"C -2.973736 -3.477355 -3.247852 \",\"C -2.571098 -1.191342 -3.910439 \",\"C -1.578130 -3.716612 -3.148687 \",\"H -3.659017 -4.289975 -3.013958 \",\"C -1.207245 -1.392639 -3.841278 \",\"H -2.965910 -0.219175 -4.195135 \",\"C -1.044759 -4.967796 -2.737958 \",\"C -0.667250 -2.645445 -3.435103 \",\"H -0.521962 -0.584487 -4.091295 \",\"C 0.314456 -5.134718 -2.562657 \",\"H -1.727079 -5.793872 -2.550954 \",\"C 0.725153 -2.860018 -3.262455 \",\"C 1.216873 -4.069775 -2.801262 \",\"H 0.703063 -6.097139 -2.236014 \",\"H 1.417440 -2.052883 -3.486511 \",\"C -4.958291 -1.970008 -3.581823 \",\"H -5.282621 -1.462222 -4.506399 \"]","page_idx":"101","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[842,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"101","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S102 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[117,80,394,505]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"H -5.514103 -2.918714 -3.514278 \",\"O -9.080949 -0.793936 -0.033917\",\"H -8.760994 -0.804977 0.892485 \",\"O -2.917465 -1.381970 2.896292 \",\"H -2.183667 -1.922076 2.527232 \",\"O -7.711153 -0.979743 2.415359 \",\"H -7.633691 -0.709346 3.346590 \",\"C -8.369360 0.205460 -0.726738 \",\"H -8.901840 0.364415 -1.673144 \",\"C 0.267284 0.358419 1.820783 \",\"H 0.032426 -0.682131 2.056664 \",\"H 0.980682 0.709379 2.569861 \",\"C -1.009273 1.214830 1.853790 \",\"H -0.782854 2.273105 1.702954 \",\"H -1.708503 0.912060 1.065555 \",\"O -1.599713 1.095059 3.132058 \",\"H -2.143367 0.279876 3.123937 \",\"C 1.539293 1.670393 0.111928 \",\"H 2.069619 1.590268 -0.838615 \",\"H 0.715204 2.375506 0.017078 \",\"H 2.234293 1.997748 0.886776 \",\"C 2.181354 -0.632571 0.623869 \",\"H 1.803704 -1.638414 0.801183 \",\"H 2.759361 -0.600374 -0.301960 \",\"H 2.800738 -0.318576 1.464260 \",\"C 0.107790 -0.206638 -0.599379 \",\"H 0.711952 -0.405361 -1.484670 \",\"H -0.355585 -1.133197 -0.254372 \",\"H -0.652686 0.539503 -0.827940 \",\"N 1.012651 0.314164 0.487669 \"]","page_idx":"102","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[114,535,307,550]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"102","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imaginary Frequency $= 0$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,562,361,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"102","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E(RB3LYP) = -4393.317892 a.u. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[840,927,880,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"102","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S103 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[366,143,631,162]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supporting Information for \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[132,242,868,324]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fluorescent Molecular Cages with Sucrose and Cyclotriveratrylene Units for the Selective Recognition of Choline and Acetylcholine \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[159,357,836,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Łukasz Szyszka,* Marcin Górecki, Piotr Cmoch, and Sławomir Jarosz* \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[144,388,850,407]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[388,420,611,437]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"01-224 Warsaw, Poland\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[860,928,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[115,83,347,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table of Contents \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,134,880,151]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table S1. Comparison of ${}^{1}\\\\mathrm{H}$ and ${}^{13}\\\\mathrm{C}$ NMR signals of P-5a,P-5b,M-5a,and M-5b. S3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,156,880,171]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure S1-S12. Fluorescence titration experiments.. .S5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,177,880,192]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table S2. Fit parameters.. .S9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,197,880,212]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure S13-S22. $^1\\\\mathsf{H}$ NMR titration experiments.. .S9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,219,880,234]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure S23-S71. NMR spectra . S15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,239,880,254]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure S72-S80. MS spectra . 64 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,260,880,275]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geometry of calculated structures. S73 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[860,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[77,107,894,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0416/eb7ccfbc56b3ed28561e3dcc0f27ddc4a966c5329dcb87833301328516d06662.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td colspan=\\\"4\\\">\\\\( ^1\\\\text{H} \\\\) and \\\\( ^{13}\\\\text{C} \\\\) NMR chemical shifts δ (ppm)</td></tr><tr><td>Glucose part</td><td>P-5a</td><td>P-5b</td><td>M-5a</td><td>M-5b</td></tr><tr><td>H-1/C-1</td><td>5.19/90.7</td><td>5.55/88.7</td><td>5.60/91.4</td><td>5.54/88.9</td></tr><tr><td>H-2/C-2</td><td>3.30/79.9</td><td>3.61/79.3</td><td>3.38/79.7</td><td>3.64/79.5</td></tr><tr><td>H-3/C-3</td><td>3.79/81.6</td><td>3.92/82.3</td><td>3.72/81.4</td><td>3.93/82.4</td></tr><tr><td>H-4/C-4</td><td>3.56/77.5</td><td>3.57/78.0</td><td>3.41/77.7</td><td>3.70/77.9</td></tr><tr><td>H-5/C-5</td><td>3.81/70.6</td><td>4.13/69.9</td><td>3.90/70.4</td><td>4.19/69.4</td></tr><tr><td>H-6a+H-6b/C-6</td><td>3.17+3.53/68.1</td><td>3.26+3.31/67.6</td><td>3.06+3.39/67.9</td><td>3.20+3.46/65.9</td></tr><tr><td>Fructose part</td><td></td><td></td><td></td><td></td></tr><tr><td>H-1'a+H-1'b/C-1'</td><td>3.45+3.65/69.9</td><td>3.58+3.71/74.8</td><td>3.66+3.72/69.1</td><td>3.43+3.80/74.8</td></tr><tr><td>C-2'</td><td>104.1</td><td>104.0</td><td>104.6</td><td>103.0</td></tr><tr><td>H-3'/C-3'</td><td>4.38/84.1</td><td>4.24/82.5</td><td>4.35/84.9</td><td>4.29/83.4</td></tr><tr><td>H-4'/C-4'</td><td>3.83/82.4</td><td>3.53/81.3</td><td>4.03/83.1</td><td>3.06/81.8</td></tr><tr><td>H-5'/C-5'</td><td>4.07/80.9</td><td>3.32/79.2</td><td>3.92/80.8</td><td>3.76/77.6</td></tr><tr><td>H-6'a+H-6'b/C-6'</td><td>3.36+3.54/73.0</td><td>2.84+3.37/70.9</td><td>3.46+3.49/73.1</td><td>2.25+2.95/72.7</td></tr><tr><td>Naphthalene linkers</td><td></td><td></td><td></td><td></td></tr><tr><td>H-7a+H-7b/C-7</td><td>4.15+4.45/73.1</td><td>4.23+4.78/73.0</td><td>4.04+4.64/73.4</td><td>4.23+4.94/72.8</td></tr><tr><td>H-7'a+H-7'b/C-7'</td><td>4.30+4.46/72.5</td><td>3.95+4.21/72.6</td><td>4.34/72.3</td><td>3.73+3.96/71.6</td></tr><tr><td>H-7\\\"a+H-7\\\"b/C-7\\\"</td><td>4.27+4.76/73.0</td><td>4.58+4.66/74.4</td><td>4.50+5.07/73.9</td><td>4.59+4.67/74.2</td></tr><tr><td>C-8</td><td>135.9</td><td>135.3</td><td>135.4</td><td>135.4</td></tr><tr><td>C-8'</td><td>136.9</td><td>136.1</td><td>136.3</td><td>136.5</td></tr><tr><td>C-8\\\"</td><td>135.8</td><td>136.5</td><td>135.9</td><td>136.6</td></tr><tr><td>H-9/C-9</td><td>7.47/126.1</td><td>7.62/127.0</td><td>7.36/126.7</td><td>7.78/128.5</td></tr><tr><td>H-9'/C-9'</td><td>7.51/124.5</td><td>7.47/126.0</td><td>7.40/124.4</td><td>7.16/123.1</td></tr><tr><td>H-9\\\"/C-9\\\"</td><td>7.64/126.2</td><td>7.49/125.5</td><td>7.83/127.4</td><td>7.62/125.1</td></tr><tr><td>C-10</td><td>132.78/132.0</td><td>132.6</td><td>nd</td><td>132.8</td></tr><tr><td>C-10'</td><td>132.6</td><td>132.4</td><td>nd</td><td>132.2</td></tr><tr><td>C-10\\\"</td><td>132.6</td><td>132.82/132.3</td><td>nd</td><td>132.8</td></tr><tr><td>H-11/C-11</td><td>7.51/127.8</td><td>7.65/127.8</td><td>7.30/127.8</td><td>7.67/128.0</td></tr><tr><td>H-11'/C-11'</td><td>7.46/126.1</td><td>7.55/127.6</td><td>7.44/127.2</td><td>7.18/126.4</td></tr><tr><td>H-11\\\"/C-11\\\"</td><td>7.65/128.1</td><td>7.23/125.3</td><td>7.76/128.4</td><td>7.49/128.8</td></tr><tr><td>H-12/C-12</td><td>7.16/125.4</td><td>7.27/125.3</td><td>7.21/125.9</td><td>7.14/127.2</td></tr><tr><td>H-12'/C-12'</td><td>7.11/125.6</td><td>7.32/125.8</td><td>7.17/126.6</td><td>7.12/128.0</td></tr><tr><td>H-12\\\"/C-12\\\"</td><td>7.35/124.8</td><td>6.87/125.4</td><td>7.38/125.5</td><td>7.32/123.7</td></tr><tr><td>C-13</td><td>134.2</td><td>135.1</td><td>134.3</td><td>134.2</td></tr><tr><td>C-13'</td><td>133.3</td><td>133.5</td><td>133.6</td><td>131.1</td></tr><tr><td>C-13\\\"</td><td>135.3</td><td>134.7</td><td>134.9</td><td>135.2</td></tr><tr><td>H-14/C-14</td><td>7.46/126.3</td><td>7.57/125.9</td><td>7.45/126.6</td><td>7.58/128.1</td></tr><tr><td>H-14'/C-14'</td><td>6.94/126.8</td><td>7.06/126.3</td><td>6.84/128.2</td><td>6.55/129.9</td></tr><tr><td>H-14\\\"/C-14\\\"</td><td>7.77/125.4</td><td>7.56/126.3</td><td>7.73/126.3</td><td>7.70/124.1</td></tr><tr><td>C-15</td><td>132.78/132.0</td><td>132.8</td><td>nd</td><td>132.8</td></tr><tr><td>C-15'</td><td>132.5</td><td>132.2</td><td>nd</td><td>131.1</td></tr><tr><td>C-15\\\"</td><td>132.6</td><td>132.82/132.3</td><td>nd</td><td>132.5</td></tr><tr><td>H-16/C-16</td><td>7.39/127.7</td><td>7.55/128.2</td><td>7.23/128.0</td><td>7.69/128.2</td></tr><tr><td>H-16'/C-16'</td><td>6.68/127.7</td><td>6.79/127.6</td><td>6.98/127.9</td><td>6.14/126.9</td></tr><tr><td>H-16\\\"/C-16\\\"</td><td>7.58/127.9</td><td>7.52/127.7</td><td>7.79/128.0</td><td>7.49/127.6</td></tr><tr><td>H-17/C-17</td><td>7.02/126.2</td><td>7.38/126.5</td><td>7.02/126.3</td><td>7.52/128.2</td></tr><tr><td>H-17'/C-17'</td><td>6.88/125.6</td><td>6.91/126.3</td><td>7.01/125.0</td><td>6.49/124.9</td></tr><tr><td>H-17\\\"/C-17\\\"</td><td>7.36/126.3</td><td>7.04/125.4</td><td>7.48/127.2</td><td>7.21/125.3</td></tr><tr><td>H-18a+H-18b/C-18</td><td>4.81+5.24/71.4</td><td>4.87+5.09/71.3</td><td>5.31+5.40/70.2</td><td>3.94+4.87/70.6</td></tr><tr><td>H-18'a+H-18'b/C-18'</td><td>5.15+5.26/72.6</td><td>5.35+5.46/72.3</td><td>4.40+5.20/76.2</td><td>5.00+5.35/77.0</td></tr><tr><td>H-18\\\"a+H-18\\\"b/C-18\\\"</td><td>5.15+5.36/72.7</td><td>4.94+5.27/73.9</td><td>4.97+5.21/71.3</td><td>5.45+5.64/69.4</td></tr><tr><td>CTV-ring A</td><td></td><td></td><td></td><td></td></tr><tr><td>C-19</td><td>146.1</td><td>147.3</td><td>145.8</td><td>147.1</td></tr><tr><td>C-20</td><td>148.5</td><td>148.4</td><td>148.6</td><td>147.6</td></tr><tr><td>H-21/C-21</td><td>6.64/113.0</td><td>6.70/113.5</td><td>6.99/113.8</td><td>6.54/111.8</td></tr><tr><td>C-22</td><td>132.7</td><td>132.8</td><td>133.2</td><td>130.9</td></tr><tr><td>H-23a+H-23b/C-23</td><td>3.51+4.70/36.4</td><td>3.55+4.77/36.3</td><td>3.61+4.79/36.2</td><td>3.57+4.74/36.6</td></tr><tr><td>C-24</td><td>131.6</td><td>131.6</td><td>131.9</td><td>131.4</td></tr><tr><td>H-25/C-25</td><td>6.86/116.3</td><td>6.88/116.4</td><td>7.09/116.7</td><td>6.42/112.4</td></tr><tr><td>H-26/C-26 (OCH3)</td><td>3.40/55.5</td><td>3.60/56.0</td><td>3.92/56.3</td><td>3.02/54.5</td></tr><tr><td>CTV-ring B</td><td></td><td></td><td></td><td></td></tr><tr><td>C-19'</td><td>145.9</td><td>147.6</td><td>146.8</td><td>146.9</td></tr><tr><td>C-20'</td><td>149.1</td><td>149.1</td><td>150.3</td><td>148.0</td></tr><tr><td>H-21'/C-21'</td><td>6.67/113.4</td><td>6.81/114.4</td><td>6.64/113.5</td><td>7.19/113.7</td></tr><tr><td>C-22'</td><td>133.7</td><td>133.6</td><td>134.7</td><td>133.0</td></tr><tr><td>H-23'a+H-23'b/C-23'</td><td>3.47+4.70/36.4</td><td>3.57+4.77/36.6</td><td>3.51+4.74/36.5</td><td>3.67+4.79/36.0</td></tr><tr><td>C-24'</td><td>131.7</td><td>132.5</td><td>132.1</td><td>132.4</td></tr><tr><td>H-25'/C-25'</td><td>6.95/118.6</td><td>7.09/118.5</td><td>7.12/121.9</td><td>7.13/113.8</td></tr><tr><td>H-26'/C-26' (OCH3)</td><td>3.55/55.9</td><td>3.44/56.2</td><td>3.22/55.5</td><td>4.03/56.4</td></tr><tr><td>CTV-ring C</td><td></td><td></td><td></td><td></td></tr><tr><td>C-19\\\"</td><td>147.0</td><td>145.3</td><td>147.3</td><td>144.4</td></tr><tr><td>C-20\\\"</td><td>148.8</td><td>149.7</td><td>148.0</td><td>151.1</td></tr><tr><td>H-21\\\"/C-21\\\"</td><td>6.61/113.4</td><td>6.86/113.9</td><td>6.93/115.0</td><td>6.33/112.9</td></tr><tr><td>C-22\\\"</td><td>133.3</td><td>134.0</td><td>131.8</td><td>135.6</td></tr><tr><td>H-23\\\"a+H-23\\\"b/C-23\\\"</td><td>3.48+4.68/36.2</td><td>3.59+4.77/36.5</td><td>3.51+4.74/36.4</td><td>3.37+4.71/36.2</td></tr><tr><td>C-24\\\"</td><td>132.0</td><td>132.3</td><td>132.4</td><td>131.6</td></tr><tr><td>H-25\\\"/C-25\\\"</td><td>6.99/117.6</td><td>7.07/120.0</td><td>6.76/113.3</td><td>7.34/124.1</td></tr><tr><td>H-26\\\"/C-26\\\" (OCH3)</td><td>3.21/55.5</td><td>3.73/56.3</td><td>3.48/55.7</td><td>3.19/55.4</td></tr></table>\",\n \"table_caption\": \"[\\\"Table S1. Comparison of ${}^{1}\\\\\\\\mathrm{H}$ and ${}^{13}\\\\\\\\mathrm{C}$ NMR signals of P-5a, P-5b, M-5a, and M-5b. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[860,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[77,78,890,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[860,928,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[161,126,594,141]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fluorescence titration curves for acetylcholine iodide \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[154,173,524,374]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0931/69772aa599264cfe38afcac90eea103bfb54e6d7c1adc721cdcd1a4d83677784.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[531,177,875,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0140/83a61b49136a068d9e246e5eb6a3bde6dab89955c205b3ac9d235c630b18b241.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[152,411,522,611]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FigureS1. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage P-5a. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0016/1a887597f377f40079fccc688c6beb33a3aea40ed60d9145f0d19d9521c737e9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[524,412,870,611]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FigureS2. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage M-5a. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0414/5999347999979ad29295bb306c5794272d61bd7ebf192d74a5bee45c37eb60a8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[287,657,715,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FigureS3. Fluorescence titration of host P-5b with ACh in $\\\\\\\\mathrm{CH}_3\\\\\\\\mathrm{CN}$ excited at $280~\\\\\\\\mathrm{nm}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0837/73a8ee8fadd68eb7c0ce1b1ee762d78e59342fd950d541a9736a20900a938d93.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[115,83,453,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fluorescence titration experiments \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[860,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[154,84,517,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0990/dd5eb05189bf69f978712bb51a51362d953e0743674334abe0820902ca2f5094.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[522,86,860,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FigureS4. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage P-5b. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0570/fc41c01606d7afc4409a584959794360380f544cfff7dbe7c7bd1563697bbb30.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[290,330,714,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S5. Fluorescence titration of host M-5b with ACh in $\\\\\\\\mathrm{CH}_3\\\\\\\\mathrm{CN}$ excited at $280~\\\\\\\\mathrm{nm}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0864/7f70526c0b0fede270864ef2de14fef2a6a284d79dae03f8960cf13c32556635.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,623,515,822]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0016/075e2e4c59bb5bdcacc9e9a533ae30c1356e4991d922f769d71ddc787821ae49.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[522,624,860,822]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S6. Fluorescence intensity and molefraction as a functions of guest/host ratio for cage M-5b. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0865/4b0844bc9f9ea8914be498031b6f56707e9a2ce5e0f531cbc89efdc07e00897d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[860,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[159,127,519,326]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0316/97341d0dff524ff1ae3bbb747f7c392f1bb7b8cfb66fdabdd48d29701390dc48.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[522,127,867,326]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S7. Fluorescence intensity and molefraction as a function of guest/host ratio for cage P-5a. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0758/a3db01457fcb0e0b59f08cbfbdaf0dcc54c476a7fdc76b817d04096c39163296.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,378,524,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0756/613a9726c4a1b51d69e571d8aec1dc013752ad2e0b6c6038239025889b540ae7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[527,376,872,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S8. Fluorescence intensity and molefraction as a function of guest/host ratio for cage M-5a. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0098/1af02b60933327fe5a4474142cd07e176c4b91134a2572b5b99c658be805d0bc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[295,624,715,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S9. Fluorescence titration of host P-5b with Ch in $\\\\\\\\mathrm{CH}_3\\\\\\\\mathrm{CN}$ excited at $280~\\\\\\\\mathrm{nm}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0943/4e26b655aa035490fe6afb2ff77736d4da717766a1630718b6dc607f10294f15.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[161,82,547,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fluorescence titration curves for choline iodide \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[860,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[154,85,524,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0917/92dd7199a481d23898bf5818ec4d9f4b650d666fe96df5b530c87e20726efb64.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[527,85,875,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S10. Fluorescence intensity and molefraction as a function of guest/host ratio for cage P-5b. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0410/bcfc3fdb6cd29e9debcad74173afec507920b22ceb01bfa59507abafc023fca2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[285,332,712,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S11. Fluorescence titration of host M-5b with Ch in $\\\\\\\\mathrm{CH}_3\\\\\\\\mathrm{CN}$ excited at $280~\\\\\\\\mathrm{nm}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0333/70558699593e73f058532e6f1059dd1d943bdef9525f25e2f843b3d249ad654a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,606,515,807]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0294/ec01f2e4857a01a838f1bb51f224c18420464af5c7699bebcca200eb444bf677.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[522,606,867,806]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S12. Fluorescence intensity and molefraction as a function of guest/host ratio for cage M-5b. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0473/2eaf823f086b9b2c696abf45f28e4767fa59d6a316565744862e207d190f29bc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[860,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[144,82,265,97]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fit parameters \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[136,129,892,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0488/90ee1e10e49f3408512cc605f6061e34ae4c76722184484692d993defef96c01.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Host</td><td>Guest</td><td>Ka(M-1)</td><td>RMS (Intensity a.u.)</td><td>Covariance</td></tr><tr><td rowspan=\\\"2\\\">P-5a</td><td>ACh</td><td>2.2 × 103± 1.6%</td><td>1.0 × 103</td><td>2.1 × 10-2</td></tr><tr><td>Ch</td><td>3.8 × 103± 0.9%</td><td>1.6 × 103</td><td>8.5 × 10-3</td></tr><tr><td rowspan=\\\"2\\\">M-5a</td><td>ACh</td><td>5.6 × 103± 1.7%</td><td>2.2 × 103</td><td>1.8 × 10-2</td></tr><tr><td>Ch</td><td>1.8 × 103± 1.4%</td><td>1.8 × 103</td><td>2.2 × 10-2</td></tr><tr><td rowspan=\\\"2\\\">P-5b</td><td>ACh</td><td>2.4 × 103± 3.5%</td><td>6.1 × 103</td><td>7.2 × 10-2</td></tr><tr><td>Ch</td><td>2.6 × 103± 3.8%</td><td>2.6 × 103</td><td>2.8 × 10-2</td></tr><tr><td rowspan=\\\"2\\\">M-5b</td><td>ACh</td><td>0.6 × 103± 0.9%</td><td>2.8 × 103</td><td>1.7 × 10-2</td></tr><tr><td>Ch</td><td>0.5 × 103± 1.1%</td><td>2.6 × 103</td><td>2.8 × 10-2</td></tr></table>\",\n \"table_caption\": \"[\\\"Table S2. Fit parameters obtained from the fluorescence titrations. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[124,335,887,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"$^{1}$ H NMR titration experiments \\\",\\\"Figure S13. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, $\\\\\\\\mathrm{CD}_3\\\\\\\\mathrm{CN} / \\\\\\\\mathrm{CDCl}_3 = 80:20$ ) spectra of M-5a after gradual addition of acetylcholine iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0607/cf981286cf40e024d29d9fa5bc841f16b815f089f3c06b9e1ac9033a35d8c321.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[860,928,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[154,83,905,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0101/c4670f1bbdec79c0ede1f068ddb19aa2f9b604b3e08b6e4f368bb1eef93740df.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[169,510,860,865]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S14. $^{1}$ H NMR (400 MHz, CD₃CN/CDCI₃ = 80:20) spectra of aromatic part of M-5a after gradual addition of acetylcholine iodide in the same solvent. \\\",\\\"Figure S15. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, $\\\\\\\\mathrm{CD}_3\\\\\\\\mathrm{CN} / \\\\\\\\mathrm{CDCl}_3 = 80:20$ ) spectra of ACh chemical shifts during titration studies of M-5a with acetylcholine iodide. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0093/544021f6ddaadc33200f2db5a819dd3b16588e214680e5633315bf4f8b41f016.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[154,85,912,435]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S16. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, $\\\\\\\\mathrm{CD}_3\\\\\\\\mathrm{CN} / \\\\\\\\mathrm{CDCl}_3 = 80:20$ ) spectra of M-5a after gradual addition of choline iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0042/7091df360b7afab8085494f415d6e6f678287468250f2014ccdf30d3da53eca8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,475,902,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S17. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, ${\\\\\\\\mathrm{{CD}}}_{3}\\\\\\\\mathrm{{CN}}/{\\\\\\\\mathrm{{CDCl}}}_{3} = {80} : {20}$ ) spectra of aromatic part of M-5a after gradual addition of choline iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0698/24db4ec8f51ad95ea4dad89d4221e201256419d2edbcbeec5536f21ef4ac7d31.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[850,928,878,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[163,82,860,444]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S18. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, $\\\\\\\\mathrm{CD}_3\\\\\\\\mathrm{CN} / \\\\\\\\mathrm{CDCl}_3 = 80:20$ ) spectra of Ch chemical shifts during titration studies of M-5a with choline iodide. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0109/c13e2d249dd046b627ccf6f74b40c2a5d9103198f94b7d4f5991a46a8ca4759f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,500,914,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S19. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, $\\\\\\\\mathrm{CD}_3\\\\\\\\mathrm{CN} / \\\\\\\\mathrm{CDCl}_3 = 80:20$ ) spectra of $P$ -5a after gradual addition of acetylcholine iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0506/3e99d09cb3e7ace902e24e9bc2b8d39fc7afd662a768b15f0da9fa5ef5540d31.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[850,928,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[159,83,868,451]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S20. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, $\\\\\\\\mathrm{CD}_3\\\\\\\\mathrm{CN} / \\\\\\\\mathrm{CDCl}_3 = 80:20$ ) spectra of aromatic part of $P - 5a$ after gradual addition of acetylcholine iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0894/d255b0ddb95977e13bef0a10b6b3673df2cecf525bf8ead295956302af7717eb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,505,914,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S21. ${}^{1}\\\\\\\\mathrm{H}$ NMR (400 MHz, ${\\\\\\\\mathrm{{CD}}}_{3}\\\\\\\\mathrm{{CN}}/{\\\\\\\\mathrm{{CDCl}}}_{3} = {80} : {20}$ ) spectra of P-5a after gradual addition of choline iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": 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aromatic part of P-5a after gradual addition of choline iodide in the same solvent. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0941/69918e06754105cda98619fc6e65e011fdf468451147e4efc96bc7aa23b67e99.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[850,928,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[140,119,866,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S23. ${}^{1}\\\\\\\\mathrm{H}$ NMR (600 MHz,CDCl ${}_{3}$ ) spectrum of compound 3. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0163/f91020c36acdd752527f00cee7835fd973640f67b6ff3cb96fbee2268663163f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[892,897,916,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[140,122,854,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S24. $^{1}$ H NMR (600 MHz, CDCl₃) spectrum of compound 3 (aliphatic part). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0928/21a1958acfab8034ff74e3a754cea3161e8276faff0360dcfe009dabe466f1a8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[894,897,916,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[137,119,860,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S25. $^{13}\\\\\\\\mathrm{C}\\\\\\\\{^1\\\\\\\\mathrm{H}\\\\\\\\}$ NMR (150 MHz, CDCl₃) spectrum of compound 3. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0308/0428371ecf5556162e4ce674c14c161699f13fba489a85c6d3480c620b81aa4e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[892,897,915,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[140,122,854,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S26. $^{13}\\\\\\\\mathrm{C}\\\\\\\\{^1\\\\\\\\mathrm{H}\\\\\\\\}$ DEPT (150 MHz, CDCl₃) spectrum of compound 3. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0969/c9c179c2610da25d497cb9c374de3f2cf852e53822726bb6cc3ed525131e06dc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[894,897,915,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S18 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n 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\"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S72. ESI-MS spectrum of compound 3. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0207/cf18ec92a377c445fa9b4ea6c37203c0270695eb4f49bf1990f30216fac8b396.jpg\",\n \"list_items\": null,\n \"page_idx\": \"63\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[894,897,916,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"63\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S64 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[265,142,511,159]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"64\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C:0-150 H:0-150 O:0-17 Na:1-1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[262,166,749,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0987/5e6b1622776319dc03a56c20a36944f5bfe005f8074d1e43bb6c0e8a2cd55447.jpg\",\n \"list_items\": null,\n \"page_idx\": \"64\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Mass</td><td>Calc. Mass</td><td>mDa</td><td>PPM</td><td>DBE</td><td>Formula</td><td>C</td><td>H</td><td>O</td><td>Na</td><td></td></tr><tr><td rowspan=\\\"3\\\">1679.6844</td><td>1679.6858</td><td>-1.4</td><td>-0.8</td><td>57.5</td><td>C107 H100 O17 Na</td><td>107</td><td>100</td><td>17</td><td>1</td><td></td></tr><tr><td>1679.6799</td><td>4.5</td><td>2.7</td><td>66.5</td><td>C114 H96 O12 Na</td><td>114</td><td>96</td><td>12</td><td>1</td><td></td></tr><tr><td>1679.6893</td><td>-4.9</td><td>-2.9</td><td>79.5</td><td>C125 H92 O4 Na</td><td>125</td><td>92</td><td>4</td><td>1</td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Elements Used: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[776,248,822,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"64\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1:TOFMSES+ 2.69e3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[170,248,824,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S73. HRMS spectrum of compound P-5a. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1009/3ec27106f4faec7d87d83da1ada40fb992d5d3a66a876c8ca833968bd23fffdf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"64\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[894,897,915,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"64\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S65 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[214,136,456,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Elements Used: \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0010/7c17ba0adbad2f81fd24b16dc002d903f14bcd870726f54d9584f19e82c14b89.jpg\",\n \"list_items\": null,\n \"page_idx\": \"65\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[208,166,778,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0664/d61c2eb7825350628621140dba3e0858face0268ab1d2014b3ca22c7a71fcee5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"65\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Mass</td><td>Calc. Mass</td><td>mDa</td><td>PPM</td><td>DBE</td><td>Formula</td><td>i-FIT</td><td>i-FIT Norm</td><td>Fit Conf %</td><td>C</td><td>H</td><td>O</td><td>Na</td></tr><tr><td rowspan=\\\"3\\\">1679.6866</td><td>1679.6858</td><td>0.8</td><td>0.5</td><td>57.5</td><td>C107 H100 O17 Na</td><td>152.4</td><td>0.155</td><td>85.63</td><td>107</td><td>100</td><td>17</td><td>1</td></tr><tr><td>1679.6882</td><td>-1.6</td><td>-1.0</td><td>60.5</td><td>C109 H99 O17</td><td>154.2</td><td>1.940</td><td>14.36</td><td>109</td><td>99</td><td>17</td><td></td></tr><tr><td>1679.6893</td><td>-2.7</td><td>-1.6</td><td>79.5</td><td>C125 H92 O4 Na</td><td>162.4</td><td>10.119</td><td>0.00</td><td>125</td><td>92</td><td>4</td><td>1</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[202,245,795,808]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S74. HRMS spectrum of compound M-5a. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0774/c349be6551309709389f5b6269a07c28de5204ed759c2818f1f6fdd902c3cb11.jpg\",\n \"list_items\": null,\n \"page_idx\": \"65\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[894,897,915,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"65\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S66 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[126,144,879,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0218/c8b6ca745af1cee5642d8c7110b479ed681691b622b80105e00ed6a7ecfa3ded.jpg\",\n \"list_items\": null,\n \"page_idx\": \"66\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Mass</td><td>Calc. Mass</td><td>mDa</td><td>PPM</td><td>DBE</td><td>Formula</td><td>i-FIT</td><td>i-FIT Norm</td><td>Fit Conf %</td><td>C</td><td>H</td><td>O</td><td>Na</td></tr><tr><td>1679.6836</td><td>1679.6858</td><td>-2.2</td><td>-1.3</td><td>57.5</td><td>C107 H100 O17 Na</td><td>97.7</td><td>n/a</td><td>n/a</td><td>107</td><td>100</td><td>17</td><td>1</td></tr><tr><td colspan=\\\"11\\\">z04_s1217 12 (0.259)</td><td colspan=\\\"2\\\">1: TOF MS ES+2.53e3</td></tr><tr><td rowspan=\\\"8\\\">100</td><td colspan=\\\"4\\\">[M+Na]+</td><td colspan=\\\"8\\\">1680.69</td></tr><tr><td colspan=\\\"4\\\">1679.69</td><td colspan=\\\"8\\\">1681.68</td></tr><tr><td colspan=\\\"4\\\">[ M+NH4]+</td><td colspan=\\\"8\\\">1682.68</td></tr><tr><td colspan=\\\"4\\\">1674.72</td><td colspan=\\\"8\\\">1683.68</td></tr><tr><td colspan=\\\"4\\\">1679.46</td><td colspan=\\\"8\\\">1685</td></tr><tr><td colspan=\\\"4\\\">1685</td><td colspan=\\\"8\\\">1690</td></tr><tr><td colspan=\\\"4\\\">1700</td><td colspan=\\\"8\\\">1705</td></tr><tr><td colspan=\\\"4\\\">1710</td><td colspan=\\\"8\\\">1715</td></tr></table>\",\n \"table_caption\": \"[\\\"Elements Used: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[366,838,629,860]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"66\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure S75. HRMS spectrum of compound P-5b. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[892,897,915,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"66\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S67 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[185,142,815,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Elements Used: \\\",\\\"Figure S76. 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ESI-MS spectrum of adduct $[P - 5a + ACh]^+$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0078/aba4b31aedaca62e1e7f0b1dfee17afc17f928f3de4c765a6f91a9ba7178dafe.jpg\",\n \"list_items\": null,\n \"page_idx\": \"69\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[894,897,916,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"69\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S70 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[85,117,130,136]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"70\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KN3_Ch \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[86,136,209,147]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"70\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"z04_1s180 17 (0.364) Cm (17:27-(4:14+35:42)) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[818,134,863,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"70\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1:TOF MS ES+ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[841,146,863,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"70\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.05e4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[86,146,863,818]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S79. ESI-MS spectrum of adduct $[M - 5a + Ch]^{+}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0881/8fda6523444f32dedb387502a50458b96c961a982334ddf60297a654c42c655f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"70\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[892,897,915,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"70\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S71 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[105,114,884,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure S80. 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\"table_footnote\": null,\n \"text\": \"Conformation #1 (Pop. = 68.98%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,168,257,183]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"72\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Symbolic Z-matrix: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,195,485,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0099/9e206501eae78bdcbbfcd7f9ae627e66104293070d07ef0ab4922b5873bbd644.jpg\",\n \"list_items\": null,\n \"page_idx\": \"72\",\n \"sub_type\": null,\n \"table_body\": 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><td>-3.52988900</td></tr><tr><td>C</td><td>-1.82460000</td><td>-4.18128700</td><td>-1.96023000</td></tr><tr><td>C</td><td>-3.05202300</td><td>-3.80362700</td><td>-2.46887200</td></tr><tr><td>H</td><td>-4.15874900</td><td>-2.22106000</td><td>-3.45669300</td></tr><tr><td>H</td><td>-1.71160000</td><td>-5.15522900</td><td>-1.49255200</td></tr><tr><td>C</td><td>6.10148700</td><td>-2.43140000</td><td>3.13521400</td></tr><tr><td>H</td><td>6.89726500</td><td>-1.83392500</td><td>3.59088800</td></tr><tr><td>H</td><td>6.16689000</td><td>-3.45035300</td><td>3.54351200</td></tr><tr><td>C</td><td>4.74497900</td><td>-1.82073300</td><td>3.42546900</td></tr><tr><td>C</td><td>4.53009200</td><td>-0.48654700</td><td>3.13633900</td></tr><tr><td>C</td><td>3.66845100</td><td>-2.59347500</td><td>3.93401700</td></tr><tr><td>C</td><td>3.26199500</td><td>0.11604200</td><td>3.31515500</td></tr><tr><td>H</td><td>5.34508300</td><td>0.12071900</td><td>2.74803000</td></tr><tr><td>C</td><td>2.41928200</td><td>-2.03745800</td><td>4.12193500</td></tr><tr><td>H</td><td>3.83488200</td><td>-3.64154800</td><td>4.17226300</td></tr><tr><td>C</td><td>3.03102700</td><td>1.48511200</td><td>3.00458800</td></tr><tr><td>C</td><td>2.17250800</td><td>-0.67499900</td><td>3.80654300</td></tr><tr><td>H</td><td>1.60211400</td><td>-2.64543800</td><td>4.50275600</td></tr><tr><td>C</td><td>1.77997400</td><td>2.02967200</td><td>3.15287400</td></tr><tr><td>H</td><td>3.85628800</td><td>2.08616900</td><td>2.63124200</td></tr><tr><td>C</td><td>0.88466200</td><td>-0.07852400</td><td>3.93442600</td></tr><tr><td>C</td><td>0.68079000</td><td>1.24226800</td><td>3.60333500</td></tr><tr><td>H</td><td>1.61501500</td><td>3.07676300</td><td>2.90976900</td></tr><tr><td>H</td><td>0.05263500</td><td>-0.68293200</td><td>4.28270700</td></tr><tr><td>C</td><td>-5.08237300</td><td>2.86100900</td><td>-3.36173500</td></tr><tr><td>H</td><td>-5.38510600</td><td>3.43452300</td><td>-4.24231900</td></tr><tr><td>H</td><td>-4.92797500</td><td>1.82501900</td><td>-3.66697000</td></tr><tr><td>O</td><td>-4.44770300</td><td>-5.23859400</td><td>-1.03376600</td></tr><tr><td>C</td><td>-4.24212400</td><td>-4.73543700</td><td>-2.36916800</td></tr><tr><td>H</td><td>-4.09311600</td><td>-5.63889200</td><td>-2.96847200</td></tr><tr><td>H</td><td>-5.14748200</td><td>-4.23773200</td><td>-2.73685000</td></tr></table>\",\n 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\"list_items\": null,\n \"page_idx\": \"74\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,848,371,862]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"74\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5336189 a.u. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"74\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S75 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,164,487,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0677/a8fe657d57ef49b701a0e9592636231c817df15bbe003d1f9afee79615c71102.jpg\",\n \"list_items\": null,\n \"page_idx\": \"75\",\n \"sub_type\": null,\n \"table_body\": 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</td></tr><tr><td>C</td><td>1.38495900</td><td>4.49482400</td><td>-0.39893000</td></tr><tr><td>C</td><td>2.60699300</td><td>4.34109300</td><td>-1.02530700</td></tr><tr><td>H</td><td>3.67505600</td><td>3.32178400</td><td>-2.61466800</td></tr><tr><td>H</td><td>1.29799900</td><td>5.16121400</td><td>0.45404600</td></tr><tr><td>C</td><td>-5.93850300</td><td>1.01752400</td><td>3.35057500</td></tr><tr><td>H</td><td>-6.58862400</td><td>0.29251400</td><td>3.85261100</td></tr><tr><td>H</td><td>-5.92876500</td><td>1.93134900</td><td>3.95906600</td></tr><tr><td>C</td><td>-4.54349600</td><td>0.44585600</td><td>3.21264400</td></tr><tr><td>C</td><td>-4.29837500</td><td>-0.88463900</td><td>3.48130500</td></tr><tr><td>C</td><td>-3.46715700</td><td>1.26659200</td><td>2.76391800</td></tr><tr><td>C</td><td>-3.00766600</td><td>-1.45641200</td><td>3.30579600</td></tr><tr><td>H</td><td>-5.10732100</td><td>-1.52670300</td><td>3.82355500</td></tr><tr><td>C</td><td>-2.20848900</td><td>0.74832200</td><td>2.57752200</td></tr><tr><td>H</td><td>-3.64464100</td><td>2.32046300</td><td>2.56930600</td></tr><tr><td>C</td><td>-2.74295200</td><td>-2.82828100</td><td>3.55642900</td></tr><tr><td>C</td><td>-1.94004600</td><td>-0.62651500</td><td>2.83243900</td></tr><tr><td>H</td><td>-1.40143600</td><td>1.38497200</td><td>2.22343800</td></tr><tr><td>C</td><td>-1.49124500</td><td>-3.35775400</td><td>3.32646400</td></tr><tr><td>H</td><td>-3.54798000</td><td>-3.46098600</td><td>3.92110500</td></tr><tr><td>C</td><td>-0.66497200</td><td>-1.20414900</td><td>2.60870900</td></tr><tr><td>C</td><td>-0.43362600</td><td>-2.54900400</td><td>2.83344900</td></tr><tr><td>H</td><td>-1.30597300</td><td>-4.41277300</td><td>3.51296100</td></tr><tr><td>H</td><td>0.13647600</td><td>-0.57171400</td><td>2.23247700</td></tr><tr><td>C</td><td>5.71079100</td><td>-1.33656400</td><td>-4.16223100</td></tr><tr><td>H</td><td>6.00019100</td><td>-1.75914100</td><td>-5.12834000</td></tr><tr><td>H</td><td>5.55478700</td><td>-0.26289700</td><td>-4.28637000</td></tr><tr><td>O</td><td>3.96897800</td><td>5.18487500</td><td>0.85523000</td></tr><tr><td>C</td><td>3.81498400</td><td>5.13891900</td><td>-0.57414200</td></tr><tr><td>H</td><td>3.71546000</td><td>6.18997500</td><td>-0.86453700</td></tr><tr><td>H</td><td>4.72383600</td><td>4.75068500</td><td>-1.04854300</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,110,369,124]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"75\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #2 (Pop. = 20.28%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"75\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S76 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,489,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"76\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"76\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S77 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,760]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"77\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,777,307,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"77\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,804,371,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"77\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5324641 a.u. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"77\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S78 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[115,110,157,123]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"78\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"M-5a \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,137,369,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"78\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #1 (Pop. = 81.87%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,191,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0236/62f969cb93085ea7ed557e9bd066c3e294640fe5da3ace564c7dde3d6e76aa7e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"78\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>C</td><td>-5.80016800</td><td>-0.71927100</td><td>3.10539100</td></tr><tr><td>C</td><td>-6.86809800</td><td>-1.52981300</td><td>2.38272100</td></tr><tr><td>C</td><td>-6.42566900</td><td>-1.82120200</td><td>0.94043400</td></tr><tr><td>C</td><td>-4.11168000</td><td>-1.81589900</td><td>1.59341900</td></tr><tr><td>C</td><td>-4.46098100</td><td>-1.45032300</td><td>3.04999700</td></tr><tr><td>O</td><td>-5.19618600</td><td>-2.51798400</td><td>0.96911900</td></tr><tr><td>O</td><td>-6.26107600</td><td>-0.53720000</td><td>4.44345000</td></tr><tr><td>O</td><td>-6.34247200</td><td>-0.58743500</td><td>0.25625900</td></tr><tr><td>C</td><td>-2.92890400</td><td>-2.77726700</td><td>1.49683700</td></tr><tr><td>O</td><td>-1.79427300</td><td>-2.16753000</td><td>2.11023900</td></tr><tr><td>C</td><td>-7.42087800</td><td>1.81154100</td><td>-1.50694600</td></tr><tr><td>C</td><td>-8.57397700</td><td>1.17992300</td><td>-0.73347800</td></tr><tr><td>C</td><td>-6.84792800</td><td>-0.44765300</td><td>-1.08363900</td></tr><tr><td>O</td><td>-6.38044700</td><td>0.80581400</td><td>-1.53225000</td></tr><tr><td>C</td><td>-6.33043800</td><td>-1.52750200</td><td>-2.03393300</td></tr><tr><td>O</td><td>-4.91984300</td><td>-1.56355600</td><td>-1.98220700</td></tr><tr><td>H</td><td>-6.98820900</td><td>-2.49541900</td><td>2.89382600</td></tr><tr><td>H</td><td>-8.42902500</td><td>1.32204800</td><td>0.34537500</td></tr><tr><td>H</td><td>-7.75614300</td><td>1.99295300</td><td>-2.53843800</td></tr><tr><td>H</td><td>-5.69366800</td><td>0.25353300</td><td>2.60619300</td></tr><tr><td>H</td><td>-4.55445800</td><td>-2.38203900</td><td>3.63268600</td></tr><tr><td>H</td><td>-3.88748900</td><td>-0.89682700</td><td>1.03841400</td></tr><tr><td>H</td><td>-3.18253400</td><td>-3.71608800</td><td>2.01207000</td></tr><tr><td>H</td><td>-2.72080100</td><td>-3.00695500</td><td>0.44362500</td></tr><tr><td>H</td><td>-6.68570300</td><td>-1.27423000</td><td>-3.04435400</td></tr><tr><td>H</td><td>-6.75682500</td><td>-2.50833600</td><td>-1.77054600</td></tr><tr><td>C</td><td>4.97649600</td><td>-3.41454300</td><td>-1.45188500</td></tr><tr><td>C</td><td>5.13722200</td><td>-2.40565100</td><td>-2.39325900</td></tr><tr><td>C</td><td>5.80674100</td><td>-3.42348100</td><td>-0.30960300</td></tr><tr><td>C</td><td>6.05895200</td><td>-1.35711800</td><td>-2.23292400</td></tr><tr><td>H</td><td>4.51273900</td><td>-2.45381500</td><td>-3.28084300</td></tr><tr><td>C</td><td>6.70790300</td><td>-2.37558900</td><td>-0.13078000</td></tr><tr><td>C</td><td>6.83550900</td><td>-1.32877600</td><td>-1.06197600</td></tr><tr><td>H</td><td>7.34762200</td><td>-2.36837200</td><td>0.74465500</td></tr><tr><td>C</td><td>2.77679100</td><td>1.45275400</td><td>-3.60871000</td></tr><tr><td>C</td><td>3.00315900</td><td>2.66765000</td><td>-2.91907200</td></tr><tr><td>C</td><td>3.82976500</td><td>0.55629800</td><td>-3.74590300</td></tr><tr><td>C</td><td>4.27747300</td><td>2.94405900</td><td>-2.43997500</td></tr><tr><td>C</td><td>5.10670500</td><td>0.80627100</td><td>-3.20457100</td></tr><tr><td>H</td><td>3.66600500</td><td>-0.37742600</td><td>-4.27161000</td></tr><tr><td>C</td><td>5.34056800</td><td>2.02564300</td><td>-2.55498900</td></tr><tr><td>H</td><td>4.46345700</td><td>3.89963800</td><td>-1.96071800</td></tr><tr><td>C</td><td>6.22350900</td><td>2.95537800</td><td>1.81699900</td></tr><tr><td>C</td><td>6.62532300</td><td>1.71405000</td><td>2.35644400</td></tr><tr><td>C</td><td>6.27760300</td><td>3.13111800</td><td>0.43444200</td></tr><tr><td>C</td><td>7.12829200</td><td>0.74447500</td><td>1.49579900</td></tr><tr><td>C</td><td>6.74699200</td><td>2.13191100</td><td>-0.43629100</td></tr><tr><td>H</td><td>5.96382500</td><td>4.07759900</td><td>0.00911400</td></tr><tr><td>C</td><td>7.21491100</td><td>0.92280200</td><td>0.10598100</td></tr><tr><td>O</td><td>6.65234100</td><td>1.43635600</td><td>3.70450300</td></tr><tr><td>O</td><td>1.92062500</td><td>3.49430900</td><td>-2.79587900</td></tr><tr><td>C</td><td>1.90294700</td><td>4.46718900</td><td>-1.74229200</td></tr><tr><td>H</td><td>2.54295500</td><td>4.12489600</td><td>-0.91905500</td></tr><tr><td>H</td><td>2.30593700</td><td>5.42075000</td><td>-2.10602900</td></tr><tr><td>C</td><td>6.14576200</td><td>-0.30220400</td><td>-3.33355800</td></tr><tr><td>H</td><td>5.98975500</td><td>-0.80549300</td><td>-4.29471300</td></tr><tr><td>H</td><td>7.15345600</td><td>0.11639400</td><td>-3.37901500</td></tr><tr><td>C</td><td>6.67948200</td><td>2.41626800</td><td>-1.93316700</td></tr><tr><td>H</td><td>6.82532900</td><td>3.49195700</td><td>-2.08524200</td></tr><tr><td>H</td><td>7.50320400</td><td>1.92744400</td><td>-2.45780200</td></tr><tr><td>H</td><td>7.46905700</td><td>-0.18298200</td><td>1.94752900</td></tr><tr><td>C</td><td>7.81448100</td><td>-0.20890900</td><td>-0.72702600</td></tr><tr><td>H</td><td>8.64209200</td><td>-0.64241400</td><td>-0.15386700</td></tr><tr><td>H</td><td>8.26412200</td><td>0.19161000</td><td>-1.63826600</td></tr><tr><td>H</td><td>-7.12895600</td><td>-2.49920500</td><td>0.45555200</td></tr><tr><td>H</td><td>-5.60396800</td><td>0.01867200</td><td>4.89375200</td></tr><tr><td>O</td><td>4.07414200</td><td>-4.42097200</td><td>-1.70642000</td></tr><tr><td>O</td><td>-6.57034600</td><td>2.99877400</td><td>0.41062400</td></tr><tr><td>O</td><td>-9.80567500</td><td>1.73618100</td><td>-1.16340200</td></tr><tr><td>H</td><td>-10.50716400</td><td>1.29965800</td><td>-0.65286500</td></tr><tr><td>C</td><td>3.06497700</td><td>-4.67528800</td><td>-0.69399800</td></tr><tr><td>H</td><td>3.19208100</td><td>-5.70885100</td><td>-0.35859000</td></tr><tr><td>H</td><td>3.23319000</td><td>-4.01880200</td><td>0.16218100</td></tr><tr><td>C</td><td>5.46290800</td><td>1.66122700</td><td>4.50362300</td></tr><tr><td>H</td><td>5.28361200</td><td>2.73309600</td><td>4.60398700</td></tr><tr><td>H</td><td>5.74620800</td><td>1.25905000</td><td>5.48001100</td></tr><tr><td>O</td><td>5.66776100</td><td>-4.48900000</td><td>0.53492500</td></tr><tr><td>O</td><td>5.82103900</td><td>3.91672600</td><td>2.70323500</td></tr><tr><td>O</td><td>1.51175700</td><td>1.25994400</td><td>-4.08571100</td></tr><tr><td>C</td><td>1.25496300</td><td>0.07205800</td><td>-4.82888400</td></tr><tr><td>H</td><td>1.41063000</td><td>-0.82594100</td><td>-4.21891000</td></tr><tr><td>H</td><td>0.20665200</td><td>0.12806800</td><td>-5.12594500</td></tr><tr><td>H</td><td>1.88647000</td><td>0.01700500</td><td>-5.72416900</td></tr><tr><td>C</td><td>6.45173600</td><td>-4.51142700</td><td>1.72466500</td></tr><tr><td>H</td><td>6.23640400</td><td>-3.64456300</td><td>2.36098700</td></tr><tr><td>H</td><td>6.17081900</td><td>-5.42635000</td><td>2.24830700</td></tr><tr><td>H</td><td>7.52407000</td><td>-4.53753600</td><td>1.49642500</td></tr><tr><td>C</td><td>5.41858000</td><td>5.18432600</td><td>2.18951900</td></tr><tr><td>H</td><td>4.54955400</td><td>5.09011500</td><td>1.52744300</td></tr><tr><td>H</td><td>5.14908700</td><td>5.78439600</td><td>3.05967300</td></tr><tr><td>H</td><td>6.23774400</td><td>5.67255500</td><td>1.64839400</td></tr><tr><td>C</td><td>-6.87247500</td><td>3.12158200</td><td>-0.97090000</td></tr><tr><td>H</td><td>-7.62408700</td><td>3.91081400</td><td>-1.13139900</td></tr><tr><td>H</td><td>-5.97588600</td><td>3.38742000</td><td>-1.54635100</td></tr><tr><td>C</td><td>-0.67801000</td><td>-3.04780200</td><td>2.19136500</td></tr><tr><td>H</td><td>-0.91391000</td><td>-3.89156700</td><td>2.85821300</td></tr><tr><td>H</td><td>-0.47975300</td><td>-3.47206200</td><td>1.19456500</td></tr><tr><td>C</td><td>-5.70817100</td><td>4.01731500</td><td>0.90547000</td></tr><tr><td>H</td><td>-5.72619200</td><td>3.89200800</td><td>1.99460100</td></tr><tr><td>H</td><td>-6.11276600</td><td>5.01617200</td><td>0.68212700</td></tr><tr><td>C</td><td>0.54732700</td><td>-2.31805500</td><td>2.68872200</td></tr><tr><td>C</td><td>0.67718200</td><td>-0.94849100</td><td>2.59861700</td></tr><tr><td>C</td><td>1.61709500</td><td>-3.08559100</td><td>3.23067800</td></tr><tr><td>C</td><td>1.85609900</td><td>-0.29019900</td><td>3.04705200</td></tr><tr><td>H</td><td>-0.13221600</td><td>-0.35434700</td><td>2.18502500</td></tr><tr><td>C</td><td>2.77291100</td><td>-2.48099300</td><td>3.66512200</td></tr><tr><td>H</td><td>1.51054000</td><td>-4.16523900</td><td>3.30609200</td></tr><tr><td>C</td><td>2.00974300</td><td>1.11994500</td><td>2.97625700</td></tr><tr><td>C</td><td>2.92905100</td><td>-1.06846600</td><td>3.59238600</td></tr><tr><td>H</td><td>3.57987900</td><td>-3.07809800</td><td>4.08280100</td></tr><tr><td>C</td><td>3.16032500</td><td>1.72770700</td><td>3.42860800</td></tr><tr><td>H</td><td>1.20249000</td><td>1.71603800</td><td>2.55761200</td></tr><tr><td>C</td><td>4.09654700</td><td>-0.40851900</td><td>4.05507400</td></tr><tr><td>C</td><td>4.22279900</td><td>0.96658300</td><td>3.98597000</td></tr><tr><td>H</td><td>3.26479400</td><td>2.80757500</td><td>3.36781100</td></tr><tr><td>H</td><td>4.90043300</td><td>-1.00663400</td><td>4.47994300</td></tr><tr><td>C</td><td>-4.28465700</td><td>3.90213100</td><td>0.38917500</td></tr><tr><td>C</td><td>-3.51924300</td><td>5.02410400</td><td>0.14860100</td></tr><tr><td>C</td><td>-3.72195800</td><td>2.61230000</td><td>0.17319400</td></tr><tr><td>C</td><td>-2.17471600</td><td>4.91981300</td><td>-0.30388900</td></tr><tr><td>H</td><td>-3.94239200</td><td>6.01583300</td><td>0.29882300</td></tr><tr><td>C</td><td>-2.43017600</td><td>2.47630600</td><td>-0.27491900</td></tr><tr><td>H</td><td>-4.34518100</td><td>1.73761400</td><td>0.32886100</td></tr><tr><td>C</td><td>-1.36297800</td><td>6.05599200</td><td>-0.56521700</td></tr><tr><td>C</td><td>-1.61992500</td><td>3.61784300</td><td>-0.52880000</td></tr><tr><td>H</td><td>-2.01098700</td><td>1.48753400</td><td>-0.44728600</td></tr><tr><td>C</td><td>-0.07358700</td><td>5.91262400</td><td>-1.03202200</td></tr><tr><td>H</td><td>-1.77776500</td><td>7.04770500</td><td>-0.40173000</td></tr><tr><td>C</td><td>-0.29154800</td><td>3.50690200</td><td>-1.00743200</td></tr><tr><td>C</td><td>0.47793600</td><td>4.62562300</td><td>-1.26105200</td></tr><tr><td>H</td><td>0.52967500</td><td>6.79403800</td><td>-1.23590100</td></tr><tr><td>H</td><td>0.11653200</td><td>2.51744900</td><td>-1.19528900</td></tr><tr><td>C</td><td>-2.89198100</td><td>-2.65250300</td><td>-2.59831900</td></tr><tr><td>C</td><td>-2.35128400</td><td>-3.91836800</td><td>-2.51697400</td></tr><tr><td>C</td><td>-2.06353200</td><td>-1.52432000</td><td>-2.33412000</td></tr><tr><td>C</td><td>-0.99315400</td><td>-4.12345400</td><td>-2.14818500</td></tr><tr><td>H</td><td>-2.97256900</td><td>-4.78958400</td><td>-2.71362300</td></tr><tr><td>C</td><td>-0.74855700</td><td>-1.68630500</td><td>-1.96573100</td></tr><tr><td>H</td><td>-2.49191900</td><td>-0.52891500</td><td>-2.40426200</td></tr><tr><td>C</td><td>-0.42832200</td><td>-5.42036100</td><td>-2.02434700</td></tr><tr><td>C</td><td>-0.17660100</td><td>-2.98540000</td><td>-1.84462200</td></tr><tr><td>H</td><td>-0.12899800</td><td>-0.81865500</td><td>-1.75187500</td></tr><tr><td>C</td><td>0.86763000</td><td>-5.58487500</td><td>-1.58747700</td></tr><tr><td>H</td><td>-1.04142000</td><td>-6.28599900</td><td>-2.26287800</td></tr><tr><td>C</td><td>1.15298800</td><td>-3.19320600</td><td>-1.39388000</td></tr><tr><td>C</td><td>1.67445100</td><td>-4.46663000</td><td>-1.24758800</td></tr><tr><td>H</td><td>1.28039000</td><td>-6.58513800</td><td>-1.48114500</td></tr><tr><td>H</td><td>1.75653100</td><td>-2.32586400</td><td>-1.13463900</td></tr><tr><td>C</td><td>-4.34878100</td><td>-2.45247100</td><td>-2.93951300</td></tr><tr><td>H</td><td>-4.46728900</td><td>-2.02816200</td><td>-3.95089300</td></tr><tr><td>H</td><td>-4.87201900</td><td>-3.41999900</td><td>-2.92820900</td></tr><tr><td>O</td><td>-9.10964400</td><td>-1.19065300</td><td>-0.23259600</td></tr><tr><td>H</td><td>-8.90801500</td><td>-0.96507100</td><td>0.70129100</td></tr><tr><td>O</td><td>-3.48780400</td><td>-0.58997600</td><td>3.63014300</td></tr><tr><td>H</td><td>-2.62452300</td><td>-1.01918600</td><td>3.47352000</td></tr><tr><td>O</td><td>-8.11441200</td><td>-0.83949600</td><td>2.35533600</td></tr><tr><td>H</td><td>-8.28207700</td><td>-0.50854300</td><td>3.25430400</td></tr><tr><td>C</td><td>-8.39747400</td><td>-0.30670500</td><td>-1.06733400</td></tr><tr><td>H</td><td>-8.77223400</td><td>-0.47382600</td><td>-2.08459400</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"78\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S79 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,489,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"79\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"79\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S80 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"80\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,804,307,820]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"80\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,832,371,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"80\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5398342 a.u. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"80\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S81 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,164,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0958/98f1b995356575bd1b530e3424b3300b5ccfaa2c689183ebf78047c45649a07e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"81\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>C</td><td>-5.79521100</td><td>-0.67942100</td><td>3.06253500</td></tr><tr><td>C</td><td>-6.84753000</td><td>-1.48341600</td><td>2.31054600</td></tr><tr><td>C</td><td>-6.39366400</td><td>-1.73257600</td><td>0.86277600</td></tr><tr><td>C</td><td>-4.08482100</td><td>-1.72349800</td><td>1.54199700</td></tr><tr><td>C</td><td>-4.44988200</td><td>-1.39699700</td><td>3.00392500</td></tr><tr><td>O</td><td>-5.15695700</td><td>-2.41790600</td><td>0.88694800</td></tr><tr><td>O</td><td>-6.27423400</td><td>-0.53391600</td><td>4.39918600</td></tr><tr><td>O</td><td>-6.31213400</td><td>-0.48570600</td><td>0.20493300</td></tr><tr><td>C</td><td>-2.89576500</td><td>-2.67547100</td><td>1.43504200</td></tr><tr><td>O</td><td>-1.77080400</td><td>-2.08148300</td><td>2.08135500</td></tr><tr><td>C</td><td>-7.36411200</td><td>2.00044900</td><td>-1.36809700</td></tr><tr><td>C</td><td>-8.52265700</td><td>1.34182300</td><td>-0.62239500</td></tr><tr><td>C</td><td>-6.84710400</td><td>-0.29604600</td><td>-1.11807000</td></tr><tr><td>O</td><td>-6.36942000</td><td>0.96132700</td><td>-1.54016600</td></tr><tr><td>C</td><td>-6.38751500</td><td>-1.35919700</td><td>-2.11477800</td></tr><tr><td>O</td><td>-4.97855600</td><td>-1.45851900</td><td>-2.10517600</td></tr><tr><td>H</td><td>-6.95788900</td><td>-2.46413200</td><td>2.79441300</td></tr><tr><td>H</td><td>-8.36327500</td><td>1.40487100</td><td>0.46146000</td></tr><tr><td>H</td><td>-7.72193800</td><td>2.30150100</td><td>-2.36283100</td></tr><tr><td>H</td><td>-5.69295000</td><td>0.30619800</td><td>2.58863200</td></tr><tr><td>H</td><td>-4.54074500</td><td>-2.34325900</td><td>3.56320500</td></tr><tr><td>H</td><td>-3.86107400</td><td>-0.78795700</td><td>1.01477200</td></tr><tr><td>H</td><td>-3.15393900</td><td>-3.62939100</td><td>1.91959200</td></tr><tr><td>H</td><td>-2.67117300</td><td>-2.87570300</td><td>0.37964800</td></tr><tr><td>H</td><td>-6.75884100</td><td>-1.06015900</td><td>-3.10698900</td></tr><tr><td>H</td><td>-6.84919000</td><td>-2.32938600</td><td>-1.87133900</td></tr><tr><td>C</td><td>4.75469700</td><td>-3.55627000</td><td>-1.41835500</td></tr><tr><td>C</td><td>4.94268000</td><td>-2.56876800</td><td>-2.37680100</td></tr><tr><td>C</td><td>5.59714300</td><td>-3.57976200</td><td>-0.28580900</td></tr><tr><td>C</td><td>5.90420100</td><td>-1.55427600</td><td>-2.24321500</td></tr><tr><td>H</td><td>4.30787000</td><td>-2.60794200</td><td>-3.25742700</td></tr><tr><td>C</td><td>6.54383500</td><td>-2.56656500</td><td>-0.13682000</td></tr><tr><td>C</td><td>6.70139600</td><td>-1.54043300</td><td>-1.08607000</td></tr><tr><td>H</td><td>7.19668200</td><td>-2.57356900</td><td>0.72891300</td></tr><tr><td>C</td><td>2.71902600</td><td>1.41178600</td><td>-3.48157900</td></tr><tr><td>C</td><td>3.05239300</td><td>2.64943100</td><td>-2.89676600</td></tr><tr><td>C</td><td>3.70866100</td><td>0.45138800</td><td>-3.63871200</td></tr><tr><td>C</td><td>4.36969300</td><td>2.87208200</td><td>-2.50059000</td></tr><tr><td>C</td><td>5.02777100</td><td>0.64628500</td><td>-3.19662800</td></tr><tr><td>H</td><td>3.42149000</td><td>-0.49013100</td><td>-4.09842500</td></tr><tr><td>C</td><td>5.36201300</td><td>1.88200300</td><td>-2.61530500</td></tr><tr><td>H</td><td>4.63730800</td><td>3.83703300</td><td>-2.08159300</td></tr><tr><td>C</td><td>6.39319500</td><td>2.85500400</td><td>1.69214100</td></tr><tr><td>C</td><td>6.72368300</td><td>1.60289800</td><td>2.25465900</td></tr><tr><td>C</td><td>6.43646300</td><td>2.99606300</td><td>0.30552600</td></tr><tr><td>C</td><td>7.14796700</td><td>0.58320600</td><td>1.41041800</td></tr><tr><td>C</td><td>6.82656000</td><td>1.94868800</td><td>-0.54796900</td></tr><tr><td>H</td><td>6.17567000</td><td>3.95052200</td><td>-0.13720500</td></tr><tr><td>C</td><td>7.22293900</td><td>0.72361600</td><td>0.01527800</td></tr><tr><td>O</td><td>6.75274300</td><td>1.36001700</td><td>3.60938600</td></tr><tr><td>O</td><td>2.04141500</td><td>3.56185900</td><td>-2.77272700</td></tr><tr><td>C</td><td>2.05447600</td><td>4.48697400</td><td>-1.67687600</td></tr><tr><td>H</td><td>2.74958100</td><td>4.13118100</td><td>-0.90604500</td></tr><tr><td>H</td><td>2.41376200</td><td>5.46339400</td><td>-2.02448000</td></tr><tr><td>C</td><td>6.00427600</td><td>-0.51419900</td><td>-3.35434400</td></tr><tr><td>H</td><td>5.78440000</td><td>-1.01411400</td><td>-4.30455000</td></tr><tr><td>H</td><td>7.02886600</td><td>-0.14706800</td><td>-3.44338300</td></tr><tr><td>C</td><td>6.74409700</td><td>2.20291400</td><td>-2.05036000</td></tr><tr><td>H</td><td>6.95358600</td><td>3.26264900</td><td>-2.23420400</td></tr><tr><td>H</td><td>7.51868100</td><td>1.64744400</td><td>-2.58296800</td></tr><tr><td>H</td><td>7.43520900</td><td>-0.35412300</td><td>1.87859700</td></tr><tr><td>C</td><td>7.74065100</td><td>-0.46274600</td><td>-0.79641400</td></tr><tr><td>H</td><td>8.55543200</td><td>-0.92413700</td><td>-0.22663400</td></tr><tr><td>H</td><td>8.19335700</td><td>-0.11222100</td><td>-1.72669800</td></tr><tr><td>H</td><td>-7.08658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<td>0.65557300</td><td>4.59532700</td><td>-1.10997600</td></tr><tr><td>H</td><td>0.83573500</td><td>6.70596200</td><td>-0.63562900</td></tr><tr><td>H</td><td>0.17303100</td><td>2.54496700</td><td>-1.47856300</td></tr><tr><td>C</td><td>-3.03554100</td><td>-2.66335100</td><td>-2.78778400</td></tr><tr><td>C</td><td>-2.62484000</td><td>-3.90287900</td><td>-2.34532600</td></tr><tr><td>C</td><td>-2.07145600</td><td>-1.62482300</td><td>-2.93381500</td></tr><tr><td>C</td><td>-1.26959900</td><td>-4.15534700</td><td>-1.99677700</td></tr><tr><td>H</td><td>-3.34854800</td><td>-4.70743300</td><td>-2.23264700</td></tr><tr><td>C</td><td>-0.75012500</td><td>-1.83354500</td><td>-2.61305500</td></tr><tr><td>H</td><td>-2.39490500</td><td>-0.65323100</td><td>-3.29810100</td></tr><tr><td>C</td><td>-0.83966700</td><td>-5.41194100</td><td>-1.49640700</td></tr><tr><td>C</td><td>-0.31160800</td><td>-3.09533500</td><td>-2.11508600</td></tr><tr><td>H</td><td>-0.02433800</td><td>-1.03228400</td><td>-2.73421800</td></tr><tr><td>C</td><td>0.46583100</td><td>-5.60139200</td><td>-1.09918800</td></tr><tr><td>H</td><td>-1.56031600</td><td>-6.22236600</td><td>-1.41894500</td></tr><tr><td>C</td><td>1.02476800</td><td>-3.32752400</td><td>-1.69836800</td></tr><tr><td>C</td><td>1.41597800</td><td>-4.54966700</td><td>-1.17963700</td></tr><tr><td>H</td><td>0.77768600</td><td>-6.56634800</td><td>-0.70705400</td></tr><tr><td>H</td><td>1.74176500</td><td>-2.51285600</td><td>-1.77018200</td></tr><tr><td>C</td><td>-4.49131500</td><td>-2.39233800</td><td>-3.07229100</td></tr><tr><td>H</td><td>-4.63028300</td><td>-1.97842500</td><td>-4.08428800</td></tr><tr><td>H</td><td>-5.06489900</td><td>-3.32905500</td><td>-3.01618300</td></tr><tr><td>O</td><td>-9.10767600</td><td>-1.04819000</td><td>-0.27776000</td></tr><tr><td>H</td><td>-8.90103000</td><td>-0.87859500</td><td>0.66689100</td></tr><tr><td>O</td><td>-3.48864200</td><td>-0.54314200</td><td>3.61239400</td></tr><tr><td>H</td><td>-2.62021200</td><td>-0.95947400</td><td>3.44850500</td></tr><tr><td>O</td><td>-8.10206500</td><td>-0.80792600</td><td>2.30169700</td></tr><tr><td>H</td><td>-8.26248000</td><td>-0.48581100</td><td>3.20544400</td></tr><tr><td>C</td><td>-8.39055900</td><td>-0.12229200</td><td>-1.06045500</td></tr><tr><td>H</td><td>-8.78435700</td><td>-0.20862900</td><td>-2.08070000</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,110,369,124]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"81\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #2 (Pop. = 12.04%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"81\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S82 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,489,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"82\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"82\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S83 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,760]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"83\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,776,307,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"83\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,803,369,816]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"83\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5380266 a.u. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"83\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S84 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[115,110,156,122]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"84\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"P-5b \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,137,369,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"84\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #1 (Pop. = 75.32%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,191,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0637/8d967e44b96163d515a262d5f8e5ec282cae11cc3383201fd16cf4bc39cc5b6e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"84\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>C</td><td>-5.74916800</td><td>4.67505000</td><td>-1.18282900</td></tr><tr><td>C</td><td>-5.74829200</td><td>4.39628600</td><td>0.31511100</td></tr><tr><td>C</td><td>-4.69552300</td><td>3.33385500</td><td>0.65252800</td></tr><tr><td>C</td><td>-3.34115300</td><td>3.98482800</td><td>-1.22653300</td></tr><tr><td>C</td><td>-4.34621300</td><td>5.07931300</td><td>-1.63043600</td></tr><tr><td>O</td><td>-3.42680700</td><td>3.74490600</td><td>0.19491800</td></tr><tr><td>O</td><td>-6.70400100</td><td>5.70577700</td><td>-1.41050700</td></tr><tr><td>O</td><td>-7.01343000</td><td>3.94676800</td><td>0.78279500</td></tr><tr><td>O</td><td>-5.12283000</td><td>2.11066700</td><td>0.06935000</td></tr><tr><td>O</td><td>-4.39509700</td><td>5.24859900</td><td>-3.04762700</td></tr><tr><td>C</td><td>-1.89380300</td><td>4.32524900</td><td>-1.53925600</td></tr><tr><td>O</td><td>-1.58506900</td><td>5.60583700</td><td>-1.00634000</td></tr><tr><td>C</td><td>-5.86001400</td><td>-1.21335500</td><td>0.51959700</td></tr><tr><td>C</td><td>-5.86225500</td><td>-0.85441600</td><td>2.02426400</td></tr><tr><td>C</td><td>-4.78213100</td><td>0.88561900</td><td>0.72722600</td></tr><tr><td>C</td><td>-5.65849500</td><td>0.67123400</td><td>1.99890800</td></tr><tr><td>O</td><td>-5.17436100</td><td>-0.13518000</td><td>-0.16817100</td></tr><tr><td>O</td><td>-6.94016600</td><td>1.25703500</td><td>1.85334400</td></tr><tr><td>O</td><td>-4.88065700</td><td>-1.54667800</td><td>2.77432100</td></tr><tr><td>C</td><td>-3.24948800</td><td>0.83058800</td><td>0.91966000</td></tr><tr><td>O</td><td>-2.78650900</td><td>-0.45646600</td><td>1.33694500</td></tr><tr><td>O</td><td>-7.99860900</td><td>-2.44097500</td><td>0.43561100</td></tr><tr><td>H</td><td>-5.46158800</td><td>5.31865200</td><td>0.84010600</td></tr><tr><td>H</td><td>-5.15693600</td><td>1.01970000</td><td>2.91270900</td></tr><tr><td>H</td><td>-6.82491600</td><td>-1.08808900</td><td>2.48377200</td></tr><tr><td>H</td><td>-5.28116900</td><td>-2.12671500</td><td>0.37028500</td></tr><tr><td>H</td><td>-6.04268600</td><td>3.76105200</td><td>-1.71990900</td></tr><tr><td>H</td><td>-4.07267900</td><td>6.01887400</td><td>-1.13722700</td></tr><tr><td>H</td><td>-3.59120900</td><td>3.06240500</td><td>-1.76683300</td></tr><tr><td>H</td><td>-1.24627800</td><td>3.55028000</td><td>-1.10806000</td></tr><tr><td>H</td><td>-1.75043200</td><td>4.32004000</td><td>-2.63052200</td></tr><tr><td>H</td><td>-2.92372400</td><td>1.55160200</td><td>1.67436300</td></tr><tr><td>H</td><td>-2.78811700</td><td>1.10436300</td><td>-0.03181100</td></tr><tr><td>C</td><td>5.20040600</td><td>2.55837300</td><td>3.91397700</td></tr><tr><td>H</td><td>6.24063200</td><td>2.43710600</td><td>3.59389700</td></tr><tr><td>H</td><td>5.20443600</td><td>3.22032200</td><td>4.78472400</td></tr><tr><td>C</td><td>1.57382400</td><td>-4.04251200</td><td>-3.96615800</td></tr><tr><td>H</td><td>1.94918100</td><td>-3.02659600</td><td>-4.13548700</td></tr><tr><td>H</td><td>0.66816200</td><td>-4.19826300</td><td>-4.55408500</td></tr><tr><td>O</td><td>4.66603300</td><td>1.32988000</td><td>4.43296600</td></tr><tr><td>O</td><td>1.18949000</td><td>-4.22802300</td><td>-2.60537900</td></tr><tr><td>C</td><td>2.14565300</td><td>-4.08416800</td><td>-1.64076700</td></tr><tr><td>C</td><td>3.48563100</td><td>-3.79115400</td><td>-1.88601100</td></tr><tr><td>C</td><td>1.72469000</td><td>-4.24830100</td><td>-0.30392400</td></tr><tr><td>C</td><td>4.41818400</td><td>-3.62506100</td><td>-0.84619400</td></tr><tr><td>H</td><td>3.82609400</td><td>-3.67237800</td><td>-2.90818200</td></tr><tr><td>C</td><td>2.65515300</td><td>-4.12425700</td><td>0.71947600</td></tr><tr><td>C</td><td>4.00367000</td><td>-3.80372400</td><td>0.48464800</td></tr><tr><td>H</td><td>2.29938900</td><td>-4.27303700</td><td>1.73542800</td></tr><tr><td>C</td><td>5.68876300</td><td>0.28298000</td><td>-2.74794000</td></tr><tr><td>C</td><td>6.31958600</td><td>1.06948200</td><td>-1.76699600</td></tr><tr><td>C</td><td>5.59050100</td><td>-1.09014300</td><td>-2.54180100</td></tr><tr><td>C</td><td>6.74902800</td><td>0.46138900</td><td>-0.59110400</td></tr><tr><td>C</td><td>6.02693400</td><td>-1.71149300</td><td>-1.36237500</td></tr><tr><td>H</td><td>5.12938300</td><td>-1.67885400</td><td>-3.32938600</td></tr><tr><td>C</td><td>6.58431900</td><td>-0.91040700</td><td>-0.34648100</td></tr><tr><td>H</td><td>7.22372800</td><td>1.09395100</td><td>0.15381500</td></tr><tr><td>C</td><td>4.78200600</td><td>0.17867800</td><td>3.69421900</td></tr><tr><td>C</td><td>3.85297000</td><td>-0.84421600</td><td>3.99686500</td></tr><tr><td>C</td><td>5.76499600</td><td>-0.07056400</td><td>2.74443400</td></tr><tr><td>C</td><td>3.95544200</td><td>-2.06354200</td><td>3.33412100</td></tr><tr><td>C</td><td>5.86517300</td><td>-1.29898000</td><td>2.06270500</td></tr><tr><td>H</td><td>6.49539700</td><td>0.69923800</td><td>2.52305200</td></tr><tr><td>C</td><td>4.94131200</td><td>-2.31140500</td><td>2.35927300</td></tr><tr><td>O</td><td>2.92271700</td><td>-0.54550000</td><td>4.95061500</td></tr><tr><td>O</td><td>6.47601900</td><td>2.43458100</td><td>-1.90476800</td></tr><tr><td>O</td><td>0.39628200</td><td>-4.44351400</td><td>0.00409500</td></tr><tr><td>C</td><td>1.95701900</td><td>-1.54055200</td><td>5.27433300</td></tr><tr><td>H</td><td>2.42995600</td><td>-2.44148600</td><td>5.68454800</td></tr><tr><td>H</td><td>1.31213600</td><td>-1.09369100</td><td>6.03268400</td></tr><tr><td>H</td><td>1.35503000</td><td>-1.81469700</td><td>4.39916100</td></tr><tr><td>C</td><td>7.40557700</td><td>2.83376400</td><td>-2.92480800</td></tr><tr><td>H</td><td>8.40717600</td><td>2.44540400</td><td>-2.70383600</td></tr><tr><td>H</td><td>7.08611500</td><td>2.48456500</td><td>-3.91140100</td></tr><tr><td>H</td><td>7.42576300</td><td>3.92524000</td><td>-2.90829600</td></tr><tr><td>C</td><td>5.83529500</td><td>-3.22187900</td><td>-1.24006000</td></tr><tr><td>H</td><td>6.05878600</td><td>-3.66926300</td><td>-2.21504600</td></tr><tr><td>H</td><td>6.56404500</td><td>-3.64387000</td><td>-0.54515600</td></tr><tr><td>C</td><td>6.97983300</td><td>-1.43967400</td><td>1.02733200</td></tr><tr><td>H</td><td>7.84572300</td><td>-0.86734500</td><td>1.37893600</td></tr><tr><td>H</td><td>7.31486000</td><td>-2.47708100</td><td>0.96316300</td></tr><tr><td>H</td><td>3.25606300</td><td>-2.85660500</td><td>3.57341700</td></tr><tr><td>C</td><td>4.93610700</td><td>-3.68197100</td><td>1.68748700</td></tr><tr><td>H</td><td>4.61603700</td><td>-4.41921100</td><td>2.43285100</td></tr><tr><td>H</td><td>5.95193400</td><td>-3.97019600</td><td>1.40705800</td></tr><tr><td>H</td><td>2.33459100</td><td>-4.77120600</td><td>-4.27048600</td></tr><tr><td>H</td><td>-4.59283100</td><td>3.23415300</td><td>1.73738600</td></tr><tr><td>H</td><td>-3.72796400</td><td>5.90753700</td><td>-3.29497800</td></tr><tr><td>H</td><td>-7.69159200</td><td>4.46424700</td><td>0.31523900</td></tr><tr><td>H</td><td>-6.88107200</td><td>2.08232600</td><td>1.32953900</td></tr><tr><td>H</td><td>-4.01120200</td><td>-1.31300000</td><td>2.38527000</td></tr><tr><td>H</td><td>-6.67651600</td><td>5.89772500</td><td>-2.36316200</td></tr><tr><td>C</td><td>4.09343500</td><td>1.75550100</td><td>-3.76259100</td></tr><tr><td>H</td><td>4.42103400</td><td>2.58432800</td><td>-3.12980500</td></tr><tr><td>H</td><td>3.92297300</td><td>2.12825700</td><td>-4.77540800</td></tr><tr><td>O</td><td>5.19503900</td><td>0.81423500</td><td>-3.92149800</td></tr><tr><td>C</td><td>-0.20147700</td><td>5.93348900</td><td>-1.05095200</td></tr><tr><td>H</td><td>0.20861300</td><td>5.75690000</td><td>-2.05665300</td></tr><tr><td>H</td><td>-0.16484100</td><td>7.01418700</td><td>-0.86816100</td></tr><tr><td>C</td><td>-2.19009500</td><td>-1.26360500</td><td>0.30089000</td></tr><tr><td>H</td><td>-2.91782500</td><td>-1.45354600</td><td>-0.49532800</td></tr><tr><td>H</td><td>-1.96640800</td><td>-2.21459400</td><td>0.79537700</td></tr><tr><td>C</td><td>0.63519300</td><td>5.21014800</td><td>-0.00877100</td></tr><tr><td>C</td><td>1.96296400</td><td>4.91981900</td><td>-0.24518100</td></tr><tr><td>C</td><td>0.06515800</td><td>4.88316700</td><td>1.25347300</td></tr><tr><td>C</td><td>2.78088600</td><td>4.32424300</td><td>0.75447400</td></tr><tr><td>H</td><td>2.40969200</td><td>5.15461800</td><td>-1.20969200</td></tr><tr><td>C</td><td>0.82232700</td><td>4.29058700</td><td>2.23620900</td></tr><tr><td>H</td><td>-0.98721000</td><td>5.09113000</td><td>1.41852400</td></tr><tr><td>C</td><td>4.15602400</td><td>4.03510700</td><td>0.54469900</td></tr><tr><td>C</td><td>2.19922000</td><td>3.99973100</td><td>2.02423100</td></tr><tr><td>H</td><td>0.37596600</td><td>4.03887800</td><td>3.19532600</td></tr><tr><td>C</td><td>4.91843900</td><td>3.46650400</td><td>1.54282600</td></tr><tr><td>H</td><td>4.60583400</td><td>4.26093000</td><td>-0.41876600</td></tr><tr><td>C</td><td>3.01274600</td><td>3.41041300</td><td>3.02519700</td></tr><tr><td>C</td><td>4.35262600</td><td>3.14928200</td><td>2.80518700</td></tr><tr><td>H</td><td>5.96999400</td><td>3.25929600</td><td>1.36229500</td></tr><tr><td>H</td><td>2.56516600</td><td>3.16419100</td><td>3.98547000</td></tr><tr><td>C</td><td>-0.92940500</td><td>-0.64887000</td><td>-0.26873400</td></tr><tr><td>C</td><td>-0.68571200</td><td>-0.67028000</td><td>-1.62720700</td></tr><tr><td>C</td><td>0.02481600</td><td>-0.05067100</td><td>0.60097400</td></tr><tr><td>C</td><td>0.49828500</td><td>-0.10564400</td><td>-2.17558600</td></tr><tr><td>H</td><td>-1.40882300</td><td>-1.12333100</td><td>-2.30230800</td></tr><tr><td>C</td><td>1.16892900</td><td>0.52538800</td><td>0.10187800</td></tr><tr><td>H</td><td>-0.17258300</td><td>-0.03738700</td><td>1.66887600</td></tr><tr><td>C</td><td>0.77625300</td><td>-0.11816000</td><td>-3.57059700</td></tr><tr><td>C</td><td>1.43646800</td><td>0.52300100</td><td>-1.29558800</td></tr><tr><td>H</td><td>1.88624100</td><td>0.99047000</td><td>0.77305600</td></tr><tr><td>C</td><td>1.91974900</td><td>0.46683900</td><td>-4.06753000</td></tr><tr><td>H</td><td>0.06529800</td><td>-0.59144700</td><td>-4.24343300</td></tr><tr><td>C</td><td>2.59371700</td><td>1.13403100</td><td>-1.84519200</td></tr><tr><td>C</td><td>2.84526000</td><td>1.11563000</td><td>-3.20427600</td></tr><tr><td>H</td><td>2.11585600</td><td>0.45072200</td><td>-5.13699400</td></tr><tr><td>H</td><td>3.28751000</td><td>1.62969500</td><td>-1.17058800</td></tr><tr><td>C</td><td>-0.17703600</td><td>-5.73382200</td><td>-0.33427500</td></tr><tr><td>H</td><td>-0.01384000</td><td>-6.41989900</td><td>0.50599800</td></tr><tr><td>H</td><td>0.32063700</td><td>-6.13639400</td><td>-1.22039600</td></tr><tr><td>C</td><td>-6.57714800</td><td>-4.35227000</td><td>-0.16319000</td></tr><tr><td>C</td><td>-5.68705200</td><td>-4.36534700</td><td>-1.21759600</td></tr><tr><td>C</td><td>-6.16831900</td><td>-4.87327000</td><td>1.09652300</td></tr><tr><td>C</td><td>-4.34897300</td><td>-4.81305500</td><td>-1.05076600</td></tr><tr><td>H</td><td>-5.98812100</td><td>-3.97607200</td><td>-2.18821300</td></tr><tr><td>C</td><td>-4.88780800</td><td>-5.33606800</td><td>1.28770200</td></tr><tr><td>H</td><td>-6.87734600</td><td>-4.87844700</td><td>1.92053200</td></tr><tr><td>C</td><td>-3.39011000</td><td>-4.74186400</td><td>-2.09829600</td></tr><tr><td>C</td><td>-3.93192100</td><td>-5.28779100</td><td>0.23468400</td></tr><tr><td>H</td><td>-4.58026400</td><td>-5.71794100</td><td>2.25816900</td></tr><tr><td>C</td><td>-2.07432900</td><td>-5.06964300</td><td>-1.86974800</td></tr><tr><td>H</td><td>-3.70839600</td><td>-4.39524600</td><td>-3.07854900</td></tr><tr><td>C</td><td>-2.56978400</td><td>-5.64211000</td><td>0.42799400</td></tr><tr><td>C</td><td>-1.64492800</td><td>-5.51510600</td><td>-0.58885700</td></tr><tr><td>H</td><td>-1.33887200</td><td>-4.97451300</td><td>-2.66261400</td></tr><tr><td>H</td><td>-2.25362800</td><td>-5.98490700</td><td>1.41113200</td></tr><tr><td>C</td><td>-7.25227400</td><td>-1.35696800</td><td>-0.11353700</td></tr><tr><td>H</td><td>-7.14561200</td><td>-1.46539200</td><td>-1.20175800</td></tr><tr><td>H</td><td>-7.82184000</td><td>-0.44498700</td><td>0.08782100</td></tr><tr><td>C</td><td>-7.92538200</td><td>-3.67904500</td><td>-0.28676200</td></tr><tr><td>H</td><td>-8.71382600</td><td>-4.29875500</td><td>0.15256300</td></tr><tr><td>H</td><td>-8.17112900</td><td>-3.50874600</td><td>-1.34454500</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"84\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S85 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,487,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"85\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"85\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S86 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"86\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,804,307,820]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"86\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,832,366,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"86\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5350289 a.u \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"86\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S87 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,164,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0061/ac509ece88ff0440a5740ba323dbb66e33bbb29bc05f042e0f31fa252314f477.jpg\",\n \"list_items\": null,\n \"page_idx\": \"87\",\n \"sub_type\": null,\n \"table_body\": 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td>-0.53518800</td><td>4.98590000</td></tr><tr><td>O</td><td>6.46555700</td><td>2.67901400</td><td>-2.05162600</td></tr><tr><td>O</td><td>0.54999400</td><td>-4.29181500</td><td>-0.01937300</td></tr><tr><td>C</td><td>2.64963500</td><td>-1.51759600</td><td>5.34220700</td></tr><tr><td>H</td><td>3.12600500</td><td>-2.46378100</td><td>5.62557800</td></tr><tr><td>H</td><td>2.11615300</td><td>-1.10881400</td><td>6.20139700</td></tr><tr><td>H</td><td>1.94260800</td><td>-1.69641200</td><td>4.52348100</td></tr><tr><td>C</td><td>7.31359200</td><td>3.13607000</td><td>-3.11701000</td></tr><tr><td>H</td><td>8.33295800</td><td>2.75259400</td><td>-2.98722900</td></tr><tr><td>H</td><td>6.92671800</td><td>2.82709500</td><td>-4.09283500</td></tr><tr><td>H</td><td>7.32344400</td><td>4.22599300</td><td>-3.05236800</td></tr><tr><td>C</td><td>5.88904200</td><td>-3.00319400</td><td>-1.59321100</td></tr><tr><td>H</td><td>6.03509500</td><td>-3.41396200</td><td>-2.59846800</td></tr><tr><td>H</td><td>6.66348100</td><td>-3.45615000</td><td>-0.97112100</td></tr><tr><td>C</td><td>7.24749400</td><td>-1.32680200</td><td>0.63185200</td></tr><tr><td>H</td><td>8.15390000</td><td>-0.78234300</td><td>0.91901800</td></tr><tr><td>H</td><td>7.55397800</td><td>-2.36594600</td><td>0.49490400</td></tr><tr><td>H</td><td>3.70189300</td><td>-2.73659600</td><td>3.42476700</td></tr><tr><td>C</td><td>5.19551300</td><td>-3.53822400</td><td>1.37890800</td></tr><tr><td>H</td><td>4.91461700</td><td>-4.29042200</td><td>2.12500800</td></tr><tr><td>H</td><td>6.18185900</td><td>-3.83900000</td><td>1.01726200</td></tr><tr><td>H</td><td>2.20488900</td><td>-4.52146500</td><td>-4.40242000</td></tr><tr><td>H</td><td>-4.77038600</td><td>3.13668600</td><td>1.66801600</td></tr><tr><td>H</td><td>-3.82196700</td><td>5.81864600</td><td>-3.34565300</td></tr><tr><td>H</td><td>-7.85658400</td><td>4.28423500</td><td>0.15188600</td></tr><tr><td>H</td><td>-6.99373000</td><td>1.91714300</td><td>1.24038500</td></tr><tr><td>H</td><td>-4.01339200</td><td>-1.36282000</td><td>2.38874900</td></tr><tr><td>H</td><td>-6.78624500</td><td>5.73697300</td><td>-2.50457000</td></tr><tr><td>C</td><td>3.94624200</td><td>2.06236200</td><td>-3.74502500</td></tr><tr><td>H</td><td>4.29530500</td><td>2.83342500</td><td>-3.05332300</td></tr><tr><td>H</td><td>3.73028400</td><td>2.52470500</td><td>-4.71131400</td></tr><tr><td>O</td><td>5.04365400</td><td>1.14882100</td><td>-4.03457400</td></tr><tr><td>C</td><td>-0.32983300</td><td>5.82646000</td><td>-0.83362500</td></tr><tr><td>H</td><td>0.17893100</td><td>5.66821700</td><td>-1.79646200</td></tr><tr><td>H</td><td>-0.28945900</td><td>6.90070100</td><td>-0.61686500</td></tr><tr><td>C</td><td>-2.20384200</td><td>-1.29747200</td><td>0.25429600</td></tr><tr><td>H</td><td>-2.92180300</td><td>-1.50341600</td><td>-0.54681600</td></tr><tr><td>H</td><td>-1.95586400</td><td>-2.24364100</td><td>0.74589800</td></tr><tr><td>C</td><td>0.37863500</td><td>5.05307300</td><td>0.26763000</td></tr><tr><td>C</td><td>1.73272700</td><td>4.79337600</td><td>0.19046400</td></tr><tr><td>C</td><td>-0.34355500</td><td>4.64069800</td><td>1.42052500</td></tr><tr><td>C</td><td>2.42342500</td><td>4.14232700</td><td>1.24835700</td></tr><tr><td>H</td><td>2.29690400</td><td>5.09588500</td><td>-0.69013100</td></tr><tr><td>C</td><td>0.29063300</td><td>3.98704600</td><td>2.45206900</td></tr><tr><td>H</td><td>-1.41158200</td><td>4.82764000</td><td>1.46009800</td></tr><tr><td>C</td><td>3.82302000</td><td>3.88498900</td><td>1.20855800</td></tr><tr><td>C</td><td>1.68650300</td><td>3.72401800</td><td>2.40330300</td></tr><tr><td>H</td><td>-0.27258300</td><td>3.66676800</td><td>3.32559700</td></tr><tr><td>C</td><td>4.46048600</td><td>3.26586500</td><td>2.26014300</td></tr><tr><td>H</td><td>4.39022600</td><td>4.19320300</td><td>0.33314600</td></tr><tr><td>C</td><td>2.37176400</td><td>3.05983000</td><td>3.45572900</td></tr><tr><td>C</td><td>3.73373500</td><td>2.84115800</td><td>3.40677600</td></tr><tr><td>H</td><td>5.53128500</td><td>3.09129700</td><td>2.22031900</td></tr><tr><td>H</td><td>1.80034800</td><td>2.73484800</td><td>4.32317800</td></tr><tr><td>C</td><td>-0.95936500</td><td>-0.64098600</td><td>-0.30303700</td></tr><tr><td>C</td><td>-0.73553900</td><td>-0.58797400</td><td>-1.66397100</td></tr><tr><td>C</td><td>-0.00216900</td><td>-0.07148900</td><td>0.58264700</td></tr><tr><td>C</td><td>0.42783500</td><td>0.02967200</td><td>-2.19921700</td></tr><tr><td>H</td><td>-1.46084000</td><td>-1.01792100</td><td>-2.35167700</td></tr><tr><td>C</td><td>1.12446600</td><td>0.54945300</td><td>0.09799300</td></tr><tr><td>H</td><td>-0.18343700</td><td>-0.11625800</td><td>1.65264900</td></tr><tr><td>C</td><td>0.68017100</td><td>0.10065200</td><td>-3.59736700</td></tr><tr><td>C</td><td>1.36861800</td><td>0.62856600</td><td>-1.30154500</td></tr><tr><td>H</td><td>1.84396900</td><td>0.99117300</td><td>0.78208000</td></tr><tr><td>C</td><td>1.80010100</td><td>0.73970000</td><td>-4.08038500</td></tr><tr><td>H</td><td>-0.03296700</td><td>-0.35028300</td><td>-4.28315700</td></tr><tr><td>C</td><td>2.50289200</td><td>1.29480300</td><td>-1.83598300</td></tr><tr><td>C</td><td>2.72717000</td><td>1.36038200</td><td>-3.19808300</td></tr><tr><td>H</td><td>1.97634800</td><td>0.78888300</td><td>-5.15227700</td></tr><tr><td>H</td><td>3.19958400</td><td>1.76594500</td><td>-1.14660700</td></tr><tr><td>C</td><td>0.02232400</td><td>-5.61824400</td><td>-0.28748600</td></tr><tr><td>H</td><td>0.23867200</td><td>-6.26096100</td><td>0.57475000</td></tr><tr><td>H</td><td>0.51520800</td><td>-6.03655000</td><td>-1.16962800</td></tr><tr><td>C</td><td>-6.43498300</td><td>-4.54588100</td><td>-0.02185500</td></tr><tr><td>C</td><td>-5.56806900</td><td>-4.56371100</td><td>-1.09521000</td></tr><tr><td>C</td><td>-5.97345500</td><td>-4.98756000</td><td>1.24996900</td></tr><tr><td>C</td><td>-4.20593200</td><td>-4.93644100</td><td>-0.93992200</td></tr><tr><td>H</td><td>-5.90900900</td><td>-4.23575000</td><td>-2.07525800</td></tr><tr><td>C</td><td>-4.66720200</td><td>-5.37645400</td><td>1.43168900</td></tr><tr><td>H</td><td>-6.66354000</td><td>-4.98999100</td><td>2.08987300</td></tr><tr><td>C</td><td>-3.27575400</td><td>-4.86925400</td><td>-2.01295700</td></tr><tr><td>C</td><td>-3.73724100</td><td>-5.32840400</td><td>0.35561700</td></tr><tr><td>H</td><td>-4.32012700</td><td>-5.69709300</td><td>2.41094100</td></tr><tr><td>C</td><td>-1.94057300</td><td>-5.12050100</td><td>-1.80160000</td></tr><tr><td>H</td><td>-3.63307000</td><td>-4.58759100</td><td>-3.00054300</td></tr><tr><td>C</td><td>-2.35455900</td><td>-5.60391600</td><td>0.53231200</td></tr><tr><td>C</td><td>-1.46012600</td><td>-5.47972200</td><td>-0.51199100</td></tr><tr><td>H</td><td>-1.22903400</td><td>-5.03028300</td><td>-2.61631600</td></tr><tr><td>H</td><td>-1.99993400</td><td>-5.88382700</td><td>1.52224200</td></tr><tr><td>C</td><td>-7.25253100</td><td>-1.59027900</td><td>-0.07513800</td></tr><tr><td>H</td><td>-7.15079900</td><td>-1.73775100</td><td>-1.15917500</td></tr><tr><td>H</td><td>-7.86253900</td><td>-0.69833300</td><td>0.09569900</td></tr><tr><td>C</td><td>-7.81795800</td><td>-3.94714300</td><td>-0.14493400</td></tr><tr><td>H</td><td>-8.56549000</td><td>-4.58613100</td><td>0.33629900</td></tr><tr><td>H</td><td>-8.09167800</td><td>-3.83523600</td><td>-1.20363800</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,110,369,124]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"87\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #2 (Pop. = 21.14%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"87\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S88 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,487,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"88\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"88\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S89 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,760]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"89\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,791,307,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"89\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,818,366,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"89\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5338306 a.u \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"89\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S90 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[115,110,159,123]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"90\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"M-5b \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,137,369,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"90\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #1 (Pop. = 52.95%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,191,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0942/368e97f340003c449278029e5f2b649d1eab0588e45269842ee1c39b1f0bf235.jpg\",\n \"list_items\": null,\n \"page_idx\": \"90\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>C</td><td>7.28986400</td><td>-2.78527500</td><td>-2.16707300</td></tr><tr><td>C</td><td>6.36770200</td><td>-1.69230000</td><td>-2.72740900</td></tr><tr><td>C</td><td>6.46688500</td><td>-0.44477000</td><td>-1.84339600</td></tr><tr><td>C</td><td>6.92881700</td><td>-3.07787100</td><td>-0.69188400</td></tr><tr><td>O</td><td>6.06553100</td><td>-0.75992500</td><td>-0.51859300</td></tr><tr><td>O</td><td>8.62321500</td><td>-2.30392400</td><td>-2.31966000</td></tr><tr><td>O</td><td>5.03220200</td><td>-2.20045200</td><td>-2.72957200</td></tr><tr><td>O</td><td>5.58923900</td><td>0.51314600</td><td>-2.40594300</td></tr><tr><td>O</td><td>5.72002400</td><td>-3.82818900</td><td>-0.63322000</td></tr><tr><td>C</td><td>5.55318600</td><td>2.35399000</td><td>-0.69546400</td></tr><tr><td>O</td><td>4.15557800</td><td>2.22111700</td><td>-2.61994700</td></tr><tr><td>O</td><td>6.85089900</td><td>1.96081700</td><td>-0.30245800</td></tr><tr><td>O</td><td>5.86480400</td><td>4.81885700</td><td>-0.84082400</td></tr><tr><td>H</td><td>6.68391800</td><td>-1.42963400</td><td>-3.74574500</td></tr><tr><td>H</td><td>4.92399600</td><td>2.59234500</td><td>0.17089100</td></tr><tr><td>H</td><td>7.13452600</td><td>-3.70927400</td><td>-2.73981800</td></tr><tr><td>H</td><td>7.70891100</td><td>-3.71360000</td><td>-0.25402200</td></tr><tr><td>O</td><td>-0.86786500</td><td>-3.53945600</td><td>2.16725300</td></tr><tr><td>C</td><td>-6.36437400</td><td>2.74559900</td><td>1.01693800</td></tr><tr><td>C</td><td>-7.01704100</td><td>1.53558600</td><td>0.81524800</td></tr><tr><td>C</td><td>-6.81396300</td><td>0.41539000</td><td>1.63837800</td></tr><tr><td>H</td><td>-7.72599400</td><td>1.47898400</td><td>-0.00700000</td></tr><tr><td>C</td><td>-5.27151800</td><td>1.77029400</td><td>2.93141200</td></tr><tr><td>C</td><td>-5.90615200</td><td>0.53565000</td><td>2.70609900</td></tr><tr><td>H</td><td>-4.60052300</td><td>1.85639300</td><td>3.77868100</td></tr><tr><td>C</td><td>-6.87843000</td><td>-2.28916600</td><td>-2.11979800</td></tr><tr><td>C</td><td>-5.97436700</td><td>-3.33504100</td><td>-1.83057200</td></tr><tr><td>C</td><td>-7.36709700</td><td>-1.51532200</td><td>-1.06664300</td></tr><tr><td>C</td><td>-5.64313300</td><td>-3.57876100</td><td>-0.50157800</td></tr><tr><td>C</td><td>-7.01735100</td><td>-1.75638500</td><td>0.27323400</td></tr><tr><td>H</td><td>-8.06682100</td><td>-0.71514300</td><td>-1.27985000</td></tr><tr><td>C</td><td>-6.15056300</td><td>-2.82270700</td><td>0.56625500</td></tr><tr><td>H</td><td>-4.97561700</td><td>-4.41399700</td><td>-0.30850200</td></tr><tr><td>C</td><td>-1.99011900</td><td>-2.81357200</td><td>2.50749700</td></tr><tr><td>C</td><td>-1.90507900</td><td>-1.65428700</td><td>3.29884400</td></tr><tr><td>C</td><td>-3.24381600</td><td>-3.27385300</td><td>2.12045900</td></tr><tr><td>C</td><td>-3.07650900</td><td>-0.98401000</td><td>3.64151000</td></tr><tr><td>C</td><td>-4.42991000</td><td>-2.60720200</td><td>2.46304500</td></tr><tr><td>H</td><td>-3.28284000</td><td>-4.18916900</td><td>1.53623100</td></tr><tr><td>C</td><td>-4.34416400</td><td>-1.42714000</td><td>3.22907700</td></tr><tr><td>C</td><td>-7.62012100</td><td>-0.84604400</td><td>1.33808300</td></tr><tr><td>H</td><td>-8.61046300</td><td>-0.53148400</td><td>0.98976600</td></tr><tr><td>H</td><td>-7.79762600</td><td>-1.40749200</td><td>2.25838200</td></tr><tr><td>C</td><td>-5.74308700</td><td>-3.21606800</td><td>1.98250300</td></tr><tr><td>H</td><td>-5.63228700</td><td>-4.30588000</td><td>2.00724500</td></tr><tr><td>H</td><td>-6.54771400</td><td>-2.98589600</td><td>2.68424100</td></tr><tr><td>H</td><td>-2.98488200</td><td>-0.09527900</td><td>4.25999300</td></tr><tr><td>C</td><td>-5.56163600</td><td>-0.60944700</td><td>3.65570200</td></tr><tr><td>H</td><td>-5.35002800</td><td>-0.17974800</td><td>4.64089200</td></tr><tr><td>H</td><td>-6.42639100</td><td>-1.26172300</td><td>3.79642400</td></tr><tr><td>H</td><td>7.48588100</td><td>-0.04487100</td><td>-1.85035000</td></tr><tr><td>H</td><td>5.11569300</td><td>-3.37682900</td><td>-1.25974100</td></tr><tr><td>H</td><td>9.23012000</td><td>-3.02807700</td><td>-2.09723500</td></tr><tr><td>H</td><td>4.41686100</td><td>-1.46871300</td><td>-2.48804600</td></tr><tr><td>H</td><td>6.82266900</td><td>1.17604400</td><td>0.27929200</td></tr><tr><td>H</td><td>6.69449100</td><td>4.73653100</td><td>-0.34265200</td></tr><tr><td>C</td><td>-0.06427200</td><td>-2.94621100</td><td>1.13461100</td></tr><tr><td>H</td><td>-0.63473900</td><td>-2.86164400</td><td>0.20186300</td></tr><tr><td>H</td><td>0.30087400</td><td>-1.95975500</td><td>1.43596100</td></tr><tr><td>H</td><td>0.78231700</td><td>-3.61908000</td><td>0.98340600</td></tr><tr><td>O</td><td>-7.23344900</td><td>-2.11931400</td><td>-3.43032000</td></tr><tr><td>C</td><td>-8.17755200</td><td>-1.09910300</td><td>-3.75029900</td></tr><tr><td>H</td><td>-7.80097800</td><td>-0.10573800</td><td>-3.47936600</td></tr><tr><td>H</td><td>-8.31584200</td><td>-1.15294600</td><td>-4.83091100</td></tr><tr><td>H</td><td>-9.13679000</td><td>-1.27473000</td><td>-3.24925800</td></tr><tr><td>O</td><td>-0.68805000</td><td>-1.14789600</td><td>3.70366700</td></tr><tr><td>O</td><td>-5.49068800</td><td>-4.21857400</td><td>-2.76796300</td></tr><tr><td>C</td><td>-5.48441200</td><td>2.87966700</td><td>2.11061800</td></tr><tr><td>O</td><td>-4.92020300</td><td>4.10540200</td><td>2.29516800</td></tr><tr><td>C</td><td>-3.99653100</td><td>4.26463600</td><td>3.36763000</td></tr><tr><td>H</td><td>-3.13672900</td><td>3.59253500</td><td>3.25844800</td></tr><tr><td>H</td><td>-3.65653800</td><td>5.29997500</td><td>3.31457300</td></tr><tr><td>H</td><td>-4.47394200</td><td>4.08802700</td><td>4.33934600</td></tr><tr><td>C</td><td>5.70227700</td><td>3.61064500</td><td>-1.55921100</td></tr><tr><td>H</td><td>6.56437900</td><td>3.43565100</td><td>-2.21993000</td></tr><tr><td>C</td><td>6.81763300</td><td>-1.79152100</td><td>0.15665100</td></tr><tr><td>H</td><td>6.18940400</td><td>-2.04106200</td><td>1.01389800</td></tr><tr><td>C</td><td>8.15509700</td><td>-1.24509600</td><td>0.67581400</td></tr><tr><td>H</td><td>8.82266000</td><td>-0.99579700</td><td>-0.15243900</td></tr><tr><td>H</td><td>8.64627300</td><td>-2.01902500</td><td>1.28211600</td></tr><tr><td>O</td><td>8.00329100</td><td>-0.04481800</td><td>1.43559800</td></tr><tr><td>C</td><td>4.76192600</td><td>1.38627500</td><td>-1.63371500</td></tr><tr><td>C</td><td>3.62599000</td><td>0.60581100</td><td>-0.93941900</td></tr><tr><td>H</td><td>4.00357600</td><td>0.08864300</td><td>-0.05971000</td></tr><tr><td>H</td><td>2.86746700</td><td>1.33456800</td><td>-0.63765200</td></tr><tr><td>C</td><td>4.43280400</td><td>3.61790400</td><td>-2.41244400</td></tr><tr><td>H</td><td>4.61790100</td><td>4.05651100</td><td>-3.39949100</td></tr><tr><td>O</td><td>3.04742500</td><td>-0.40478600</td><td>-1.76517900</td></tr><tr><td>C</td><td>3.23250100</td><td>4.35520900</td><td>-1.82534300</td></tr><tr><td>H</td><td>2.37213200</td><td>4.21603300</td><td>-2.49626100</td></tr><tr><td>H</td><td>3.46798100</td><td>5.42907300</td><td>-1.79108400</td></tr><tr><td>O</td><td>2.93989800</td><td>3.87392800</td><td>-0.52125300</td></tr><tr><td>O</td><td>-6.63113200</td><td>3.83095400</td><td>0.20523600</td></tr><tr><td>C</td><td>-5.97428900</td><td>3.81580300</td><td>-1.08926300</td></tr><tr><td>H</td><td>-6.10154300</td><td>2.82819300</td><td>-1.54759900</td></tr><tr><td>H</td><td>-6.52711500</td><td>4.54981900</td><td>-1.68144200</td></tr><tr><td>C</td><td>-4.85218600</td><td>-3.72609900</td><td>-3.97542100</td></tr><tr><td>H</td><td>-5.58795800</td><td>-3.20484900</td><td>-4.59038300</td></tr><tr><td>H</td><td>-4.55074200</td><td>-4.64422000</td><td>-4.48523000</td></tr><tr><td>C</td><td>0.05321900</td><td>-1.96349900</td><td>4.63157500</td></tr><tr><td>H</td><td>-0.23709700</td><td>-1.67169000</td><td>5.65181400</td></tr><tr><td>H</td><td>-0.20823300</td><td>-3.01657900</td><td>4.49866700</td></tr><tr><td>C</td><td>7.72611200</td><td>-0.19731400</td><td>2.83871200</td></tr><tr><td>H</td><td>8.14238700</td><td>0.70525100</td><td>3.29981000</td></tr><tr><td>H</td><td>8.27559900</td><td>-1.06224700</td><td>3.23153300</td></tr><tr><td>C</td><td>2.17152000</td><td>0.05833100</td><td>-2.81229600</td></tr><tr><td>H</td><td>1.83833600</td><td>1.07602800</td><td>-2.59465700</td></tr><tr><td>H</td><td>2.74121400</td><td>0.09952300</td><td>-3.75019100</td></tr><tr><td>C</td><td>1.94494400</td><td>4.61965400</td><td>0.17636900</td></tr><tr><td>H</td><td>2.10910700</td><td>4.38135700</td><td>1.23417300</td></tr><tr><td>H</td><td>2.11638700</td><td>5.69812600</td><td>0.04916200</td></tr><tr><td>C</td><td>6.25224300</td><td>-0.31205600</td><td>3.16501000</td></tr><tr><td>C</td><td>5.73069100</td><td>-1.43675300</td><td>3.77062400</td></tr><tr><td>C</td><td>5.37944400</td><td>0.76335800</td><td>2.83604300</td></tr><tr><td>C</td><td>4.33882200</td><td>-1.55805700</td><td>4.03581400</td></tr><tr><td>H</td><td>6.38557500</td><td>-2.26308500</td><td>4.04037400</td></tr><tr><td>C</td><td>4.02731000</td><td>0.67663300</td><td>3.07149200</td></tr><tr><td>H</td><td>5.79607900</td><td>1.66150900</td><td>2.38715800</td></tr><tr><td>C</td><td>3.77645800</td><td>-2.71748900</td><td>4.63405500</td></tr><tr><td>C</td><td>3.46249200</td><td>-0.48988400</td><td>3.65949500</td></tr><tr><td>H</td><td>3.37032200</td><td>1.50170100</td><td>2.80726500</td></tr><tr><td>C</td><td>2.41707900</td><td>-2.82532100</td><td>4.81919400</td></tr><tr><td>H</td><td>4.43492700</td><td>-3.53208000</td><td>4.92536500</td></tr><tr><td>C</td><td>2.06490500</td><td>-0.63084700</td><td>3.86931100</td></tr><tr><td>C</td><td>1.53857600</td><td>-1.78001800</td><td>4.42354000</td></tr><tr><td>H</td><td>2.00264500</td><td>-3.72919800</td><td>5.25937500</td></tr><tr><td>H</td><td>1.40335000</td><td>0.17328800</td><td>3.56122800</td></tr><tr><td>C</td><td>0.97962300</td><td>-0.85913200</td><td>-2.94653500</td></tr><tr><td>C</td><td>-0.28207100</td><td>-0.32225400</td><td>-3.09811700</td></tr><tr><td>C</td><td>1.13847300</td><td>-2.27355400</td><td>-2.97144900</td></tr><tr><td>C</td><td>-1.42297100</td><td>-1.14551600</td><td>-3.29474200</td></tr><tr><td>H</td><td>-0.41976200</td><td>0.75655500</td><td>-3.07392900</td></tr><tr><td>C</td><td>0.05230700</td><td>-3.10096300</td><td>-3.14324000</td></tr><tr><td>H</td><td>2.13117200</td><td>-2.69842400</td><td>-2.85307200</td></tr><tr><td>C</td><td>-2.72283400</td><td>-0.60529300</td><td>-3.48575800</td></tr><tr><td>C</td><td>-1.25686800</td><td>-2.56812500</td><td>-3.31597800</td></tr><tr><td>H</td><td>0.18462500</td><td>-4.18009900</td><td>-3.16080700</td></tr><tr><td>C</td><td>-3.80301500</td><td>-1.43071300</td><td>-3.69987400</td></tr><tr><td>H</td><td>-2.85005500</td><td>0.47452200</td><td>-3.47348600</td></tr><tr><td>C</td><td>-2.39582900</td><td>-3.38921000</td><td>-3.52816600</td></tr><tr><td>C</td><td>-3.65123500</td><td>-2.84448600</td><td>-3.72512100</td></tr><tr><td>H</td><td>-4.78867000</td><td>-1.00599500</td><td>-3.86724200</td></tr><tr><td>H</td><td>-2.26327500</td><td>-4.46922000</td><td>-3.55164600</td></tr><tr><td>C</td><td>0.51976300</td><td>4.26558700</td><td>-0.20250100</td></tr><tr><td>C</td><td>-0.43438500</td><td>5.24474900</td><td>-0.38976500</td></tr><tr><td>C</td><td>0.13240200</td><td>2.89894600</td><td>-0.28384900</td></tr><tr><td>C</td><td>-1.79839900</td><td>4.91672100</td><td>-0.62374100</td></tr><tr><td>H</td><td>-0.15454800</td><td>6.29504400</td><td>-0.33321800</td></tr><tr><td>C</td><td>-1.17203700</td><td>2.54549500</td><td>-0.53669300</td></tr><tr><td>H</td><td>0.88015000</td><td>2.12795800</td><td>-0.12787300</td></tr><tr><td>C</td><td>-2.80898100</td><td>5.90773100</td><td>-0.76309300</td></tr><tr><td>C</td><td>-2.17711900</td><td>3.53789900</td><td>-0.70069800</td></tr><tr><td>H</td><td>-1.45528300</td><td>1.49729500</td><td>-0.59072000</td></tr><tr><td>C</td><td>-4.12675100</td><td>5.55004100</td><td>-0.93237300</td></tr><tr><td>H</td><td>-2.52575400</td><td>6.95662800</td><td>-0.71868200</td></tr><tr><td>C</td><td>-3.54265100</td><td>3.20561000</td><td>-0.90326900</td></tr><tr><td>C</td><td>-4.51361500</td><td>4.18296400</td><td>-0.99585300</td></tr><tr><td>H</td><td>-4.89078000</td><td>6.31919100</td><td>-1.01651300</td></tr><tr><td>H</td><td>-3.81989200</td><td>2.15521300</td><td>-0.96051200</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"90\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S91 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,487,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"91\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"91\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S92 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"92\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,804,307,820]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"92\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imaginary Frequency $= 0$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,832,371,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"92\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5224152 a.u. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"92\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S93 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,166,485,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0277/391a07491042356f1ac31f858dc219f73fcc09ee0445c37c45f0abfd726f1445.jpg\",\n \"list_items\": null,\n \"page_idx\": \"93\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>C</td><td>-7.28565600</td><td>2.80017600</td><td>-2.15052900</td></tr><tr><td>C</td><td>-6.36295200</td><td>1.70456900</td><td>-2.71924400</td></tr><tr><td>C</td><td>-6.46544300</td><td>0.45336100</td><td>-1.84150400</td></tr><tr><td>C</td><td>-6.92819300</td><td>3.07877600</td><td>-0.67757700</td></tr><tr><td>O</td><td>-6.06490800</td><td>0.76104600</td><td>-0.51519000</td></tr><tr><td>O</td><td>-8.65158600</td><td>2.39592500</td><td>-2.20225600</td></tr><tr><td>O</td><td>-5.02551800</td><td>2.20834000</td><td>-2.72495100</td></tr><tr><td>O</td><td>-5.59203100</td><td>-0.50631400</td><td>-2.40734700</td></tr><tr><td>O</td><td>-5.71554100</td><td>3.82174600</td><td>-0.61373400</td></tr><tr><td>C</td><td>-5.55854100</td><td>-2.35126200</td><td>-0.70111500</td></tr><tr><td>O</td><td>-4.16197800</td><td>-2.21654300</td><td>-2.62681200</td></tr><tr><td>O</td><td>-6.85744300</td><td>-1.95893300</td><td>-0.31142500</td></tr><tr><td>O</td><td>-5.86723300</td><td>-4.81644500</td><td>-0.84699800</td></tr><tr><td>H</td><td>-6.67492600</td><td>1.44175800</td><td>-3.74133000</td></tr><tr><td>H</td><td>-4.93129200</td><td>-2.58935700</td><td>0.16667200</td></tr><tr><td>H</td><td>-7.12738100</td><td>3.73050000</td><td>-2.71209300</td></tr><tr><td>H</td><td>-7.71054500</td><td>3.71239500</td><td>-0.24485800</td></tr><tr><td>O</td><td>0.87072900</td><td>3.54757700</td><td>2.15640700</td></tr><tr><td>C</td><td>6.36112800</td><td>-2.74627600</td><td>1.02811400</td></tr><tr><td>C</td><td>7.01506100</td><td>-1.53756200</td><td>0.82274300</td></tr><tr><td>C</td><td>6.81284100</td><td>-0.41453500</td><td>1.64221600</td></tr><tr><td>H</td><td>7.72436100</td><td>-1.48428800</td><td>0.00057200</td></tr><tr><td>C</td><td>5.26884100</td><td>-1.76384600</td><td>2.93925200</td></tr><tr><td>C</td><td>5.90474100</td><td>-0.53054300</td><td>2.71016800</td></tr><tr><td>H</td><td>4.59762700</td><td>-1.84663900</td><td>3.78667400</td></tr><tr><td>C</td><td>6.88060100</td><td>2.27866000</td><td>-2.12429200</td></tr><tr><td>C</td><td>5.97779000</td><td>3.32651100</td><td>-1.83834600</td></tr><tr><td>C</td><td>7.36815100</td><td>1.50737400</td><td>-1.06873900</td></tr><tr><td>C</td><td>5.64662400</td><td>3.57458600</td><td>-0.51014500</td></tr><tr><td>C</td><td>7.01852300</td><td>1.75289800</td><td>0.27036000</td></tr><tr><td>H</td><td>8.06696200</td><td>0.70573200</td><td>-1.27944900</td></tr><tr><td>C</td><td>6.15296600</td><td>2.82113200</td><td>0.56003600</td></tr><tr><td>H</td><td>4.98009600</td><td>4.41120900</td><td>-0.31967700</td></tr><tr><td>C</td><td>1.99208400</td><td>2.82163900</td><td>2.49948300</td></tr><tr><td>C</td><td>1.90567000</td><td>1.66465100</td><td>3.29404400</td></tr><tr><td>C</td><td>3.24639600</td><td>3.27976600</td><td>2.11186300</td></tr><tr><td>C</td><td>3.07637800</td><td>0.99451000</td><td>3.63941200</td></tr><tr><td>C</td><td>4.43174900</td><td>2.61311300</td><td>2.45697700</td></tr><tr><td>H</td><td>3.28648500</td><td>4.19332900</td><td>1.52497300</td></tr><tr><td>C</td><td>4.34462600</td><td>1.43541000</td><td>3.22646000</td></tr><tr><td>C</td><td>7.62024700</td><td>0.84518100</td><td>1.33806100</td></tr><tr><td>H</td><td>8.61030300</td><td>0.52857100</td><td>0.99079900</td></tr><tr><td>H</td><td>7.79821900</td><td>1.40928400</td><td>2.25663900</td></tr><tr><td>C</td><td>5.74566400</td><td>3.21923400</td><td>1.97500400</td></tr><tr><td>H</td><td>5.63597800</td><td>4.30922700</td><td>1.99642100</td></tr><tr><td>H</td><td>6.54989400</td><td>2.99034400</td><td>2.67761600</td></tr><tr><td>H</td><td>2.98362300</td><td>0.10760200</td><td>4.26033500</td></tr><tr><td>C</td><td>5.56117000</td><td>0.61791300</td><td>3.65604900</td></tr><tr><td>H</td><td>5.34889100</td><td>0.19157300</td><td>4.64255300</td></tr><tr><td>H</td><td>6.42653700</td><td>1.26977600</td><td>3.79489600</td></tr><tr><td>H</td><td>-7.48669200</td><td>0.05896000</td><td>-1.85165800</td></tr><tr><td>H</td><td>-5.11022700</td><td>3.37023100</td><td>-1.23903300</td></tr><tr><td>H</td><td>-8.90217400</td><td>2.29178900</td><td>-3.13480000</td></tr><tr><td>H</td><td>-4.41137100</td><td>1.47360900</td><td>-2.48877600</td></tr><tr><td>H</td><td>-6.83089800</td><td>-1.17961800</td><td>0.27781700</td></tr><tr><td>H</td><td>-6.69637700</td><td>-4.73422400</td><td>-0.34788500</td></tr><tr><td>C</td><td>0.06664100</td><td>2.95176100</td><td>1.12561700</td></tr><tr><td>H</td><td>0.63730800</td><td>2.86306300</td><td>0.19337800</td></tr><tr><td>H</td><td>-0.29998800</td><td>1.96690300</td><td>1.43036800</td></tr><tr><td>H</td><td>-0.77893100</td><td>3.62529400</td><td>0.97171700</td></tr><tr><td>O</td><td>7.23568600</td><td>2.10449000</td><td>-3.43423800</td></tr><tr><td>C</td><td>8.17874800</td><td>1.08230900</td><td>-3.75098100</td></tr><tr><td>H</td><td>7.80102700</td><td>0.09015300</td><td>-3.47723400</td></tr><tr><td>H</td><td>8.31736400</td><td>1.13282500</td><td>-4.83171200</td></tr><tr><td>H</td><td>9.13805500</td><td>1.25835700</td><td>-3.25021900</td></tr><tr><td>O</td><td>0.68808100</td><td>1.15984500</td><td>3.69916600</td></tr><tr><td>O</td><td>5.49541600</td><td>4.20794500</td><td>-2.77838700</td></tr><tr><td>C</td><td>5.48072900</td><td>-2.87598900</td><td>2.12195300</td></tr><tr><td>O</td><td>4.91515500</td><td>-4.10055200</td><td>2.31015900</td></tr><tr><td>C</td><td>3.99152800</td><td>-4.25556800</td><td>3.38328600</td></tr><tr><td>H</td><td>3.13236200</td><td>-3.58296300</td><td>3.27220900</td></tr><tr><td>H</td><td>3.65050800</td><td>-5.29073200</td><td>3.33350600</td></tr><tr><td>H</td><td>4.46930500</td><td>-4.07642100</td><td>4.35435700</td></tr><tr><td>C</td><td>-5.70555000</td><td>-3.60802900</td><td>-1.56516000</td></tr><tr><td>H</td><td>-6.56756700</td><td>-3.43377300</td><td>-2.22622800</td></tr><tr><td>C</td><td>-6.81938500</td><td>1.78795200</td><td>0.16430600</td></tr><tr><td>H</td><td>-6.19280200</td><td>2.03469000</td><td>1.02351700</td></tr><tr><td>C</td><td>-8.15636000</td><td>1.23768800</td><td>0.68050400</td></tr><tr><td>H</td><td>-8.82341200</td><td>0.98713800</td><td>-0.14744600</td></tr><tr><td>H</td><td>-8.64982400</td><td>2.00909100</td><td>1.28792700</td></tr><tr><td>O</td><td>-8.00071900</td><td>0.03628000</td><td>1.43858200</td></tr><tr><td>C</td><td>-4.76579300</td><td>-1.38279900</td><td>-1.63780400</td></tr><tr><td>C</td><td>-3.62764800</td><td>-0.60603300</td><td>-0.94303500</td></tr><tr><td>H</td><td>-4.00360300</td><td>-0.08843400</td><td>-0.06290600</td></tr><tr><td>H</td><td>-2.87104600</td><td>-1.33702800</td><td>-0.64204400</td></tr><tr><td>C</td><td>-4.43599000</td><td>-3.61375300</td><td>-2.41807500</td></tr><tr><td>H</td><td>-4.62003700</td><td>-4.05324100</td><td>-3.40492300</td></tr><tr><td>O</td><td>-3.04646100</td><td>0.40360000</td><td>-1.76835600</td></tr><tr><td>C</td><td>-3.23472600</td><td>-4.34910900</td><td>-1.83031600</td></tr><tr><td>H</td><td>-2.37409900</td><td>-4.20844500</td><td>-2.50058800</td></tr><tr><td>H</td><td>-3.46865600</td><td>-5.42332500</td><td>-1.79658700</td></tr><tr><td>O</td><td>-2.94379900</td><td>-3.86795400</td><td>-0.52579900</td></tr><tr><td>O</td><td>6.62707200</td><td>-3.83457000</td><td>0.22010200</td></tr><tr><td>C</td><td>5.97198100</td><td>-3.82238100</td><td>-1.07528300</td></tr><tr><td>H</td><td>6.10098700</td><td>-2.83624200</td><td>-1.53628100</td></tr><tr><td>H</td><td>6.52476000</td><td>-4.55870800</td><td>-1.66463000</td></tr><tr><td>C</td><td>4.85679100</td><td>3.71287100</td><td>-3.98469300</td></tr><tr><td>H</td><td>5.59219700</td><td>3.18918500</td><td>-4.59801800</td></tr><tr><td>H</td><td>4.55647100</td><td>4.62992800</td><td>-4.49707600</td></tr><tr><td>C</td><td>-0.05377200</td><td>1.97811100</td><td>4.62402900</td></tr><tr><td>H</td><td>0.23935600</td><td>1.69314500</td><td>5.64542000</td></tr><tr><td>H</td><td>0.20393600</td><td>3.03130400</td><td>4.48460700</td></tr><tr><td>C</td><td>-7.72317600</td><td>0.18706600</td><td>2.84176500</td></tr><tr><td>H</td><td>-8.13636400</td><td>-0.71760600</td><td>3.30153800</td></tr><tr><td>H</td><td>-8.27513700</td><td>1.04958700</td><td>3.23639500</td></tr><tr><td>C</td><td>-2.17142700</td><td>-0.06113000</td><td>-2.81549200</td></tr><tr><td>H</td><td>-1.83933900</td><td>-1.07906100</td><td>-2.59725900</td></tr><tr><td>H</td><td>-2.74135900</td><td>-0.10229200</td><td>-3.75324200</td></tr><tr><td>C</td><td>-1.95128800</td><td>-4.61472700</td><td>0.17420800</td></tr><tr><td>H</td><td>-2.11744000</td><td>-4.37577800</td><td>1.23155600</td></tr><tr><td>H</td><td>-2.12398200</td><td>-5.69300100</td><td>0.04705700</td></tr><tr><td>C</td><td>-6.24944300</td><td>0.30590400</td><td>3.16729800</td></tr><tr><td>C</td><td>-5.73094000</td><td>1.43124400</td><td>3.77438200</td></tr><tr><td>C</td><td>-5.37341400</td><td>-0.76585600</td><td>2.83516900</td></tr><tr><td>C</td><td>-4.33909700</td><td>1.55697700</td><td>4.03756000</td></tr><tr><td>H</td><td>-6.38828400</td><td>2.25486900</td><td>4.04640900</td></tr><tr><td>C</td><td>-4.02123900</td><td>-0.67486500</td><td>3.06877800</td></tr><tr><td>H</td><td>-5.78755300</td><td>-1.66468500</td><td>2.38532400</td></tr><tr><td>C</td><td>-3.77976900</td><td>2.71748300</td><td>4.63665800</td></tr><tr><td>C</td><td>-3.45962100</td><td>0.49264500</td><td>3.65781700</td></tr><tr><td>H</td><td>-3.36174900</td><td>-1.49712600</td><td>2.80203600</td></tr><tr><td>C</td><td>-2.42044000</td><td>2.83007900</td><td>4.81910000</td></tr><tr><td>H</td><td>-4.44065500</td><td>3.52915000</td><td>4.93063100</td></tr><tr><td>C</td><td>-2.06210200</td><td>0.63843500</td><td>3.86494600</td></tr><tr><td>C</td><td>-1.53889500</td><td>1.78870400</td><td>4.41973700</td></tr><tr><td>H</td><td>-2.00842200</td><td>3.73480800</td><td>5.25982000</td></tr><tr><td>H</td><td>-1.39820100</td><td>-0.16266500</td><td>3.55410400</td></tr><tr><td>C</td><td>-0.97848100</td><td>0.85480200</td><td>-2.95072700</td></tr><tr><td>C</td><td>0.28264700</td><td>0.31618100</td><td>-3.10084300</td></tr><tr><td>C</td><td>-1.13568700</td><td>2.26936600</td><td>-2.97840900</td></tr><tr><td>C</td><td>1.42455800</td><td>1.13772200</td><td>-3.29877100</td></tr><tr><td>H</td><td>0.41908300</td><td>-0.76273400</td><td>-3.07450000</td></tr><tr><td>C</td><td>-0.04851000</td><td>3.09516300</td><td>-3.15158400</td></tr><tr><td>H</td><td>-2.12790000</td><td>2.69567200</td><td>-2.86106100</td></tr><tr><td>C</td><td>2.72383500</td><td>0.59559500</td><td>-3.48834200</td></tr><tr><td>C</td><td>1.26008900</td><td>2.56046900</td><td>-3.32299700</td></tr><tr><td>H</td><td>-0.17957300</td><td>4.17441400</td><td>-3.17131000</td></tr><tr><td>C</td><td>3.80499700</td><td>1.41931500</td><td>-3.70404700</td></tr><tr><td>H</td><td>2.84981800</td><td>-0.48433500</td><td>-3.47367200</td></tr><tr><td>C</td><td>2.40001800</td><td>3.37979100</td><td>-3.53680300</td></tr><tr><td>C</td><td>3.65481900</td><td>2.83319500</td><td>-3.73244100</td></tr><tr><td>H</td><td>4.79020900</td><td>0.99312200</td><td>-3.87026500</td></tr><tr><td>H</td><td>2.26871800</td><td>4.45989900</td><td>-3.56263400</td></tr><tr><td>C</td><td>-0.52472300</td><td>-4.26287200</td><td>-0.20159800</td></tr><tr><td>C</td><td>0.42882100</td><td>-5.24351300</td><td>-0.38423100</td></tr><tr><td>C</td><td>-0.13550700</td><td>-2.89686000</td><td>-0.28455700</td></tr><tr><td>C</td><td>1.79383100</td><td>-4.91754300</td><td>-0.61527100</td></tr><tr><td>H</td><td>0.14762600</td><td>-6.29336800</td><td>-0.32627600</td></tr><tr><td>C</td><td>1.17000600</td><td>-2.54544500</td><td>-0.53471900</td></tr><tr><td>H</td><td>-0.88269600</td><td>-2.12464600</td><td>-0.13208500</td></tr><tr><td>C</td><td>2.80363500</td><td>-5.90998600</td><td>-0.75001600</td></tr><tr><td>C</td><td>2.17433800</td><td>-3.53932700</td><td>-0.69421100</td></tr><tr><td>H</td><td>1.45459700</td><td>-1.49768400</td><td>-0.59011500</td></tr><tr><td>C</td><td>4.12218200</td><td>-5.55415100</td><td>-0.91718400</td></tr><tr><td>H</td><td>2.51914300</td><td>-6.95846600</td><td>-0.70389400</td></tr><tr><td>C</td><td>3.54068600</td><td>-3.20901700</td><td>-0.89453900</td></tr><tr><td>C</td><td>4.51074000</td><td>-4.18765700</td><td>-0.98305000</td></tr><tr><td>H</td><td>4.88551500</td><td>-6.32435300</td><td>-0.99795200</td></tr><tr><td>H</td><td>3.81920000</td><td>-2.15905900</td><td>-0.95362000</td></tr></table>\",\n \"table_caption\": \"[\\\"Symbolic Z-matrix: \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,111,369,126]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"93\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conformation #2 (Pop. = 40.31%) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"93\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S94 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,487,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"94\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"94\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S95 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[117,80,485,774]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n 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\"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4064.5221581 a.u \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[850,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"95\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S96 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[115,110,201,123]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"96\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"M-5acAch \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": 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null,\n \"table_footnote\": null,\n \"text\": \"E(RB3LYP) = -4393.317892 a.u. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[840,927,880,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"102\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S103 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1021/acs.joc.1c00019.s001"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Chemistry"},"sha256":{"kind":"string","value":"05699f6fbd95dd25d6601b8d13036220a7949ccb5a4f8cc859231ea6602aacf8"},"title":{"kind":"string","value":"Fluorescent Molecular\\nCages with Sucrose and Cyclotriveratrylene\\nUnits for the Selective Recognition of Choline and Acetylcholine"}}},{"rowIdx":147,"cells":{"abstract":{"kind":"string","value":"To investigate temporal changes in clinical reasoning quality of physicians who requested abdominal CT scans at a tertiary care center during on-call hours within a 15-year period. This retrospective study included 531 patients who underwent abdominal CT at a tertiary care center during on-call hours on 36 randomly sampled unique calendar days in each of the years between 2005 and 2019. Clinical reasoning quality was expressed as a percentage (0–100%), taking into account the degree by which the differential diagnoses on the CT request form matched the CT diagnosis. Temporal changes in the quality of clinical reasoning and number of CT scans were assessed using Mann-Kendall tests. Associations between the quality of clinical reasoning with patient age and gender, requesting department, and time of CT scanning were determined with linear regression analyses. The median annual clinical reasoning score was 14.7% (interquartile range: 12.2 to 16.0%; range: 7.7 to 34.6%). The quality of clinical reasoning significantly decreased between 2005 and 2019 (Mann-Kendall Tau of −0.390, p = 0.048), while the number of abdominal CT scans significantly increased (Mann-Kendall tau of 0.790, p < 0.001). The clinical reasoning quality of physicians who request abdominal CT scans during on-call hours has deteriorated over time. Clinical reasoning appears to be worse in younger patients. \n • In patients with suspected acute abdominal pathology who are scheduled to undergo CT scanning, referring physicians generally have difficulties in making an accurate pretest (differential) diagnosis.\n \n • Clinical reasoning quality of physicians who request acute abdominal CT scans has deteriorated over the years, while the number of CT scans has shown a significant increase.\n \n • Clinical reasoning quality appears to be worse in younger patients in this setting.\n "},"author":{"kind":"string","value":"Selin Ersoydan|Derya Yakar|Thomas C. Kwee"},"content_list":{"kind":"list like","value":[{"bbox":"[80,135,794,182]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Did medical doctors who order abdominal CT scans during on-call hours truly become worse at clinical reasoning? Yes, they did ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,200,581,218]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Selin Ersoydan $^{1}$ · Derya Yakar $^{1}$ · Omer Kasalak $^{1}$ · Thomas C. Kwee $^{1}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,239,485,265]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 22 April 2022 / Revised: 25 July 2022 / Accepted: 18 August 2022 $\\langle \\widehat{\\mathbb{C}}\\rangle$ The Author(s) 2022 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,282,149,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,298,915,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objective To investigate temporal changes in clinical reasoning quality of physicians who requested abdominal CT scans at a tertiary care center during on-call hours within a 15-year period. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,329,915,421]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods This retrospective study included 531 patients who underwent abdominal CT at a tertiary care center during on-call hours on 36 randomly sampled unique calendar days in each of the years between 2005 and 2019. Clinical reasoning quality was expressed as a percentage $(0 - 100\\%)$ , taking into account the degree by which the differential diagnoses on the CT request form matched the CT diagnosis. Temporal changes in the quality of clinical reasoning and number of CT scans were assessed using Mann-Kendall tests. Associations between the quality of clinical reasoning with patient age and gender, requesting department, and time of CT scanning were determined with linear regression analyses. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,422,915,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results The median annual clinical reasoning score was $0.4\\%$ (interquartile range: 0.3 to $0.6\\%$ ; range: 0.1 to $1.9\\%$ ). The quality of clinical reasoning significantly decreased between 2005 and 2019 (Mann-Kendall Tau of $-0.829, p < 0.001$ ), while the number of abdominal CT scans significantly increased (Mann-Kendall tau of $0.790, p < 0.001$ ). There was a significant association between the quality of clinical reasoning and patient age ( $\\beta$ coefficient of $0.210, p = 0.002$ ). The quality of clinical reasoning was not significantly associated with patient gender, requesting department, or time of CT scanning. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,501,915,532]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion The clinical reasoning quality of physicians who request abdominal CT scans during on-call hours has deteriorated over time. Clinical reasoning appears to be worse in younger patients. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,532,157,546]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Key Points ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,546,915,626]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- In patients with suspected acute abdominal pathology who are scheduled to undergo CT scanning, referring physicians generally have difficulties in making an accurate pretest (differential) diagnosis. \",\"- Clinical reasoning quality of physicians who request acute abdominal CT scans has deteriorated over the years, while the number of CT scans has shown a significant increase. \",\"- Clinical reasoning quality appears to be worse in younger patients in this setting. \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,641,786,656]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords Abdomen $\\cdot$ Clinical reasoning $\\cdot$ Differential diagnosis $\\cdot$ Computed tomography $\\cdot$ Night shift work ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,689,176,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abbreviations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,703,284,718]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CI Confidence interval ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,720,275,735]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IQR Interquartile range ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,736,416,751]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LOESS Locally estimated scatterplot smoothing ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,687,626,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,718,915,830]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Medical imaging utilization keeps on increasing in the Western world, and this particularly applies to CT examinations [1, 2]. This growth in CT examinations is due to the relatively widespread availability of CT systems, continuous improvements in technology (which increase image quality, reduce scan time, and decrease radiation dose), decreasing costs of CT scans, and new clinical CT applications. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,831,915,893]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although medical imaging is generally considered beneficial to patients, a part of its increase has been attributed to overutilization [3]. Anecdotal data indicate that clinicians request more and more imaging simply because it is available, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,321,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology \nhttps://doi.org/10.1007/s00330-022-09121-7 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,79,200,94]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"EXPERIMENTAL ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,81,915,120]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,836,252,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thomas C. Kwee thomaskwee@gmail.com ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[80,875,470,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[80,934,300,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published online: 07 September 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[838,927,914,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,70,485,289]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and to rule out disease rather than to confirm disease that is most likely based on probabilistic hypothetico-deductive reasoning [4-6]. Based on these anecdotal data and our own experience, it is hypothesized that the clinical reasoning quality of physicians who request medical imaging has deteriorated over the years. However, establishing a good differential diagnosis based on clinical history, physical examination, and laboratory findings, is considered important to optimize the interpretation and diagnostic yield of an imaging examination [4-7]. In addition, a good differential diagnosis is necessary to avoid unnecessary imaging studies that may be costly, that may have potential side effects due to the use of ionizing radiation and contrast agents, and that may yield incidental findings. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,292,485,417]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"During on-call hours, CT scans of the abdomen are frequently ordered, because the list of acute abdominal diseases is long and they may be challenging to diagnose based on clinical grounds [8]. As such, they provide an excellent setting to test our hypothesis. The purpose of our study was therefore to investigate temporal changes in clinical reasoning quality of physicians who requested abdominal CT scans at a tertiary care center during on-call hours within a 15-year period. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,448,287,463]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Materials and methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[84,479,183,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Study design ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,513,485,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. A random sample of 36 unique calendar days was selected using the Random Calendar Date Generator [9]. All patients who underwent abdominal CT at a tertiary care center in The Netherlands during on-call evening and night hours on each of these 36 unique calendar days in each of the years between 2005 and 2019, were potentially eligible for inclusion. The University Medical Center Groningen is one of the seven university medical centers in the Netherlands, with more than 2 million people in its direct catchment area in the north-east of the country. It has more than 10,000 employees and 1,300 beds, and all medical specialties are represented. The hospital is also a recognized Level 1 trauma center, and performs all organ transplants. Patients were included if CT scanning was done to evaluate for acute abdominal pathology, and if the scan range included the region from the diaphragm to the pubic symphysis. Patients who underwent CT scanning to guide an intervention (e.g., drainage), patients whose CT scan was performed for non-acute reasons, and patients whose CT report or clinical records were missing, were excluded. Note that the cases that were selected for the present study were derived from a previously published study that had a different purpose, namely to investigate temporal changes in the utilization and patient impact of abdominal CT during duty ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,70,914,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"shifts in terms of negative scan proportion, same-day hospital discharge, and incidental findings [10]. When ordering abdominal CT during on-call hours, the referring physician both calls the attending radiology resident or radiologist, and submits a digital request form. Other details regarding on-call logistics, CT acquisition, and CT interpretation can be read elsewhere [10]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,205,628,218]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data extraction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,237,914,362]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Patient age, patient gender, indication for CT scanning, requesting department, use of intravenous CT contrast agents, use of gastrointestinal CT contrast agents, time of CT scanning (before or after midnight), and year in which the CT scan was performed, were recorded. The digital request form of each CT scan was evaluated to extract the differential diagnosis that was compiled by the referring physician, and the CT report was evaluated to extract the diagnosis made. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,386,613,401]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,417,914,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The quality of referring physicians' clinical reasoning before ordering a CT scan was quantified using a scoring system. To that end, the differential diagnosis made by the referring physician on the CT request form was compared to the CT diagnosis. Each of the differential diagnoses on the CT request form that matched the CT diagnosis received 1 point. If no differential diagnosis was provided, or if the CT scan diagnosis did not match any of the differential diagnoses on the CT request form, 0 points were assigned. The clinical reasoning score was then calculated by dividing the total number of points by the total number of differential diagnoses that was listed on the CT request form, and expressed as a percentage. For example, if the clinical differential diagnosis included ruptured abdominal aortic aneurysm, urolithiasis, and cholecystitis, and CT demonstrated urolithiasis, the clinical reasoning score would be $33\\%$ . Mann-Kendall tests were performed to test for any temporal changes in both clinical reasoning scores in each year between 2005 and 2019, and number of abdominal CT scans during on-call hours on the 36 randomly sampled unique calendar days in each year between 2005 and 2019. Subsequently, linear regression analyses were performed to determine the association between the quality of clinical reasoning (all years combined) and the following variables: patient age, patient gender, requesting department (surgery, internal medicine, emergency medicine, intensive care, or other), and time of CT scanning (before or after midnight). $p$ values $< 0.05$ were considered statistically significant. Statistical analyses were executed using R version 3.6.3 software (R Foundation for Statistical Computing) and IBM Statistical Package for the Social Sciences (SPSS) version 23 (SPSS). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[803,40,915,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[84,927,154,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,69,149,86]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,101,149,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Patients ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,134,489,324]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The 36 randomly selected unique calendar days are displayed in Table 1. Of 639 potentially eligible patients, 531 remained for inclusion in this study (Fig. 1). In these 531 patients, median age was 59.0 years (interquartile range (IQR): 42.3-70.0 years; range: 10-107 years), male/female ratio was 327/204, requesting department was most frequently surgery $(51.8\\%)$ , indication for CT scanning was most frequently other/mixed $(26.6\\%)$ , most CT scans were performed with intravenous contrast agents in either multiple phases $(37.7\\%)$ or in the venous phase $(37.1\\%)$ , and without gastrointestinal contrast agents $(63.8\\%)$ , and most CT scans were performed before midnight $(75.5\\%)$ (Table 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,353,468,387]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Clinical reasoning quality and number of CT scans: temporal changes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,401,489,622]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The median annual clinical reasoning score was $0.4\\%$ (IQR: 0.3 to $0.6\\%$ ; range: 0.1 to $1.9\\%$ ) (note that the clinical reasoning scores are given as percentages). Clinical reasoning scores significantly decreased over time (Mann-Kendall tau of $-0.829$ , $p < 0.001$ ) (Fig. 2). Note the appearance of a rapid drop from the years 2005/2006 to 2007 (Fig. 2), but the overall decrease in clinical reasoning scores remained significant after excluding the years 2005 and 2006 (Mann-Kendall tau of $-0.795$ , $p < 0.001$ ). The median annual number of abdominal CT scans during on-call hours on the 36 randomly sampled unique calendar days was 35 (IQR: 23.25 to 46.75; range: 17-55). The number of abdominal CT scans significantly increased over time (Mann-Kendall tau of $0.790$ , $p < 0.001$ ) (Fig. 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[247,683,487,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0707/6de6353b0a0076bd5c4336c298971752e3d73357ca4e7cda84ea6d09f774296c.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>Month</td><td>Day(s)</td></tr><tr><td>January</td><td>6, 11, 20, 29</td></tr><tr><td>February</td><td>1, 10, 18</td></tr><tr><td>March</td><td>1, 4, 21</td></tr><tr><td>May</td><td>8, 21</td></tr><tr><td>June</td><td>2, 4, 6, 7, 8, 23, 26, 30</td></tr><tr><td>July</td><td>7, 14</td></tr><tr><td>August</td><td>26, 28</td></tr><tr><td>September</td><td>3, 15, 30</td></tr><tr><td>October</td><td>2, 9, 11, 21</td></tr><tr><td>November</td><td>29</td></tr><tr><td>December</td><td>16, 21, 22, 28</td></tr></table>","table_caption":"[\"Table 1 Thirty-six randomly selected unique calendar days \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[510,65,915,392]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1 Flowchart of patient selection \"]","image_footnote":"[]","img_path":"images/0628/9efb9e273e62106279106148792f5bc0835bc8726f51faa649bd57ac938e328f.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[507,432,800,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Clinical reasoning skills: determinants ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,464,915,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There was a significant association between the quality of clinical reasoning and patient age ( $\\beta$ coefficient of 0.210, $p = 0.002$ ). The quality of clinical reasoning was not significantly associated with patient gender, requesting department, or time of CT scanning (Table 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,573,608,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,606,915,764]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study has four main findings. First, in patients with suspected acute abdominal pathology who are scheduled to undergo CT scanning during on-call hours, referring physicians generally have difficulties in making an accurate pretest (differential) diagnosis. Second, clinical reasoning quality of physicians who request abdominal CT scans in these patients has significantly deteriorated over the years. Third, the number of CT scans has shown a significant increase during the same time frame. Fourth, clinical reasoning quality was significantly lower in younger patients in this setting. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,764,917,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our results underline the importance of CT scanning complementary to clinical history, physical examination, and laboratory findings, in increasing or decreasing the likelihood of acute diseases in the abdomen in the appropriate clinical setting. Most importantly, they confirm our hypothesis that the clinical reasoning quality of physicians who request acute abdominal CT scans has deteriorated over the years, while the number of CT scans has shown an opposite temporal trend. We speculate that this is mainly due to the CT scan capacity that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,39,194,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[838,927,914,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[292,69,919,512]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0743/45eb0b182e0091a565ec15e4429dbcbeeafe7cc34b8349ad713318cf8a6fe870.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Variable</td><td></td><td>Count (percentage)</td></tr><tr><td>Patient age (years)</td><td></td><td>59.0 (42.3–70.0)a</td></tr><tr><td rowspan=\"2\">Patient gender</td><td>Male</td><td>327 (61.6%)</td></tr><tr><td>Female</td><td>204 (38.4%)</td></tr><tr><td rowspan=\"5\">Requesting department</td><td>Surgery</td><td>275 (51.8%)</td></tr><tr><td>Internal medicine</td><td>82 (15.4%)</td></tr><tr><td>Emergency medicine</td><td>67 (29.0%)</td></tr><tr><td>Intensive care</td><td>21 (4.0%)</td></tr><tr><td>Other</td><td>86 (16.2%)</td></tr><tr><td rowspan=\"7\">Indication for CT scanning</td><td>Other/mixed</td><td>141 (26.6%)</td></tr><tr><td>Non-traumatic vascular</td><td>130 (24.5%)</td></tr><tr><td>Infection or inflammation</td><td>108 (20.3%)</td></tr><tr><td>Trauma</td><td>90 (16.9%)</td></tr><tr><td>Acute bowel pathology</td><td>35 (6.6%)</td></tr><tr><td>Urolithiasis</td><td>16 (3.0%)</td></tr><tr><td>Acute oncology</td><td>11 (2.1%)</td></tr><tr><td rowspan=\"4\">Use of intravenous CT contrast agents</td><td>Multiple phases</td><td>200 (37.7%)</td></tr><tr><td>Venous phase</td><td>197 (37.1%)</td></tr><tr><td>Arterial phase</td><td>97 (18.3%)</td></tr><tr><td>Unenhanced</td><td>37 (7.0%)</td></tr><tr><td rowspan=\"4\">Use of gastrointestinal CT contrast agents</td><td>No oral or rectal contrast agents</td><td>339 (63.8%)</td></tr><tr><td>Oral contrast agents only</td><td>136 (25.6%)</td></tr><tr><td>Both oral and rectal contrast agents</td><td>43 (8.1%)</td></tr><tr><td>Rectal contrast agents only</td><td>13 (24.5%)</td></tr><tr><td rowspan=\"2\">Time of CT scanning</td><td>Before midnight</td><td>404 (76.1%)</td></tr><tr><td>After midnight</td><td>127 (23.9%)</td></tr></table>","table_caption":"[\"Table 2 Characteristics of included cases \"]","table_footnote":"[\"a Median with interquartile range between parentheses \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[78,558,490,874]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"increased over the years. In 2005, our hospital had two CT systems, which increased to three, four, and five CT systems in the course of 2006, 2008, and 2015, respectively. Notably, the largest relative increase in CT scan capacity occurred in the course of 2006 (150%), which coincided with the largest subsequent drop in clinical reasoning quality (Fig. 2). Because of the virtually unlimited CT scan capacity, the need to carefully select those patients who would benefit most from CT scanning has been eliminated. We believe this has contributed to a culture change in which medical doctors spend less efforts to and have become less skilled at clinical reasoning, in essence exchanging clinical reasoning quality for CT scan quantity. Perhaps an increase in clinical productivity and other tasks (e.g., administrative) of referring physicians has also resulted in worse clinical reasoning, although there are no data available to support this notion. It remains unclear why clinical reasoning was worse in younger patients. Whether or not this is related to younger generations demanding more imaging, defensive medicine practices in younger patients, or other reasons, requires further investigation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,874,489,905]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study may have some implications. On one hand, attempts may be made to improve clinical reasoning of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,558,919,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"physicians who request CT scans. Education has been suggested as the most effective approach to reach this goal, and radiologists have been urged to accept this educational responsibility [3]. This may be attempted by participating in undergraduate medical education and by providing feedback to referring physicians (e.g., on an individual basis or during multidisciplinary meetings — highlighting the importance of communication with referring physicians), all of which take place at our institution. On the other hand, if poor clinical reasoning of referring physicians will be accepted as the status quo, healthcare policy makers may consider assigning more value to the role of medical imaging and interpreting radiologists. This may be realized by allocating more funds to train and hire radiology staff, because they save healthcare costs elsewhere, namely referring physician's efforts and time spent on comprehensive clinical history taking, physical examination, requesting and interpreting laboratory findings, and establishing an accurate differential diagnosis. In light of ongoing technical developments in cross-sectional imaging that further decrease acquisition time (CT, MRI and PET) or decrease radiation dose (CT and PET) [11-14], it is not inconceivable that CT and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[803,39,915,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,927,159,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[383,67,915,259]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2 Upper panel: clinical reasoning scores per year (gray line), calculated as $(a / (b \\\\times c)) \\\\times 100\\\\%$ , where $a$ denotes the number of differential diagnoses on the CT request forms that matched the CT diagnoses, $b$ denotes the total number of differential diagnoses on the CT request forms, and $c$ denotes the number of corresponding CT scans performed in each year. Therefore, it should be emphasized that the clinical reasoning scores along the y-axis are given as percentages. The blue line represents the non-parametric locally estimated scatterplot smoothing (LOESS) fit (Mann-Kendall tau of $-0.829$ , $p < 0.001$ ). Lower panel: number of abdominal CT scans during on-call hours on 36 randomly sampled unique calendar days per year (gray line), with LOESS fit in blue (Mann-Kendall tau of $0.790$ , $p < 0.001$ ) \"]","image_footnote":"[]","img_path":"images/0101/63f057ef38b0e7b07d8b1470aa06328957140281c342d56d2a4ecada675931c2.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[383,268,915,464]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0854/03e1747decde6511d9ff04e2153cc4a701068111d7ace541f1504f3aac67d9fc.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[78,496,485,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"other cross-sectional imaging modalities will take over more and more upfront diagnostic tasks from referring physicians. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,527,487,651]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Experts in the field of abdominal imaging have previously reported that many patients with acute abdominal pain are referred for imaging without a clear pretest diagnosis, and that in only a small proportion of patients a confident and accurate diagnosis can be made solely on the basis of medical history, physical examination, and laboratory test findings [8]. These expert statements are completely in line with the findings of the present study. Previous studies have also shown that the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,496,915,605]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"use of cross-sectional imaging (particularly CT and MRI in adults) keeps on rising, including abdominal CT utilization during on-call hours [1, 2]. These findings are again no different from that of the present study. Most importantly, however, studies investigating (temporal changes in) clinical reasoning quality of physicians who request cross-sectional imaging have been lacking so far. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,606,915,654]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present study had some limitations. First, this study was performed in a tertiary care center in a Western European country without any CT scan capacity issues. The results may be ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[292,684,917,837]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0822/9b94705a3b3ccc09683d35ade202dcce8e458eca75b0fbdcd841a5e9827ed9b1.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td>Variable</td><td>Category</td><td>β coefficient</td><td>95% CI</td><td>p-value</td></tr><tr><td>Patient age</td><td>Continuous variable</td><td>0.210</td><td>0.081 to 0.340</td><td>0.002</td></tr><tr><td>Patient gendera</td><td>Female</td><td>-2.528</td><td>-7.262 to 2.205</td><td>0.295</td></tr><tr><td rowspan=\"4\">Requesting departmentb</td><td>Internal medicine</td><td>-0.431</td><td>-7.124 to 6.262</td><td>0.899</td></tr><tr><td>Emergency medicine</td><td>-3.233</td><td>-10.480 to 4.014</td><td>0.381</td></tr><tr><td>Intensive care</td><td>-1.943</td><td>-13.986 to 10.100</td><td>0.751</td></tr><tr><td>Other</td><td>-2.901</td><td>-9.473 to 3.671</td><td>0.386</td></tr><tr><td>Time of CT scanningc</td><td>After midnight</td><td>2.989</td><td>-2.407 to 8.386</td><td>0.277</td></tr></table>","table_caption":"[\"Table 3 Linear regression analysis on the association of the quality of clinical reasoning with patient age, patient gender, requesting department, and time of CT scanning \"]","table_footnote":"[\"CI confidence interval \",\"a Male gender was used as reference category \",\"Surgery was used as reference category \",\"c Before midnight was used as reference category \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[82,39,194,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[838,927,912,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[84,70,485,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"different in other hospitals with different patient populations and CT scan capacities. It should also be noted that $61.6\\%$ of patients in this study were male, for which we do not have a clear explanation. Second, the results only apply to acute abdominal CT scans performed during on-call hours. Further research is necessary to investigate if our findings are also applicable to other clinical settings in which cross-sectional imaging is requested. Third, it can be argued that the CT request forms may not have contained all clinical reasoning considerations that may have been communicated by phone. However, providing adequate clinical information with a differential diagnosis on the CT request form can be considered a requisite to avoid miscommunication and errors, and in our experience the telephonic and written communications match in this setting. Fourth, annual data on the number of patient consultations related to acute abdominal pathology, patient expectations, clinical status and gravity of their clinical presentation, staffing of the different departments in our hospital, training level of the persons who filled in the CT request forms (e.g., medical specialist vs. non-medical specialist, and years of experience), allegations against medical doctors, and defense medicine practices, were not available, as a result of which it was not possible to correlate these metrics to clinical reasoning quality. These topics should be investigated by further studies. It also remains unclear if new guidelines have an effect on clinical reasoning quality. Nevertheless, after a national guideline on diagnostic tests for acute abdominal pain in adults (excluding abdominal pain after trauma, known intra-uterine pregnancy, gastrointestinal hemorrhage, hemorrhagic shock, chronic conditions, recurrent abdominal pain, and abdominal pain within 30 days after abdominal surgery) was published in 2013 (which recommends ultrasonography as first-line imaging, followed by CT if ultrasonography is negative or inconclusive, unless the patient is critically ill) [15], there was no clear trend change with regard to clinical reasoning quality. Fifth, CT scans were not evaluated in terms of appropriateness, influence on patient management, or effect on patient outcome. This was beyond the scope of the present study. Previous work has already shown that CT results in emergency department settings frequently change physicians' diagnoses and admission decisions [16]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,701,487,764]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In conclusion, the clinical reasoning quality of physicians who request abdominal CT scans during on-call hours has deteriorated over time. Clinical reasoning appears to be worse in younger patients. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,794,485,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements The cases that were selected for the present study were derived from a previously published study that had a different purpose, namely to investigate temporal changes in the utilization and patient impact of abdominal CT during duty shifts in terms of negative scan proportion, same-day hospital discharge, and incidental findings. (Mengou IV, Yakar D, Kasalak O, Kwee TC (2021) Towards a benchmark of abdominal CT use during duty shifts: 15-year sample from the Netherlands. Abdom Radiol (NY) 46: 1761-1767). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,69,910,82]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding The authors state that this work has not received any funding. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,100,608,113]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Declarations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,130,915,143]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Guarantor The scientific guarantor of this publication is Thomas C. Kwee. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,170,915,208]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflict of interest The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,237,915,263]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Statistics and biometry No complex statistical methods were necessary for this paper. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,289,915,316]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Informed consent Written informed consent was waived by the local Institutional Review Board. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,344,914,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ethical approval Local Institutional Review Board approval was obtained. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,384,915,486]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Study subjects or cohorts overlap The cases that were selected for the present study were derived from a previously published study that had a different purpose, namely to investigate temporal changes in the utilization and patient impact of abdominal CT during duty shifts in terms of negative scan proportion, same-day hospital discharge, and incidental findings. (Mengou IV, Yakar D, Kasalak Ö, Kwee TC (2021) Towards a benchmark of abdominal CT use during duty shifts: 15-year sample from the Netherlands. Abdom Radiol (NY) 46: 1761-1767). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,513,589,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methodology ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,527,675,564]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"retrospective \",\"- observational \",\"- performed at one institution \"]","page_idx":"5","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[507,575,915,729]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,782,611,798]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[515,812,915,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Smith-Bindman R, Kwan ML, Marlow EC et al (2019) Trends in use of medical imaging in US health care systems and in Ontario, Canada, 2000-2016. JAMA 322:843-856 \",\"2. Bruls RJM, Kwee RM (2020) Workload for radiologists during on-call hours: dramatic increase in the past 15 years. Insights Imaging 11:121 \",\"3. Hendee WR, Becker GJ, Borgstede JP et al (2010) Addressing overutilization in medical imaging. Radiology 257:240-245 \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[803,39,915,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[82,927,100,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[102,930,154,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[85,69,487,335]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"4. McCoubrie P, Reid JH (2012) Development of medical imaging technologies is the best way to advance clinical diagnostic accuracy and there is no such thing as VOMIT. J R Coll Physicians Edinb 42: 326-332 \",\"5. Jha S (2013) From imaging gatekeeper to service provider-a transatlantic journey. N Engl J Med 369:5-7 \",\"6. Jha S (2014) Stop hunting for zebras in Texas: end the diagnostic culture of \\\"rule-out\\\". BMJ 348:g2625 \",\"7. Hattori S, Yokota H, Takada T et al (2021) Impact of clinical information on CT diagnosis by radiologist and subsequent clinical management by physician in acute abdominal pain. Eur Radiol 31: 5454-5463 \",\"8. Stoker J, van Randen A, Laméris W, Boermeester MA (2009) Imaging patients with acute abdominal pain. Radiology 253:31-46 \",\"9. RANDOM.ORG. Random Calendar Date Generator. Available via https://www.random.org/calendar-dates/. Accessed 22 March 2022 \",\"10. Mengou IV, Yakar D, Kasalak Ö, Kwee TC (2021) Towards a benchmark of abdominal CT use during duty shifts: 15-year sample from the Netherlands. Abdom Radiol (NY) 46:1761-1767 \",\"11. Kreisler B (2022) Photon counting detectors: concept, technical challenges, and clinical outlook. Eur J Radiol 149:110229 \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[512,69,914,265]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"12. Greffier J, Hamard A, Pereira F et al (2020) Image quality and dose reduction opportunity of deep learning image reconstruction algorithm for CT: a phantom study. Eur Radiol 30:3951-3959 \",\"13. Cherry SR, Jones T, Karp JS, Qi J, Moses WW, Badawi RD (2018) Total-body PET: maximizing sensitivity to create new opportunities for clinical research and patient care. J Nucl Med 59:3-12 \",\"14. Chandra SS, Bran Lorenzana M, Liu X, Liu S, Bollmann S, Crozier S (2021) Deep learning in magnetic resonance image reconstruction. J Med Imaging Radiat Oncol 65:564-577 \",\"15. Richtlijn diagnostiek acute buikpijn bij volwassenen. Available via https://richtlijnen.nhg.org//files/2020-05/richtlijn_diagnostiek_acute_buikpijn.pdf. Accessed 25 July 2022 \",\"16. Pandharipande PV, Reisner AT, Binder WD et al (2016) CT in the emergency department: a real-time study of changes in physician decision making. Radiology 278:812-821 \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[509,279,915,307]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,39,193,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"European Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[838,927,912,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[80,135,794,182]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Did medical doctors who order abdominal CT scans during on-call hours truly become worse at clinical reasoning? Yes, they did \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,200,581,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Selin Ersoydan $^{1}$ · Derya Yakar $^{1}$ · Omer Kasalak $^{1}$ · Thomas C. Kwee $^{1}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,239,485,265]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 22 April 2022 / Revised: 25 July 2022 / Accepted: 18 August 2022 $\\\\langle \\\\widehat{\\\\mathbb{C}}\\\\rangle$ The Author(s) 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,282,149,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,298,915,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objective To investigate temporal changes in clinical reasoning quality of physicians who requested abdominal CT scans at a tertiary care center during on-call hours within a 15-year period. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,329,915,421]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods This retrospective study included 531 patients who underwent abdominal CT at a tertiary care center during on-call hours on 36 randomly sampled unique calendar days in each of the years between 2005 and 2019. Clinical reasoning quality was expressed as a percentage $(0 - 100\\\\%)$ , taking into account the degree by which the differential diagnoses on the CT request form matched the CT diagnosis. Temporal changes in the quality of clinical reasoning and number of CT scans were assessed using Mann-Kendall tests. Associations between the quality of clinical reasoning with patient age and gender, requesting department, and time of CT scanning were determined with linear regression analyses. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,422,915,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results The median annual clinical reasoning score was $0.4\\\\%$ (interquartile range: 0.3 to $0.6\\\\%$ ; range: 0.1 to $1.9\\\\%$ ). The quality of clinical reasoning significantly decreased between 2005 and 2019 (Mann-Kendall Tau of $-0.829, p < 0.001$ ), while the number of abdominal CT scans significantly increased (Mann-Kendall tau of $0.790, p < 0.001$ ). There was a significant association between the quality of clinical reasoning and patient age ( $\\\\beta$ coefficient of $0.210, p = 0.002$ ). The quality of clinical reasoning was not significantly associated with patient gender, requesting department, or time of CT scanning. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,501,915,532]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion The clinical reasoning quality of physicians who request abdominal CT scans during on-call hours has deteriorated over time. Clinical reasoning appears to be worse in younger patients. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,532,157,546]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Key Points \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,546,915,626]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- In patients with suspected acute abdominal pathology who are scheduled to undergo CT scanning, referring physicians generally have difficulties in making an accurate pretest (differential) diagnosis. \\\",\\\"- Clinical reasoning quality of physicians who request acute abdominal CT scans has deteriorated over the years, while the number of CT scans has shown a significant increase. \\\",\\\"- Clinical reasoning quality appears to be worse in younger patients in this setting. \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[80,641,786,656]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords Abdomen $\\\\cdot$ Clinical reasoning $\\\\cdot$ Differential diagnosis $\\\\cdot$ Computed tomography $\\\\cdot$ Night shift work \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,689,176,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abbreviations \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,703,284,718]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CI Confidence interval \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,720,275,735]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IQR Interquartile range \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,736,416,751]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LOESS Locally estimated scatterplot smoothing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,687,626,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,718,915,830]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Medical imaging utilization keeps on increasing in the Western world, and this particularly applies to CT examinations [1, 2]. This growth in CT examinations is due to the relatively widespread availability of CT systems, continuous improvements in technology (which increase image quality, reduce scan time, and decrease radiation dose), decreasing costs of CT scans, and new clinical CT applications. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,831,915,893]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although medical imaging is generally considered beneficial to patients, a part of its increase has been attributed to overutilization [3]. Anecdotal data indicate that clinicians request more and more imaging simply because it is available, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,321,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"European Radiology \\nhttps://doi.org/10.1007/s00330-022-09121-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,79,200,94]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"EXPERIMENTAL \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,81,915,120]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,836,252,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thomas C. Kwee thomaskwee@gmail.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[80,875,470,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[80,934,300,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published online: 07 September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[838,927,914,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,70,485,289]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and to rule out disease rather than to confirm disease that is most likely based on probabilistic hypothetico-deductive reasoning [4-6]. Based on these anecdotal data and our own experience, it is hypothesized that the clinical reasoning quality of physicians who request medical imaging has deteriorated over the years. However, establishing a good differential diagnosis based on clinical history, physical examination, and laboratory findings, is considered important to optimize the interpretation and diagnostic yield of an imaging examination [4-7]. In addition, a good differential diagnosis is necessary to avoid unnecessary imaging studies that may be costly, that may have potential side effects due to the use of ionizing radiation and contrast agents, and that may yield incidental findings. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,292,485,417]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"During on-call hours, CT scans of the abdomen are frequently ordered, because the list of acute abdominal diseases is long and they may be challenging to diagnose based on clinical grounds [8]. As such, they provide an excellent setting to test our hypothesis. The purpose of our study was therefore to investigate temporal changes in clinical reasoning quality of physicians who requested abdominal CT scans at a tertiary care center during on-call hours within a 15-year period. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,448,287,463]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Materials and methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,479,183,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Study design \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,513,485,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. A random sample of 36 unique calendar days was selected using the Random Calendar Date Generator [9]. All patients who underwent abdominal CT at a tertiary care center in The Netherlands during on-call evening and night hours on each of these 36 unique calendar days in each of the years between 2005 and 2019, were potentially eligible for inclusion. The University Medical Center Groningen is one of the seven university medical centers in the Netherlands, with more than 2 million people in its direct catchment area in the north-east of the country. It has more than 10,000 employees and 1,300 beds, and all medical specialties are represented. The hospital is also a recognized Level 1 trauma center, and performs all organ transplants. Patients were included if CT scanning was done to evaluate for acute abdominal pathology, and if the scan range included the region from the diaphragm to the pubic symphysis. Patients who underwent CT scanning to guide an intervention (e.g., drainage), patients whose CT scan was performed for non-acute reasons, and patients whose CT report or clinical records were missing, were excluded. Note that the cases that were selected for the present study were derived from a previously published study that had a different purpose, namely to investigate temporal changes in the utilization and patient impact of abdominal CT during duty \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,70,914,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"shifts in terms of negative scan proportion, same-day hospital discharge, and incidental findings [10]. When ordering abdominal CT during on-call hours, the referring physician both calls the attending radiology resident or radiologist, and submits a digital request form. Other details regarding on-call logistics, CT acquisition, and CT interpretation can be read elsewhere [10]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,205,628,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data extraction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,237,914,362]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Patient age, patient gender, indication for CT scanning, requesting department, use of intravenous CT contrast agents, use of gastrointestinal CT contrast agents, time of CT scanning (before or after midnight), and year in which the CT scan was performed, were recorded. The digital request form of each CT scan was evaluated to extract the differential diagnosis that was compiled by the referring physician, and the CT report was evaluated to extract the diagnosis made. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,386,613,401]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,417,914,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The quality of referring physicians' clinical reasoning before ordering a CT scan was quantified using a scoring system. To that end, the differential diagnosis made by the referring physician on the CT request form was compared to the CT diagnosis. Each of the differential diagnoses on the CT request form that matched the CT diagnosis received 1 point. If no differential diagnosis was provided, or if the CT scan diagnosis did not match any of the differential diagnoses on the CT request form, 0 points were assigned. The clinical reasoning score was then calculated by dividing the total number of points by the total number of differential diagnoses that was listed on the CT request form, and expressed as a percentage. For example, if the clinical differential diagnosis included ruptured abdominal aortic aneurysm, urolithiasis, and cholecystitis, and CT demonstrated urolithiasis, the clinical reasoning score would be $33\\\\%$ . Mann-Kendall tests were performed to test for any temporal changes in both clinical reasoning scores in each year between 2005 and 2019, and number of abdominal CT scans during on-call hours on the 36 randomly sampled unique calendar days in each year between 2005 and 2019. Subsequently, linear regression analyses were performed to determine the association between the quality of clinical reasoning (all years combined) and the following variables: patient age, patient gender, requesting department (surgery, internal medicine, emergency medicine, intensive care, or other), and time of CT scanning (before or after midnight). $p$ values $< 0.05$ were considered statistically significant. Statistical analyses were executed using R version 3.6.3 software (R Foundation for Statistical Computing) and IBM Statistical Package for the Social Sciences (SPSS) version 23 (SPSS). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[803,40,915,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"European Radiology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[84,927,154,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,69,149,86]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,101,149,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Patients \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,134,489,324]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The 36 randomly selected unique calendar days are displayed in Table 1. Of 639 potentially eligible patients, 531 remained for inclusion in this study (Fig. 1). In these 531 patients, median age was 59.0 years (interquartile range (IQR): 42.3-70.0 years; range: 10-107 years), male/female ratio was 327/204, requesting department was most frequently surgery $(51.8\\\\%)$ , indication for CT scanning was most frequently other/mixed $(26.6\\\\%)$ , most CT scans were performed with intravenous contrast agents in either multiple phases $(37.7\\\\%)$ or in the venous phase $(37.1\\\\%)$ , and without gastrointestinal contrast agents $(63.8\\\\%)$ , and most CT scans were performed before midnight $(75.5\\\\%)$ (Table 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,353,468,387]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Clinical reasoning quality and number of CT scans: temporal changes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,401,489,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The median annual clinical reasoning score was $0.4\\\\%$ (IQR: 0.3 to $0.6\\\\%$ ; range: 0.1 to $1.9\\\\%$ ) (note that the clinical reasoning scores are given as percentages). Clinical reasoning scores significantly decreased over time (Mann-Kendall tau of $-0.829$ , $p < 0.001$ ) (Fig. 2). Note the appearance of a rapid drop from the years 2005/2006 to 2007 (Fig. 2), but the overall decrease in clinical reasoning scores remained significant after excluding the years 2005 and 2006 (Mann-Kendall tau of $-0.795$ , $p < 0.001$ ). The median annual number of abdominal CT scans during on-call hours on the 36 randomly sampled unique calendar days was 35 (IQR: 23.25 to 46.75; range: 17-55). The number of abdominal CT scans significantly increased over time (Mann-Kendall tau of $0.790$ , $p < 0.001$ ) (Fig. 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[247,683,487,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0707/6de6353b0a0076bd5c4336c298971752e3d73357ca4e7cda84ea6d09f774296c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Month</td><td>Day(s)</td></tr><tr><td>January</td><td>6, 11, 20, 29</td></tr><tr><td>February</td><td>1, 10, 18</td></tr><tr><td>March</td><td>1, 4, 21</td></tr><tr><td>May</td><td>8, 21</td></tr><tr><td>June</td><td>2, 4, 6, 7, 8, 23, 26, 30</td></tr><tr><td>July</td><td>7, 14</td></tr><tr><td>August</td><td>26, 28</td></tr><tr><td>September</td><td>3, 15, 30</td></tr><tr><td>October</td><td>2, 9, 11, 21</td></tr><tr><td>November</td><td>29</td></tr><tr><td>December</td><td>16, 21, 22, 28</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1 Thirty-six randomly selected unique calendar days \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[510,65,915,392]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1 Flowchart of patient selection \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0628/9efb9e273e62106279106148792f5bc0835bc8726f51faa649bd57ac938e328f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[507,432,800,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Clinical reasoning skills: determinants \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,464,915,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There was a significant association between the quality of clinical reasoning and patient age ( $\\\\beta$ coefficient of 0.210, $p = 0.002$ ). The quality of clinical reasoning was not significantly associated with patient gender, requesting department, or time of CT scanning (Table 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,573,608,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,606,915,764]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study has four main findings. First, in patients with suspected acute abdominal pathology who are scheduled to undergo CT scanning during on-call hours, referring physicians generally have difficulties in making an accurate pretest (differential) diagnosis. Second, clinical reasoning quality of physicians who request abdominal CT scans in these patients has significantly deteriorated over the years. Third, the number of CT scans has shown a significant increase during the same time frame. Fourth, clinical reasoning quality was significantly lower in younger patients in this setting. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,764,917,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our results underline the importance of CT scanning complementary to clinical history, physical examination, and laboratory findings, in increasing or decreasing the likelihood of acute diseases in the abdomen in the appropriate clinical setting. Most importantly, they confirm our hypothesis that the clinical reasoning quality of physicians who request acute abdominal CT scans has deteriorated over the years, while the number of CT scans has shown an opposite temporal trend. We speculate that this is mainly due to the CT scan capacity that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,39,194,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"European Radiology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[838,927,914,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[292,69,919,512]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0743/45eb0b182e0091a565ec15e4429dbcbeeafe7cc34b8349ad713318cf8a6fe870.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Variable</td><td></td><td>Count (percentage)</td></tr><tr><td>Patient age (years)</td><td></td><td>59.0 (42.3–70.0)a</td></tr><tr><td rowspan=\\\"2\\\">Patient gender</td><td>Male</td><td>327 (61.6%)</td></tr><tr><td>Female</td><td>204 (38.4%)</td></tr><tr><td rowspan=\\\"5\\\">Requesting department</td><td>Surgery</td><td>275 (51.8%)</td></tr><tr><td>Internal medicine</td><td>82 (15.4%)</td></tr><tr><td>Emergency medicine</td><td>67 (29.0%)</td></tr><tr><td>Intensive care</td><td>21 (4.0%)</td></tr><tr><td>Other</td><td>86 (16.2%)</td></tr><tr><td rowspan=\\\"7\\\">Indication for CT scanning</td><td>Other/mixed</td><td>141 (26.6%)</td></tr><tr><td>Non-traumatic vascular</td><td>130 (24.5%)</td></tr><tr><td>Infection or inflammation</td><td>108 (20.3%)</td></tr><tr><td>Trauma</td><td>90 (16.9%)</td></tr><tr><td>Acute bowel pathology</td><td>35 (6.6%)</td></tr><tr><td>Urolithiasis</td><td>16 (3.0%)</td></tr><tr><td>Acute oncology</td><td>11 (2.1%)</td></tr><tr><td rowspan=\\\"4\\\">Use of intravenous CT contrast agents</td><td>Multiple phases</td><td>200 (37.7%)</td></tr><tr><td>Venous phase</td><td>197 (37.1%)</td></tr><tr><td>Arterial phase</td><td>97 (18.3%)</td></tr><tr><td>Unenhanced</td><td>37 (7.0%)</td></tr><tr><td rowspan=\\\"4\\\">Use of gastrointestinal CT contrast agents</td><td>No oral or rectal contrast agents</td><td>339 (63.8%)</td></tr><tr><td>Oral contrast agents only</td><td>136 (25.6%)</td></tr><tr><td>Both oral and rectal contrast agents</td><td>43 (8.1%)</td></tr><tr><td>Rectal contrast agents only</td><td>13 (24.5%)</td></tr><tr><td rowspan=\\\"2\\\">Time of CT scanning</td><td>Before midnight</td><td>404 (76.1%)</td></tr><tr><td>After midnight</td><td>127 (23.9%)</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2 Characteristics of included cases \\\"]\",\n \"table_footnote\": \"[\\\"a Median with interquartile range between parentheses \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[78,558,490,874]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"increased over the years. In 2005, our hospital had two CT systems, which increased to three, four, and five CT systems in the course of 2006, 2008, and 2015, respectively. Notably, the largest relative increase in CT scan capacity occurred in the course of 2006 (150%), which coincided with the largest subsequent drop in clinical reasoning quality (Fig. 2). Because of the virtually unlimited CT scan capacity, the need to carefully select those patients who would benefit most from CT scanning has been eliminated. We believe this has contributed to a culture change in which medical doctors spend less efforts to and have become less skilled at clinical reasoning, in essence exchanging clinical reasoning quality for CT scan quantity. Perhaps an increase in clinical productivity and other tasks (e.g., administrative) of referring physicians has also resulted in worse clinical reasoning, although there are no data available to support this notion. It remains unclear why clinical reasoning was worse in younger patients. Whether or not this is related to younger generations demanding more imaging, defensive medicine practices in younger patients, or other reasons, requires further investigation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,874,489,905]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study may have some implications. On one hand, attempts may be made to improve clinical reasoning of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,558,919,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"physicians who request CT scans. Education has been suggested as the most effective approach to reach this goal, and radiologists have been urged to accept this educational responsibility [3]. This may be attempted by participating in undergraduate medical education and by providing feedback to referring physicians (e.g., on an individual basis or during multidisciplinary meetings — highlighting the importance of communication with referring physicians), all of which take place at our institution. On the other hand, if poor clinical reasoning of referring physicians will be accepted as the status quo, healthcare policy makers may consider assigning more value to the role of medical imaging and interpreting radiologists. This may be realized by allocating more funds to train and hire radiology staff, because they save healthcare costs elsewhere, namely referring physician's efforts and time spent on comprehensive clinical history taking, physical examination, requesting and interpreting laboratory findings, and establishing an accurate differential diagnosis. In light of ongoing technical developments in cross-sectional imaging that further decrease acquisition time (CT, MRI and PET) or decrease radiation dose (CT and PET) [11-14], it is not inconceivable that CT and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[803,39,915,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"European Radiology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,927,159,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[383,67,915,259]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2 Upper panel: clinical reasoning scores per year (gray line), calculated as $(a / (b \\\\\\\\times c)) \\\\\\\\times 100\\\\\\\\%$ , where $a$ denotes the number of differential diagnoses on the CT request forms that matched the CT diagnoses, $b$ denotes the total number of differential diagnoses on the CT request forms, and $c$ denotes the number of corresponding CT scans performed in each year. Therefore, it should be emphasized that the clinical reasoning scores along the y-axis are given as percentages. The blue line represents the non-parametric locally estimated scatterplot smoothing (LOESS) fit (Mann-Kendall tau of $-0.829$ , $p < 0.001$ ). Lower panel: number of abdominal CT scans during on-call hours on 36 randomly sampled unique calendar days per year (gray line), with LOESS fit in blue (Mann-Kendall tau of $0.790$ , $p < 0.001$ ) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0101/63f057ef38b0e7b07d8b1470aa06328957140281c342d56d2a4ecada675931c2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[383,268,915,464]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0854/03e1747decde6511d9ff04e2153cc4a701068111d7ace541f1504f3aac67d9fc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[78,496,485,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"other cross-sectional imaging modalities will take over more and more upfront diagnostic tasks from referring physicians. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,527,487,651]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Experts in the field of abdominal imaging have previously reported that many patients with acute abdominal pain are referred for imaging without a clear pretest diagnosis, and that in only a small proportion of patients a confident and accurate diagnosis can be made solely on the basis of medical history, physical examination, and laboratory test findings [8]. These expert statements are completely in line with the findings of the present study. Previous studies have also shown that the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,496,915,605]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"use of cross-sectional imaging (particularly CT and MRI in adults) keeps on rising, including abdominal CT utilization during on-call hours [1, 2]. These findings are again no different from that of the present study. Most importantly, however, studies investigating (temporal changes in) clinical reasoning quality of physicians who request cross-sectional imaging have been lacking so far. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,606,915,654]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The present study had some limitations. First, this study was performed in a tertiary care center in a Western European country without any CT scan capacity issues. The results may be \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[292,684,917,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0822/9b94705a3b3ccc09683d35ade202dcce8e458eca75b0fbdcd841a5e9827ed9b1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Variable</td><td>Category</td><td>β coefficient</td><td>95% CI</td><td>p-value</td></tr><tr><td>Patient age</td><td>Continuous variable</td><td>0.210</td><td>0.081 to 0.340</td><td>0.002</td></tr><tr><td>Patient gendera</td><td>Female</td><td>-2.528</td><td>-7.262 to 2.205</td><td>0.295</td></tr><tr><td rowspan=\\\"4\\\">Requesting departmentb</td><td>Internal medicine</td><td>-0.431</td><td>-7.124 to 6.262</td><td>0.899</td></tr><tr><td>Emergency medicine</td><td>-3.233</td><td>-10.480 to 4.014</td><td>0.381</td></tr><tr><td>Intensive care</td><td>-1.943</td><td>-13.986 to 10.100</td><td>0.751</td></tr><tr><td>Other</td><td>-2.901</td><td>-9.473 to 3.671</td><td>0.386</td></tr><tr><td>Time of CT scanningc</td><td>After midnight</td><td>2.989</td><td>-2.407 to 8.386</td><td>0.277</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3 Linear regression analysis on the association of the quality of clinical reasoning with patient age, patient gender, requesting department, and time of CT scanning \\\"]\",\n \"table_footnote\": \"[\\\"CI confidence interval \\\",\\\"a Male gender was used as reference category \\\",\\\"Surgery was used as reference category \\\",\\\"c Before midnight was used as reference category \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[82,39,194,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"European Radiology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[838,927,912,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[84,70,485,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"different in other hospitals with different patient populations and CT scan capacities. It should also be noted that $61.6\\\\%$ of patients in this study were male, for which we do not have a clear explanation. Second, the results only apply to acute abdominal CT scans performed during on-call hours. Further research is necessary to investigate if our findings are also applicable to other clinical settings in which cross-sectional imaging is requested. Third, it can be argued that the CT request forms may not have contained all clinical reasoning considerations that may have been communicated by phone. However, providing adequate clinical information with a differential diagnosis on the CT request form can be considered a requisite to avoid miscommunication and errors, and in our experience the telephonic and written communications match in this setting. Fourth, annual data on the number of patient consultations related to acute abdominal pathology, patient expectations, clinical status and gravity of their clinical presentation, staffing of the different departments in our hospital, training level of the persons who filled in the CT request forms (e.g., medical specialist vs. non-medical specialist, and years of experience), allegations against medical doctors, and defense medicine practices, were not available, as a result of which it was not possible to correlate these metrics to clinical reasoning quality. These topics should be investigated by further studies. It also remains unclear if new guidelines have an effect on clinical reasoning quality. Nevertheless, after a national guideline on diagnostic tests for acute abdominal pain in adults (excluding abdominal pain after trauma, known intra-uterine pregnancy, gastrointestinal hemorrhage, hemorrhagic shock, chronic conditions, recurrent abdominal pain, and abdominal pain within 30 days after abdominal surgery) was published in 2013 (which recommends ultrasonography as first-line imaging, followed by CT if ultrasonography is negative or inconclusive, unless the patient is critically ill) [15], there was no clear trend change with regard to clinical reasoning quality. Fifth, CT scans were not evaluated in terms of appropriateness, influence on patient management, or effect on patient outcome. This was beyond the scope of the present study. Previous work has already shown that CT results in emergency department settings frequently change physicians' diagnoses and admission decisions [16]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,701,487,764]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In conclusion, the clinical reasoning quality of physicians who request abdominal CT scans during on-call hours has deteriorated over time. Clinical reasoning appears to be worse in younger patients. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,794,485,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements The cases that were selected for the present study were derived from a previously published study that had a different purpose, namely to investigate temporal changes in the utilization and patient impact of abdominal CT during duty shifts in terms of negative scan proportion, same-day hospital discharge, and incidental findings. (Mengou IV, Yakar D, Kasalak O, Kwee TC (2021) Towards a benchmark of abdominal CT use during duty shifts: 15-year sample from the Netherlands. Abdom Radiol (NY) 46: 1761-1767). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,69,910,82]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding The authors state that this work has not received any funding. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,100,608,113]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Declarations \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,130,915,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Guarantor The scientific guarantor of this publication is Thomas C. Kwee. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,170,915,208]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflict of interest The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,237,915,263]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Statistics and biometry No complex statistical methods were necessary for this paper. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,289,915,316]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Informed consent Written informed consent was waived by the local Institutional Review Board. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,344,914,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ethical approval Local Institutional Review Board approval was obtained. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,384,915,486]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Study subjects or cohorts overlap The cases that were selected for the present study were derived from a previously published study that had a different purpose, namely to investigate temporal changes in the utilization and patient impact of abdominal CT during duty shifts in terms of negative scan proportion, same-day hospital discharge, and incidental findings. (Mengou IV, Yakar D, Kasalak Ö, Kwee TC (2021) Towards a benchmark of abdominal CT use during duty shifts: 15-year sample from the Netherlands. Abdom Radiol (NY) 46: 1761-1767). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,513,589,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methodology \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,527,675,564]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"retrospective \\\",\\\"- observational \\\",\\\"- performed at one institution \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[507,575,915,729]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,782,611,798]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,812,915,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Smith-Bindman R, Kwan ML, Marlow EC et al (2019) Trends in use of medical imaging in US health care systems and in Ontario, Canada, 2000-2016. JAMA 322:843-856 \\\",\\\"2. 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Mengou IV, Yakar D, Kasalak Ö, Kwee TC (2021) Towards a benchmark of abdominal CT use during duty shifts: 15-year sample from the Netherlands. Abdom Radiol (NY) 46:1761-1767 \\\",\\\"11. Kreisler B (2022) Photon counting detectors: concept, technical challenges, and clinical outlook. Eur J Radiol 149:110229 \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[512,69,914,265]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"12. Greffier J, Hamard A, Pereira F et al (2020) Image quality and dose reduction opportunity of deep learning image reconstruction algorithm for CT: a phantom study. Eur Radiol 30:3951-3959 \\\",\\\"13. Cherry SR, Jones T, Karp JS, Qi J, Moses WW, Badawi RD (2018) Total-body PET: maximizing sensitivity to create new opportunities for clinical research and patient care. J Nucl Med 59:3-12 \\\",\\\"14. Chandra SS, Bran Lorenzana M, Liu X, Liu S, Bollmann S, Crozier S (2021) Deep learning in magnetic resonance image reconstruction. J Med Imaging Radiat Oncol 65:564-577 \\\",\\\"15. Richtlijn diagnostiek acute buikpijn bij volwassenen. Available via https://richtlijnen.nhg.org//files/2020-05/richtlijn_diagnostiek_acute_buikpijn.pdf. Accessed 25 July 2022 \\\",\\\"16. Pandharipande PV, Reisner AT, Binder WD et al (2016) CT in the emergency department: a real-time study of changes in physician decision making. Radiology 278:812-821 \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[509,279,915,307]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,39,193,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"European Radiology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[838,927,912,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1007/s00330-022-09121-7"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"e27f3929972f978f7051333b2ae3dec35ee8294daec3683a481001eea23c5f98"},"title":{"kind":"string","value":"Did medical doctors who order abdominal CT scans during on-call hours truly become worse at clinical reasoning? Yes, they did"}}},{"rowIdx":148,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Zimo Huang|Jiadong Qin|Yuxuan Zhu|Kelin He|Hao Chen|Hui Ying Hoh|Munkhbayar Batmunkh|Tania M. Benedetti|Qitao Zhang|Chenliang Su|Shanqing Zhang|Yu Lin Zhong"},"content_list":{"kind":"list like","value":[{"bbox":"[75,138,712,222]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Green and scalable electrochemical routes for cost-effective mass production of MXenes for supercapacitor electrodes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,250,773,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Zimo Huang1 $\\textcircled { 1 0 }$ 丨Jiadong $\\mathbf { Q i n } ^ { 1 } \\left( \\mathbb { D } \\right)$ |Yuxuan Zhu1 | Kelin He1 $\\textcircled{1}$ 一 Hao Chen² $\\textcircled{1}$ 丨Hui Ying $\\mathbf { H o h } ^ { 2 } \\mathbf { \\mathbb { \\oplus } }$ |Munkhbayar Batmunkh1 $\\textcircled{1}$ 一 Tania M.Benedetti1 $\\textcircled{1}$ | Qitao Zhang³ $\\textcircled{1}$ Chenliang $\\mathbf { S u } ^ { 3 } \\oplus$ 一 Shanqing Zhang² ① |Yu Lin Zhong1 D ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,352,931,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"QueenslandicrodanotecolgCetre,holofnviontandience,GiithUniversityuensnd,atatalia 2Centre forCatalysisandClean EnergyShoolofEnvironmentand Sience,GrifithUniversityQuensland,GoldCoast,Austral InteratioalClbatiebratorfaterafotoelectroeeholstryucatiostiutele Optoelectronics,Shenzhen University, Shenzhen, China ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,445,178,455]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Correspondence ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,457,321,554]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chenliang Su,International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education,Institute of Microscale Optoelectronics,Shenzhen University,518060 Shenzhen,China. Email: chmsuc@szu.edu.cn ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,560,317,629]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Yu Lin Zhong, Queensland Micro-and Nanotechnology Centre,School of Environment and Science,Griffith University,Nathan,QLD 41ll,Australia. Email: y.zhong@griffith.edu.au ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,645,211,658]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,662,319,801]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Australian Research Council, \nGrant/Award Numbers:DP190100120, FT200loool5;National Key Research and Development Program, \nGrant/Award Number:2021YFA1600800; Shenzhen Science and Technology \nProgram,Grant/Award Numbers: \nRCJC20200714114434086, \nJCYJ20190808142001745, \nJCYJ20200812160737002,20180921273B ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[351,453,420,468]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[351,473,914,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the most unique properties of two-dimensional carbides and nitrides of transition metals (MXenes） is their excellent water dispersibility and yet possessing superior electrical conductivity but their industrial-scale applica-tion is limited by their costly chemical synthesis methods. In this work, the niche feature of MXenes was capitalized in the packed-bed electrochemical reactor to produce MXenes at an unprecedented reaction rate and yield with minimal chemical waste. A simple $\\mathrm { N H } _ { 4 } \\mathrm { F }$ solution was employed as the green electrolyte, which could be used repeatedly without any loss in its efficacy. Surprisingly, both fluoride and ammonium were found to play critical roles in the electrochemical etching, functionalization, and expansion of the layered parent materials (MAXs) through which the liberation of ammonia gas was observed. The electrochemically produced MXenes with excellent conductivity, applied as supercapacitor electrodes, could deliver an ultrahigh volumetric capacity $( 1 4 0 8 \\mathrm { F } \\mathrm { c m } ^ { - 3 } )$ and a volumetric energy density $( 7 5 . 8 \\mathrm { W h } \\mathrm { L } ^ { - 1 } )$ ). This revolutionary green, energy-efficient, and scalable electrochemical route will not only pave the way for industrial-scale production of MXenes but also open up a myriad of versatile electrochemical modifications for improved functional MXenes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[351,831,453,842]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KEYWORDS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[349,847,873,860]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"packed-bed electrochemical reactor, electrochemical etching, MXene, supercapacitor ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,956,238,980]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Carbon Energy.2023;5:e295. https://doi.org/10.1002/cey2.295 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[73,905,926,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"iisei the original work is properly cited. $\\circledcirc$ 2023 The Authors.Carbon Energy published by Wenzhou University and John Wiley& Sons Australia,Ltd. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[870,0,998,19]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[665,956,922,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"wileyonlinelibrary.com/journal/cey2 丨1of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[75,54,191,65]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DOI: 10.1002/cey2.295 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[72,34,532,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 29 August 2022 Revised: 20 September 2022丨Accepted: 4 October 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[75,86,278,101]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[638,78,922,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CARBON ENERGY WILEY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[75,61,319,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1|INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,95,485,542]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Benefiting from their unique structure,2D materials are endowed with many extraordinary properties, exceeding their parent bulk materials.1-4 Since 20ll， the twodimensional (2D) transition metal carbides,first discovered by Naguib and Gogotsi et al.,have rapidly become a rising star material amongst the burgeoning 2D materials.The family of 2D transition metal carbides,and the subsequent nitrides and borides (MXenes)，exhibits excellent electrical conductivity,hydrophilicity,diverse chemical functionality, structure,and thickness controllability，which promoted their utilization in a large number of applications, including energy conversion, catalysis,electromagnetic interference shielding,water desalination，biosensor， neural electrodes，andso forth.5-9 To date,over 30 different types of MXenes with varying chemical and physical properties have been synthesized.1° MXenes can be represented by a general formula $\\mathbf { M } _ { n + 1 } \\mathbf { X } _ { n } \\mathbf { T } _ { x }$ $( n = 1 - 3$ )，where M represents early transition metals such as Ti,V, Ta, Cr,Mo,and so forth, and X represents C,N,and B,and $\\mathrm { T } _ { x }$ denotes various surface terminations such as -OH, $- \\mathrm { F }$ ，and O.5,9,11 MXenes are typically prepared by selective etching of the A atomic layer in MAX $\\left( \\mathbf { M } _ { n + 1 } \\mathbf { A X } _ { n } \\right)$ phase precursors, where A is typically a Group 13 or 14 element of the periodic table.12 The multivalent A atom efectively supports the stable parent MAX structure but posts a challenge in its selective removal.13,14 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,547,485,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Up to now, following the work of Gogotsi's research team in 2011,15 the use of hydrofluoric acid (HF) or in situ-generated HF solutions to prepare MXenes is still the most preferred synthesis method.However, the cost of managing highly toxic and corrosive HF and its associated chemical waste may be highly challenging at the industrial scale. Although streamlined pilot-scale production of MXenes， with comprehensive safety controls,16-18 has been demonstrated, there is still a strong motivation toward a safe, environmentally friendly,and cost-effective method to reduce the toxic chemical waste,drive down the production cost of MXenes,and realize their wide industrial applicability. In 2020,Lietal.19reported theuseof hightemperature molten salt to selectively etch the A atomic layer. However,due to the lack of hydrophilic functional groups $\\left( - \\mathrm { O H } / \\mathrm { - O } \\right)$ ，delaminating the multilayer MXenes prepared by the molten salt method could be a very difficult task.In addition, the high energy consumption and risk associated with high-temperature treatment need to be carefully considered.Concurrently，the electrochemical production route for MXenes has also been preliminarily studied by Pang et al. and Yang et al. where the electrochemical etching of MXenes in acidic and alkaline electrolytes was reported.20,21 Nevertheless, the low production yield and small-scale demonstration with preformed MAX electrodes would not be viable for industrial-scale production. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,62,924,127]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,130,924,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Herein,we report a green,cost-effective,and scalable electrochemical production of MXenes (eMXenes） with high yield,utilizing only aqueous ammonium fluoride $\\mathrm { ( N H } _ { 4 } \\mathrm { F ) }$ as the electrolyte in a simple two-electrode packedbed electrochemical reactor (PBER). Owing to the conductive nature of MXenes (even after functionalization), the PBER was remarkably successful for MXene production in terms of reaction yield $( 7 2 . 3 \\% )$ and rate $( 2 0 6 \\mathrm { m g h } ^ { - 1 } )$ . Moreover， we demonstrated the recyclability ofthe electrolyte, the versatility toward Nb-based MXenes, the unintuitive electrochemical etching mechanismwith undissociated $\\mathrm { N H } _ { 4 } \\mathrm { F }$ ，the scalability of the PBER with inexpensive graphite electrodes,and the application of eMXenes as superior supercapacitor electrodes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,393,875,410]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2| EXPERIMENTAL SECTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,427,677,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1| Materials","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,461,924,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MAX phase powders $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ ,200 mesh, ${ \\tt 2 9 9 \\% }$ ， $\\mathrm { N b } _ { 2 } \\mathrm { A l C }$ and $\\mathrm { N b } _ { 4 } \\mathrm { A l C } _ { 3 }$ ，200 mesh, $2 9 8 \\%$ ）were purchased from Laizhou KaiXi Ceramic material Co., Ltd. Tetramethylammonium hydroxide (TMAOH, $2 5 \\mathrm { w t . } \\%$ aqueous solutions） and ammonium fluoride $( \\mathrm { N H } _ { 4 } \\mathrm { F } , \\geq 9 8 \\% )$ ）were purchased from Sigma-Aldrich.The materials were used directly without any further purification. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,609,794,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2| Synthesis of eMXenes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,644,924,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"eMXenes were synthesized in a PBER under constant current,as first demonstrated in our previous work,2 22 where the conductive boron-doped diamond (BDD)- coated niobium electrode (Diaccon GmBH） was employed as the working electrode and the MAX powder was packed against the BDD under an applied pressure $( 1 \\mathrm { k g }$ top load for the small reactor and $2 \\mathrm { k g }$ top load for the large reactor). A $\\mathrm { P t }$ wire ( $\\mathrm { 0 . 2 5 ~ m m }$ diameter) with a length of $3 3 \\mathrm { c m }$ (purity $9 9 . 9 9 \\%$ ；Goodfellow）was employed as the counter electrode,and the two electrodes were separated by a hydrophilic MCE membrane (pore size $0 . 4 5 \\mu \\mathrm { m }$ ,MF; Millipore).As a proof of concept on industrial scalability, the BDD and Pt electrodes in large PBER could be replaced by a graphite plate (anode, $1 0 0 \\mathrm { m m } \\times 2 0 \\mathrm { m m } \\times 2 \\mathrm { m m } )$ and graphite rod (cathode, length: $1 8 0 \\mathrm { m m }$ ，diameter: $6 \\mathrm { m m }$ ),respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,911,924,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the small PBER,a fixed amount of MAX powder (from 0.1 to $^ { 1 \\mathrm { g } ) }$ and $4 \\mathrm { m L }$ of the $\\mathrm { N H } _ { 4 } \\mathrm { F }$ aqueous electrolyte of a specified concentration was pipetted into the reactor. The exposed surface area of the BDD electrode was measured to be $1 . 5 4 \\mathrm { c m } ^ { 2 }$ .For the large PBER,a greater quantity of MAX powder (from 1 to $2 0 \\mathrm { g }$ was fed in a single batch,with $4 0 \\mathrm { m L }$ of the added electrolyte and the exposed surface area of BDD of $8 . 0 0 \\mathrm { c m } ^ { 2 }$ . A CHI760E electrochemical workstation （CH Instruments) was employed for the galvanostatic charging (GC) with the limiting voltage set at $3 \\mathrm { V }$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[847,29,922,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[72,24,438,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 12 -WILEY-CARBON ENERGY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[75,63,485,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,213,485,310]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The as-synthesized eMXene was dispersed in deionized water with agitation and followed by copious rising through a hydrophilic polyvinylidene difluoride (PVDF) membrane (pore size $0 . 2 2 \\mu \\mathrm { m }$ ,MF;Millipore). Immediately after rising,the eMXene cake was freeze-dried to remove the residual water. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,343,398,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.3l Delamination of eMXenes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,379,485,742]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The freeze-dried eMXene $\\left( 0 . 1 { \\bf g } \\right)$ was redispersed in $5 0 \\mathrm { m L }$ of deionized water,which was subsequently deaerated with argon for $3 0 \\mathrm { { m i n } }$ .After that, delamination was achieved by adding $0 . 3 9 3 \\mathrm { m L }$ of TMAOH solution (the intercalating agent) and stirring at $3 0 0 \\mathrm { r p m }$ for $1 2 \\mathrm { h }$ at room temperature. The delaminated product was collected under high-speed centrifugation $( 1 0 , 0 0 0 ~ \\mathrm { { r p m } }$ for $1 0 \\mathrm { { m i n } } ,$ )，and the clear supernatant was discarded. The sediment was further rinsed twice with centrifuge-wash cycles ( $\\mathrm { 1 0 , 0 0 0 ~ r p m }$ for $1 0 \\mathrm { { m i n } } ,$ ); it was redispersed in $5 0 \\mathrm { m L }$ of deionized water and subjected to sonication in an ice bath under argon protection for $3 0 \\mathrm { { m i n } }$ . After sonication, the solution was centrifuged ( $3 5 0 0 ~ \\mathrm { r p m }$ for $3 0 \\mathrm { m i n } )$ ）and the dispersed eMXene supernatant solution was collected and vacuumfiltered using a hydrophilic PVDF membrane. The eMXene film was freeze-dried and removed from the PVDF membrane for further material characterizations (i.e., X-ray difraction [XRD], X-ray photoemission spectroscopy [XPS],Raman and sheet resistivity measurement).The yield of the delaminated eMXene (DE-MXene) nanosheets was calculated based on the weight ratio of the freestanding eMXene film to the MAX precursor. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,776,315,794]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.4l Characterizations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,810,484,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The XRD patterns were obtained from a Bruker D8 Advance diffractometer. The step size and the time per step were fixed at $0 . 0 1 ^ { \\circ }$ and 5 s，respectively. The morphology and element compositions of MAX phases and eMXenes were characterized using a JEOL JSM-7500FA SEM equipped with an EDS detector (Oxford EDS). The transmission electron microscopy (TEM) photographs were collected from a JEOL F200 electron microscope with energy-dispersive X-ray spectroscopy (EDS). The atomic force microscopy (AFM) characterization was carried out with a Bruker Dimension Icon atomic force microscope in tapping mode. The scanning electron microscopy (SEM) and AFM samples were prepared by spin-coating eMXenes onto a conductive $\\mathrm { S i } / \\mathrm { S i O } _ { 2 }$ wafer. The X-ray photoelectron spectroscopy (XPS) data was collected using a Kratos Axis Ultra with a monochromatized Al $K _ { \\alpha }$ X-ray source.The electrical conductivity of MXene films was measured using a Jandel RM30oo four-point probe system.Raman spectroscopy was performed on a LabRAM HR Evolution Raman microscope equipped with a $5 3 2 \\mathrm { n m }$ laser. The gas chromatogram was carried out with Agilent 7890B. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,63,924,294]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,327,852,345]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.5l Activated carbon electrodes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,361,924,478]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The activated carbon electrodes were prepared by mixing YP-50 activated carbon powder (Kuraray） and the polytetrafluoroethylene (PTFE) binder in a 95:5 weight ratio in ethanol. The resultant thick slurry could be continuously rolled into a self-supporting flexible film, the average mass loading of which was measured to be about 12 mg cm-2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,508,781,526]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.6| Electrochemical test ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,544,924,842]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The free-standing $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ MXene film was cut into a discshaped electrode (average active mass loading was between 3.0 and $4 . 2 \\mathrm { m g } \\mathrm { c m } ^ { - 2 } .$ ）witha diameter of $6 \\mathrm { m m }$ The electrochemical performance test was carried out in a Swagelok three-electrode configuration where glassy carbon electrodes were employed as current collectors for the three electrodes, namely, the MXene working electrode, the activated carbon counter electrode,and reference electrode $( \\mathrm { A g / A g C l }$ in $\\mathrm { { 1 m o l } L ^ { - 1 } \\ K C l \\mathrm { { } } }$ .For the fabrication of twoelectrode symmetric supercapacitors, two free-standing $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ MXene films of the same size served as electrodes, which were separated by a Celgard 350l membrane. $\\mathrm { H } _ { 2 } \\mathrm { S O } _ { 4 }$ solution $\\left( 3 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } \\right)$ was adopted as the electrolyte for both types of supercapacitor tests. The electrochemical characterizations, including cyclic voltammetry (CV)，galvanostatic charge-discharge (GCD)，and long-term cycling performance，were also acquired using the CHI760E electrochemical workstation at room temperature. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,843,924,893]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gravimetric capacitance $( C _ { \\mathrm { g } } , \\ \\mathrm { F } \\mathrm { g } ^ { - 1 } )$ of the working electrodes can be calculated from the CV profiles using the following equation: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[668,900,766,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0995/eadbdfc7ef6af083b6deb6c6f0f5c589175c1bbf4384b8ed713199b642059647.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nC _ { \\mathrm { g } } = { \\frac { \\displaystyle \\int I d V } { \\displaystyle \\Delta V m s } } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[75,29,151,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[557,25,926,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CARBON ENERGY-WILEY- 3 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[73,62,485,111]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $I ( \\mathbf { A } )$ is the current, $m$ is the mass of the electrodes, $s ( \\mathrm { V ~ s } ^ { - 1 } )$ is the scan rate,and $\\Delta V ( \\mathbf { V } )$ is the potential window. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,112,484,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The volumetric capacitance $( C _ { \\mathrm { v } } , \\ \\mathrm { ~ F ~ c m } ^ { - 3 } )$ can be calculated according to the following equation: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[242,158,317,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0843/b48dd3b9c57d717a50555c041c5c55b9476baa5a423def2b54fadc91127b49c6.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nC _ { \\mathrm { v } } = \\rho C _ { \\mathrm { g } } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[73,195,484,227]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\rho ( \\mathbf { g } \\thinspace \\mathrm { c m } ^ { - 3 } )$ is the density of the eMXene film electrode. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,228,485,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Energy density $( E _ { \\mathrm { g } } , \\mathrm { W h } \\mathrm { k g } ^ { - 1 }$ and $E _ { \\mathrm { v } }$ ， $\\mathrm { W h ~ L ^ { - 1 } }$ ）and power density ( $( P _ { \\mathrm { { g } } }$ $\\mathbf { \\Sigma } _ { \\mathrm { g } } ^ { } , \\mathbf { W } \\mathbf { k g } ^ { - 1 }$ and $P _ { \\mathbf { V } }$ ， $\\mathrm { ~ W ~ L ~ } ^ { - 1 }$ ）of the two-electrode symmetric supercapacitorscanbe calculated from GCD profiles according to the following equations: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[216,329,342,460]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0809/ff96135346cc55482a133ef72a03caac6ecd62ba2c6a82e1d1695408bc31a402.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { c } { E _ { \\mathrm { g } } = \\displaystyle \\int V I d t / M , } \\\\ { E _ { \\mathrm { v } } = \\rho E _ { \\mathrm { g } } , } \\\\ { P _ { \\mathrm { g } } = 3 6 0 0 E _ { \\mathrm { g } } / \\Delta t , } \\\\ { P _ { \\mathrm { v } } = \\rho P _ { \\mathrm { g } } , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[73,478,485,526]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $V ( \\mathbf { V } )$ is the discharge voltage window, $\\Delta t$ (s) is the discharge time,and $M ( { \\mathrm { m g } } )$ is the total weight of electrode materials. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,560,453,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3I RESULTS AND DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,593,413,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1| Electrochemical production of $\\mathbf { T i } _ { 3 } \\mathbf { C } _ { 2 } \\mathbf { T } _ { x }$ eMXenes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,644,485,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The electrochemical etching of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ and its concomitant functionalization process were carried out in a two-electrode PBER,as depicted in Figure 1A (in the photos of Figure S1,the synthetic process is described in detail in the Experimental Section). The aqueous $\\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte( $\\mathrm { \\langle p H } = 6 . 2 9 \\mathrm { \\rangle }$ ）was chosen as the fluoride source due to its low cost and excellent water solubility,which can afford a broad concentration range for fundamental investigation. The typical GC curve (Figure 1C) for electrochemical etching of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ exhibits three distinct stages during the electrochemical reactions: intercalation of anions (Stage I,the initial sharp rise in voltage),etching/ functionalization of MAXs/MXenes (Stage II, the long intermediate plateau steadily climbing from 0.5 to 1.5 V),and water splitting (Stage II, the sharp rise to over $3 \\mathrm { V }$ at the end of the reaction). The linear sweep voltammetry of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ MAXs performed at $1 \\mathrm { m V s } ^ { - 1 }$ (Figure S2A) revealed that the anodic etching reaction in the $\\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte could proceed at an increasing rate with increasing voltage from O.5 to $2 \\mathrm { v }$ (corresponding to Stage II in the GC curve)，while the etching current dropped sharply above $2 \\mathrm { v }$ (at Stage III, water splitting outweighed the etching reaction). The as-prepared eMXene product (denoted as $\\mathrm { E } { - } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x } )$ showed dark black color in contrast to the metallic color of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ $\\mathrm { E - T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ was further delaminated with TMAOH to obtain a monolayer or a few-layer delaminated eMXene (Dl $\\mathrm { E } { \\cdot } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x } )$ sheets. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,62,924,260]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,294,892,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2 Optimization of key parameters in the electrochemical reaction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,345,924,443]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To achieve a better understanding of the electrochemical reactions,the key experimental parameters (electrolyte concentration,applied current density,and MAX loading) were investigated and optimized in our current PBERs, relying on XRD characterization and the yield of exfoliated MXene flakes as the evaluation criteria.23,24 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,439,924,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The GC plots (Figure S3) in a wide range of $\\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte concentrations (from 2 to $1 8 \\mathrm { m o l } \\mathrm { L } ^ { - 1 }$ ）under the same constant current density $( 7 . 8 0 \\mathrm { m A } \\mathrm { c m } ^ { - 2 } )$ displayed similar charging profiles but with differences in the plateau voltages and total charges consumed. Notably，forlowerconcentrationsof $2 \\mathrm { m o l } \\mathrm { L } ^ { - 1 }$ (Figure S3), their plateau voltages were higher and the total charge consumed was smaller compared with that of the more concentrated electrolytes $( > 6 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } )$ . These imply that a higher level of electrochemical resistance and incomplete electrochemical reaction may be associated with using lower electrolyte concentrations.Evidently, the XRD patterns of the as-produced products (Figure 2A） showed a significant residual parent MAX phase (at $2 \\theta = 3 9 ^ { \\circ }$ ）and the yields of exfoliated MXenes (Figure S4) were lower for the lower electrolyte concentrations. When higher electrolyte concentrations $\\left( \\mathsf { z 6 m o l L } ^ { - 1 } \\right)$ ）were employed, successful etching of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ into $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ could be achieved as evidenced by the significant reduction of the parent MAX phase and the shift of the (O02) XRD peak from $9 . 6 ^ { \\circ }$ to $7 . 1 ^ { \\circ }$ . The XRD peaks at $2 \\theta = 3 9 ^ { \\circ }$ of the unetched $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ are minimal at concentrations from $1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 }$ onwards. In addition, the use of $1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } \\mathrm { N H } _ { 4 } \\mathrm { F }$ could achieve the highest yield of exfoliated MXenes of $7 2 . 3 \\%$ (Figure S4)，which is comparable to the currently reported MXenesynthesis methods.17,23-25 Hence, $1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } \\mathrm { N H } _ { 4 } \\mathrm { F }$ was selected as the optimal electrolyte condition in this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,24,436,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 12 -WILEY-CARBON ENERGY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[847,28,922,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[142,63,865,418]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE1Schematicdiagramand typical galvanostaticchargingcureof theelectrochemicalproductionofeMXenes.(A)Schematic drawing of the small PBER used to prepare eMXenes in which the parent $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ MAX material was anodically etched and functionalized in the $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte under the galvanostatic charging. (B) Schematic drawing of the large PBER and ${ 2 0 \\\\mathrm { g } }$ freeze-dried $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene product prepared by the large PBER. (C) Typical galvanostatic charging curve for electrochemical etching $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ with three distinct stages, i: intercalationof electrolyte ions,i: etching and functionalization,andi: water spliting on BDDat voltage over $_ { 3 \\\\mathrm { V } }$ (parameter: small PBER, $_ { 0 . 1 \\\\mathrm { g } }$ of starting $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ ， $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte and $7 . 8 0 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 }$ constant current density). BDD,boron-doped diamond; $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F } ,$ ，ammonium fluoride; PBER, packed-bed electrochemical reactor. \"]","image_footnote":"[]","img_path":"images/0225/02b6893237d1d7c676c0c06372e47a8703bc950a76fe6bddd5e508389116f39e.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,580,485,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To study the effect of current densities,a series of constant current densities,ranging from 1.30 to $6 4 . 9 6 \\mathrm { m A c m } ^ { - 2 }$ ,were employed in our small PBER with $_ { 0 . 1 \\mathrm { g } }$ of MAXs $( 0 . 0 7 \\mathrm { g } \\mathrm { c m } ^ { - 2 } )$ . The corresponding charging curves (Figure S5） share similar cell voltage profiles, consisting of a stable etching voltage plateau followed by a sharp voltage rise, but with varying charge consumed. The XRD results (Figure S6） suggest that efective electrochemical etching could be achieved in this bench-scale PBER (small PBER) when the currents were between 1.30 and $1 9 . 4 9 \\mathrm { m A c m } ^ { - 2 }$ .In this range，the production rate of eMXenes (Figure 2B) in our small PBER shows a positive correlation with the applied current, achieving around $2 0 \\mathrm { m g h ^ { - 1 } }$ with a good yield $( > 6 0 \\% )$ at the current density of $1 9 . 4 9 \\mathrm { m A } \\mathrm { c m } ^ { - 2 }$ The product yield decreased significantly when the current density exceeded $1 9 . 4 9 \\mathrm { m A c m } ^ { - 2 }$ ,and is possibly due to the limitation in electrolyte diffusion in the small PBER and the transition to the water-splitting reaction prematurely. Based on the highest product yield achieved， the current density of $7 . 8 0 \\mathrm { m A } \\mathrm { c m } ^ { - 2 }$ was selected as the optimum for our small PBER. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,576,848,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3l Characterization of $\\mathbf { T i } _ { 3 } \\mathbf { C } _ { 2 } \\mathbf { T } _ { x }$ eMXenes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,627,924,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The morphological, physical,and chemical properties of the eMXene produced using the optimized parameters (small PBER, $_ { 0 . 1 \\mathrm { g } }$ or $0 . 0 7 \\mathrm { g c m } ^ { - 2 }$ MAXs, $1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 }$ $\\mathrm { N H } _ { 4 } \\mathrm { F }$ and $7 . 8 0 \\mathrm { m A } \\mathrm { c m } ^ { - 2 }$ current density) were further investigated. The (O02) characteristic peak of DE- $\\mathbf { \\nabla } \\cdot \\mathrm { T i } _ { 3 } \\mathbf { C } _ { 2 } \\mathbf { T } _ { x }$ in XRD broadened and shifted from $7 . 1 ^ { \\circ }$ to $6 . 1 ^ { \\circ }$ (Figure S7),indicating the increase in the interlayer spacing of the adjacent $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 }$ layers. The SEM image shows that the $\\mathrm { E - T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ (Figure 3A) had a typical accordion-like morphology, similar to those prepared by chemically etching with HF.7 After delamination, the aqueous dispersion of $\\mathrm { D E - T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ shows Tyndall effect (Figure S8b） and negative zeta potential $( - 4 9 . 3 4 \\mathrm { m V }$ ， Figure S8C) lower than those of the products synthesized by using HF to chemically etch,indicative of highly stable colloidal dispersion. The DE- $\\mathbf { \\nabla } \\cdot \\mathrm { T i } _ { 3 } \\mathbf { C } _ { 2 } \\mathrm { T } _ { x }$ solution was vacuum-filtrated into a thin film (Figure S9A) composed of highly aligned, face-to-face packed sheets as seen in the cross-sectional SEM images (Figure S9B-D). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,29,151,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[557,25,926,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CARBON ENERGY-WILEY- 5 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[72,63,631,506]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0671/5c35a21750d2807aff5a2816baf49be957c833a61329387286f79f01788024ef.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[653,60,926,335]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"FIGURE 2Parameter optimization for the electrochemical reaction. (A) XRD patterns of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ and $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ eMXene products etched with $\\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte concentrations range from 2 to $1 8 \\mathrm { m o l L } ^ { - 1 }$ (parameter: small PBER, $_ { 0 . 1 \\mathrm { g } }$ of the starting material $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ and $7 . 8 0 \\mathrm { m A } \\mathrm { c m } ^ { - 2 }$ constant current density).(B) Yields and production rates of delaminated eMXene $\\left( \\mathrm { D E - T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x } \\right)$ samples etched with various constant current densities (parameter for small PBER: $_ { 0 . 1 \\mathrm { g } }$ of the starting material $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ and $1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } \\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte; parameter for large PBER: $_ { 1 \\mathrm { g } }$ of the starting material $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ and $1 0 \\mathrm { m o l L } ^ { - 1 }$ $\\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte). $\\mathrm { N H } _ { 4 } \\mathrm { F }$ ，ammonium fluoride;PBER,packed-bed electrochemical reactor;XRD,X-ray diffraction. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,544,484,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The freeze-dried D $\\mathrm { \\mathrm { F } { \\cdot } T i _ { 3 } C _ { 2 } T } _ { x }$ film has an excellent conductivity $( 1 0 , 4 7 0 \\mathrm { S c m } ^ { - 1 } )$ ） slightly higher than those prepared with HF.26,27 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,594,485,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The TEM image in Figure 3B shows the ultrathin nature of DE- $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ flakes,and the insignificant presence of Al from the EDS mapping indicates the successful removal of the Al layers from the parent MAX (Figure S1oA,B). The high-resolution transmission electron microscopy (HRTEM） image (Figure S10C） and its corresponding selected area diffraction (SEAD） pattern (the inset in Figure 3B) confirm that the DE- $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ nanosheets preserved the hexagonal lattice structure during the electrochemical etching and the following delamination. The AFM image (Figure S1l） shows bilayered or trilayered DE $\\mathbf { \\cdot } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ MXene flakes with a thickness of about $4 \\mathrm { n m }$ . The absence of the Al 2p signal in the X-ray photoelectron spectroscopy (XPS） spectra for $\\mathrm { E - T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ (Figure 3C and Figure S12A) again confirms the successful electrochemical etching of Al. Deconvolution of the XPS Ti 2p band for $\\mathrm { E } { \\cdot } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ (Figure S12B and details in Table S1) reveals the presence of several oxidation states of $\\mathrm { T i }$ atoms,which were bonded to $\\mathrm { T } _ { x }$ $\\left( - \\mathrm { O } / \\mathrm { - O H } \\right)$ and $- \\mathrm { F }$ termination.28 XPS spectra of C 1s and O 1s confirm the existence of C-Ti-O and C-Ti-OH bonds,and that of F 1s indicates ${ } _ { - \\mathrm { F } }$ termination group covalently bonded to $\\mathrm { E } { \\cdot } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ (Figure Sl2C-E). These results are all consistent with the XPS signal of Ti 2p. Raman spectra of starting materials $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ and $\\mathrm { E } { \\cdot } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ MXenes show that after electrochemical etching, the characteristic peaks $( \\omega _ { 1 } , \\omega _ { 2 } ,$ and $\\omega _ { 3 , }$ ）of the starting material $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ disappear with the appearance of new characteristic peaks $( \\omega _ { 4 } , \\omega _ { 5 }$ and $\\omega _ { 6 , - }$ from the $\\mathrm { E } { \\cdot } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { \\mathrm { x } }$ MXene sample (Figure S13). The emergence of new characteristic peaks can be attributed to the changes in the chemical states of Ti and C atomic layers associated with the removal of Al and the introduction of various termination groups during the electrochemical reaction.29 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,543,924,792]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,826,852,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.4| Electrochemical production of Nb-based eMXenes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,877,924,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Beyond $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { \\mathrm { x } } ,$ our electrochemical method can be applied to effectively etch $\\mathrm { N b } _ { 2 } \\mathrm { A l C }$ and $\\mathrm { N b } _ { 4 } \\mathrm { A l C } _ { 3 }$ MAXs to ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[847,28,922,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[72,25,438,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 12 -WILEY-CARBON ENERGY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[137,65,855,515]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 3Characterization of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ and $\\\\mathrm { N b } _ { 4 } \\\\mathrm { C } _ { 3 } \\\\mathrm { T } _ { x }$ eMXenes. (A) SEM image of as-produced eMXenes $\\\\left( \\\\mathrm { E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } \\\\right)$ . (B) TEM image of delaminated eMXene (DE- $\\\\mathrm { T i } _ { 3 } C _ { 2 } \\\\mathrm { T } _ { x } )$ nanosheets and corresponding SEAD images.(C) High-resolution XPS spectra of Al 2p of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and $\\\\mathrm { E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } .$ (D) XRD patterns of $\\\\mathrm { N b } _ { 4 } \\\\mathrm { A l C } _ { 3 }$ MAXs and $\\\\mathrm { N b } _ { 4 } \\\\mathrm { C } _ { 3 } \\\\mathrm { T } _ { x }$ eMXenes (the inset shows the SEM image of as-produced $\\\\mathrm { N b } _ { 4 } \\\\mathrm { C } _ { 3 } \\\\mathrm { T } _ { x }$ eMXenes with a $2 \\\\mu \\\\mathrm { m }$ scale bar).SEAD,selected areadifraction; SEM,scanning electronmicroscopy;TEM,transmision electronmicroscopy; XRD, X-ray diffraction. \"]","image_footnote":"[]","img_path":"images/0327/f2fb91a4f0afea4931b08e7ba92c7c2452a3e86252f70479ad66ab1f3a8fd21b.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,644,485,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2D MXenes (the corresponding charging curves are shown in Figure S14)，which typically require high concentrations of HF $( 4 8 \\% - 5 1 \\% )$ ，long reaction time (more than $9 6 \\mathrm { h }$ ),and heating.30-32 Similar to the Tibased MAX, the successful selective etching of both Nbbased MAXs was achieved,as indicated by the disappearance of the sharp XRD peaks of the parent MAX phases and the broadening and weakening of the remaining XRD peaks (see Figure 3D and Figure S15). The electrochemically prepared $\\mathrm { N b } _ { 2 } \\mathrm { C T } _ { \\boldsymbol { x } }$ and ${ \\mathrm { N b } } _ { 4 } { \\mathrm { C } } _ { 3 } { \\mathrm { T } } _ { x }$ MXenes displayed a typical accordion-like morphology in the SEM images (insets in Figure 3D and Figure S15), also consistent with the previous reports of the successful synthesis of $\\mathrm { N b } _ { 2 } \\mathrm { C T } _ { { \\boldsymbol { x } } }$ and $\\mathrm { N b } _ { 4 } \\mathrm { C } _ { 3 } \\mathrm { T } _ { x }$ MXenes.30.32 The elemental analysis by EDS (Figures S16 and S17） and XPS (Figures S18 and S19,Tables S2 and S3) further confirmed that the Al element was successfully removed from the starting materials $\\mathrm { N b } _ { 2 } \\mathrm { A l C }$ and $\\mathrm { N b } _ { 4 } \\mathrm { A l C } _ { 3 }$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,643,902,676]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.5l Cost-effectiveness and scalability of PBER ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,695,924,892]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to the huge versatility of PBER,its costeffectiveness and scalability were examined next.At the end of each experiment, the electrolyte from the PBER can be easily recovered, without contamination from the packed MXene product.As a proof of concept, the same $1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } \\ \\mathrm { N H } _ { 4 } \\mathrm { F }$ electrolyte was recovered and reused for at least five times with a similar level of high reaction yield $( > 7 0 \\% )$ maintained (Figure 4A and Figure S20). In addition to the energy efficiency of room temperature electrochemical reaction, the recyclability of the electrolyte is a major green chemistry feature,which will greatly reduce the pollution and cost of chemical wastes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,895,924,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Next, the scalability of the PBER (up to $2 0 \\mathrm { g }$ ina single batch） was demonstrated in a laterally upscaled PBER (as shown in Figure 1B and Figure S21). By conductingthe same systematic investigationof current density (Figures S22 and S23) and MAX loading (Figure S24) on the product yield and production rate (Figure 2B), it was found that applying $6 . 2 5 \\mathrm { m A c m } ^ { - 2 }$ to the large PBER containing $_ { 1 \\mathrm { g } }$ of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ $( 0 . 1 2 5 \\mathrm { g c m } ^ { - 2 } )$ could produce the highest yield $( 7 0 . 1 \\% )$ of MXene at the rate of $4 3 . 1 \\mathrm { m g h } ^ { - 1 }$ . Furthermore, the large PBER could allow the etching of $2 0 \\mathrm { g }$ of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ $( 2 . 5 \\mathrm { g c m } ^ { - 2 } )$ with similar efectiveness as the small PBER,as evidenced by XRD and SEM (Figures S24 and S25);and the high product yields were maintained ( $6 8 \\%$ for $5 { \\mathrm { g } }$ and $6 3 \\%$ for $2 0 \\mathrm { g }$ of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 } ,$ ). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,29,151,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[557,25,926,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CARBON ENERGY-WILEY- 7 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[193,66,800,469]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 4(A) Yield of $\\\\mathrm { D E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ MXenes prepared by electrochemically etching $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ with different-cycle-time electrolytes or graphite electrodes. (B) Large PBER with graphite electrodes (anode and cathode). (C) XRD patterns of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene products etched with BBD/graphite electrodes (parameter: large PBER, $_ { 1 \\\\mathrm { g } }$ and $_ { 2 0 \\\\mathrm { ~ g ~ } }$ of the starting material $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ ， $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte and 12. $5 0 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 }$ constantcurrentdensity).BDD,boron-dopeddamond;eMXene,electrochemicallyproducedcarbidesandnitridesoftrasition metals; $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ ,ammonium fluoride; PBER,packed-bed electrochemical reactor; XRD,X-ray diffraction. \"]","image_footnote":"[]","img_path":"images/0705/12f5b054272f06b06838276a8255f5169756e42e4ebdc07404fc59f6161e692f.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,595,485,792]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,795,485,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To reduce the cost of PBER and ensure its scalability, the costly BDD and Pt electrodes were replaced by graphite electrodes (plate for anode and rod for cathode, see Figure 4B) in the large PBER. Owing to the relatively low etching potential of MAXs (cell voltage plateau ${ < } 1 . 5 \\mathrm { V } )$ ,the graphite electrodes were intact even after repeated use.More importantly，the XRD and SEM results of $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ eMXenes ( $_ { 1 \\mathrm { g } }$ and $2 0 \\mathrm { g }$ ）prepared with graphite electrodes are consistent with those of $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { x }$ eMXenes prepared with Pt and BDD electrodes (Figure 4C and Figure S25). In addition，eMXenes prepared by graphite electrodes still maintained a high yieldlevel ( $7 2 . 1 \\%$ for $_ { 1 \\mathrm { g } }$ and $6 7 . 4 \\%$ for $2 0 \\mathrm { g }$ of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ ， see Figure 4A). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,594,924,694]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,726,820,759]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.6| Electrochemical etching mechanism ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,778,924,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the standard electrode potential series (Table S4)，the selective electrochemical etching of aluminum $\\left( E ^ { \\mathrm { o } } = - 1 . 6 7 7 \\mathrm { V } \\right)$ ）with fluoride is thermodynamically more favorable compared with the etching of titanium $( E ^ { 0 } = - 1 . 3 7 0 \\mathrm { V } )$ or niobium $( E ^ { 0 } = - 0 . 8 0 0 \\mathrm { V } )$ . The electrochemical etching reaction would involve the intercalation and etching of aluminum by the fluoride anion $\\left( z = 3 \\right)$ in the positively charged MAX electrode:21 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[847,28,922,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[72,25,436,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 of 12 -WILEY-CARBON ENERGY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[141,60,420,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0411/1607504df4b1ff7819572db674fe7ffb841ef3feea128fb215f046c279e5fc18.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 } + 3 \\mathrm { F } ^ { - } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } + \\mathrm { A l F } _ { 3 } + 3 \\mathrm { e } ^ { - }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[73,95,484,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Subsequently， the etched MXene could be elctrochemically fluorinated or oxidized with hydroxyl groups $( z \\approx 2 )$ ： ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,158,445,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0219/1aab223e4ae0516243a0844ed416adf139a001b9dbadb5e5fac4bb894f3f5700.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } + x \\mathrm { F } ^ { - } + y \\mathrm { O H } ^ { - } \\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } ( \\mathrm { O H } ) _ { y } \\mathrm { F } _ { x } + z \\mathrm { e } ^ { - }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[75,213,485,643]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This process is accompanied by expected hydrogen evolution reaction at the Pt cathode (Figure S26 and Table S5) and an unexpected gas from the MAX anode (as evident from the gas bubble evolution), the expansion of MAX packed-bed (Figure S27),and the accordion-like structure of the as-produced product (Figure 3A). In contrast to the well-known role of the fluoride anion, the role of the ammonium cation was surprisingly found to be critical in the electrochemical process as similar concentration $( 1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } )$ of the KF electrolyte was unable to promote the electrochemical etching of MAXs (Figure S28). It was found that ammonia gas $\\left( \\mathrm { N H } _ { 3 } \\right)$ was produced from the MAX electrode,as evident from the increased $\\mathsf { p H }$ of the electrolyte and evolution of alkaline gas(only from the MAX electrode) during the electrochemical etching process (Figure S26 and Video S1). Our proposed mechanism is summarized in Figure 5 where there is a significant presence of undissociated ammonium fluoride $( \\mathrm { { \\sim } 1 . 6 \\ m o l \\ L ^ { - 1 } }$ ； $K _ { \\mathrm { s p } } = 4 4 . 1 7 $ ）in sufficiently concentrated $\\mathrm { N H } _ { 4 } \\mathrm { F }$ $\\left( 1 0 \\mathrm { m o l } \\mathrm { L } ^ { - 1 } \\right) ,$ ),which could be intercalated into the positively charged MAX anode in its uncharged form.In a concerted event following the bond forming between Al and $\\mathrm { F ^ { - } }$ (electrochemical） and breaking of the Al-Ti bond, the Ti is expected to extract a proton from $\\mathrm { N H } _ { 4 } \\mathrm { F }$ ， thus liberating ammonia gas. Progressively，Al would be electrochemically etched away in the form of $\\mathrm { A l F } _ { 3 }$ and the etched MAX could be subjected to further electrochemical functionalization as suggested in Equation (2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,62,924,111]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,144,852,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.7lSupercapacitor applications of $\\mathbf { T i } _ { 3 } \\mathbf { C } _ { 2 } \\mathbf { T } _ { x }$ eMXenes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,195,924,644]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { \\mathrm { x } }$ free-standing membrane was directly utilized as a binder-free electrode for supercapacitors. In a three-electrode setup，the CV of the eMXene electrode at various scan rates (Figure 6A） shows pseudocapacitive charge storage as evident from a pair of broad redox peaks relating to the redox reactions of Ti atoms of multiple valence states.25,26 The GCD profiles of the eMXene electrode at various current densities $( 2 { - } 5 0 \\mathrm { A g ^ { - 1 } } )$ also confirm the pseudocapacitive behavior from the nonlinear dependence of voltage with time at constant current (Figure 6B). The eMXene electrode exhibited an ultrahigh gravimetric capacitanceof $3 4 0 . 9 \\mathrm { F } \\ : \\mathrm { g } ^ { - 1 }$ and a volumetric capacitance of $1 4 0 7 . 9 \\mathrm { F }$ $\\mathrm { c m } ^ { - 3 }$ (Figure S3O) at a scan rate of $2 \\mathrm { m V s } ^ { - 1 }$ and even retained excellent gravimetric capacitance $( 1 3 2 . 3 \\mathrm { F } \\mathrm { g } ^ { - 1 } )$ and volumetric capacitance $( 5 4 6 . 3 \\mathrm { F } \\mathrm { c m } ^ { - 3 } )$ at a high scan rate of $1 \\mathrm { V } \\mathrm { s } ^ { - 1 }$ . The long-term cycling test at $2 0 \\mathrm { A g } ^ { - 1 }$ ,as shown in Figure 6C,demonstrates that the high capacitance of the eMXene electrode was maintained with a high Coulombic efficiency $( > 9 0 \\% )$ over at least 15,000 cycles.When applied to a two-electrode symmetric supercapacitor， the eMXene-based electrode could maintain its excellent energy storage performance (as depicted in Figure 6D and Figures S31-S33), including high volumetric capacitance $\\left( 3 2 5 \\mathrm { F c m } ^ { - 3 } \\right.$ at $2 \\mathrm { m V s } ^ { - 1 } )$ and volumetric energy densities across a broad range of powerdensities(seeFigure 6D). Thesuperior electrochemical performances of the eMXene electrode are attributed to the larger interlayer spacing in the freestanding eMXene membrane $( 1 . 4 3 \\mathrm { n m } )$ compared with those chemically etched by HF $( 1 . 3 6 \\mathrm { n m } )$ ,23 resulting in more accessible and faster movement of ions during the charge and discharge processes. In addition, the high electrical conductivity of the eMXene electrode also contributed to the rapid charge transfer. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,675,894,863]","code_body":null,"code_caption":null,"image_caption":"[\"FIG URE 5Electrochemical etching mechanism.(A) Initial state with dissociated and undissociated $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ on the $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ surface. (B) Anodic etching reaction, $\\\\mathrm { F ^ { - } }$ ion bond with Al with electron transfer and concerted extraction of H from undissociated $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ by Ti. (C) Bond breaking between Al-Ti and $_ \\\\mathrm { N - H }$ resulted in liberation of $\\\\mathrm { N H } _ { 3 }$ gas.(D) Subsequent progression of concerted electrochemical etching with $\\\\mathrm { F ^ { - } }$ ions and proton transfer from undissociated $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ $\\\\mathrm { N H } _ { 3 }$ ,ammonia; $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ ，ammonium fluoride. \"]","image_footnote":"[]","img_path":"images/0880/aa34cbc3b87bbee89237b6835a07c3b2cf1010b41dcbd2ebfbd153114e7a8cb8.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,28,151,38]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[557,24,926,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CARBON ENERGY-WILEY- 9 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[151,63,848,492]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 6Electrochemical performance of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene electrodes in supercapacitors.(A) CV curves of the $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene electrode in asymmetric supercapacitors at different scan rates. (B) Galvanostatic charge/discharge curves of the $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene electrode in asymmetric supercapacitors at different current densities.(C) Cycling performance of the $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene electrode in asymmetric supercapacitors at a current density of $2 0 \\\\mathrm { A g ^ { - 1 } }$ .(D) Ragone plot showing volumetric energy and power densities of the $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene two-electrodesymmetric supercapacitor in comparison withdata reported in theliterature: $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ and $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } / \\\\mathrm { r G O } , ^ { 2 }$ wavy $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\boldsymbol { x } _ { 3 } } { } ^ { 3 }$ 3 $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } /$ conducting polymer,34 $\\\\mathrm { T i } _ { 3 } { \\\\bf C } _ { 2 } \\\\mathrm { T } _ { x } / { \\\\bf K } _ { 2 } { \\\\bf S } { \\\\bf O } _ { 4 } .$ 35 $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } /$ mesoporous carbon,36 macroporous $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\boldsymbol { x } , } { } ^ { 3 7 }$ and $\\\\mathrm { T i _ { 3 } C _ { 2 } T _ { \\\\it x } / H _ { 2 } S O _ { 4 } + K I }$ .38 cV, cyclic voltammetry. \"]","image_footnote":"[]","img_path":"images/0150/ae6f6a87dafa11c4a314d763e930793cebc842d56d74f9a51a742ec976241d5c.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,661,484,792]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,661,924,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"instrumental for anodic etching, the role of ammonium is also crucial in supplying the hydride intermediate through the liberation of ammonia gas.The excellent quality of eMXenes has been extensively characterized, and its superior electrochemical properties in supercapacitor application have been demonstrated. It is noteworthy that the performance of our PBER can be further improved through the engineering of the electrochemical reactor, electrochemistry of the electrolyte,and advanced electrochemical techniques. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,826,289,842]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4l CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,860,485,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From our investigation,it is clear that the electrochemical approach in etching MAXs and producing functional MXenes in our PBER is promising for a truly green and cost-effective industrial-scale production.Although the fluoride anion in the electrolyte (ammonium fluoride) is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,845,741,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGEMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,861,924,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was financially supported by the Australian Research Council (FT200100015 and DP190100120), Griffith University PhD Scholarships，National Key Research and Development Program (2021YFA1600800), and Shenzhen Science and Technology Program (RCJC-","text_format":null,"text_level":null,"type":"text"},{"bbox":"[847,28,922,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[73,24,443,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 of 12 -WILEY-CARBON ENERGY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[73,63,487,94]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"20200714114434086，JCYJ20190808142001745，JCYJ2020- \n0812160737002, 20180921273B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,112,329,126]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CONFLICTS OF INTEREST ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,130,393,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare no conflicts of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,163,139,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORCID ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[75,180,485,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Zimo Huang $\\textcircled{1}$ https://orcid.0rg/0000-0003-0048-8950 \nJiadong Qin $\\textcircled{1}$ http://orcid.0rg/0000-0001-7648-0221 \nKelin He $\\textcircled{1}$ https://orcid.0rg/0000-0003-1245-6868 \nHao Chen $\\textcircled{1}$ https://orcid.0rg/0000-0002-0252-7530 \nHui Ying Hoh $\\textcircled{1}$ https://orcid.0rg/0000-0001-8761-5523 \nMunkhbayar Batmunkh $\\textcircled { 1 0 }$ https://orcid.org/0000-0002- \n7493-4186 \nTania M. Benedetti $\\textcircled{1}$ https://orcid.org/0000-0002- \n4835-9384 \nQitao Zhang $\\textcircled{1}$ https://orcid.0rg/0000-0002-8817-0033 \nChenliang Su $\\textcircled{1}$ https://orcid.0rg/0000-0002-8453-1938 \nShanqing Zhang $\\textcircled{1}$ http://orcid.0rg/0000-0001-5192-1844 \nYu Lin Zhong $\\textcircled { 1 0 }$ http://orcid.0rg/0000-0001-6741-3609 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,413,205,427]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,428,489,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1．Xu M，Liang T,Shi M,Chen H.Graphene-like twodimensional materials. 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Chem Mater.2017;29(18):7633-7644. \n8.Aslam MK,Niu Y,Xu M.MXenes for non-lithium-ion (Na,K, Ca,Mg,and Al) batteries and supercapacitors.Adv Energy Mater. 2021;11(2):2000681. \n9. Gogotsi Y，Anasori B.The rise of MXenes.ACS Nano. 2019;13(8):8491-8494. \n.0．NatuV,Pai R, Sokol M,Carey M,Kalra V,Barsoum MW.2D $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { \\mathrm { z } }$ MXene synthesized by water-free etching of $\\mathrm { T i } _ { 3 } \\mathrm { A l C } _ { 2 }$ in polar organic solvents. Chem. 2020;6(3):616-630. \n.1． Shahzad F,Alhabeb M,Hatter CB,et al.Electromagnetic interference shielding with 2D transition metal carbides (MXenes). Science.2016;353(6304):1137-1140. \n.2. 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An ultrafast conducting polymer $@$ MXene positive electrode with high volumetric capacitance for advanced asymmetric supercapacitors. Small. 2020;16(4): \n1906851. \n35.Lukatskaya MR,Mashtalir O,Ren CE,etal. Cation intercalation and high volumetric capacitance of two-dimensional titanium carbide.Science.2013;341(6153):1502-1505. \n36. Allah AE,Wang J，Kaneti YV，et al. Auto-programmed heteroarchitecturing: self-assembling ordered mesoporous carbon between two-dimensional $\\mathrm { T i } _ { 3 } \\mathrm { C } _ { 2 } \\mathrm { T } _ { \\mathrm { x } }$ MXene layers. Nano Energy.2019;65:103991. \n37.Yao M,Chen Y,Wang Z,et al. Boosting gravimetric and volumetric energy density via engineering macroporous MXene films for supercapacitors. Chem Eng J. 2020;395: \n124057. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,72,926,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,28,151,38]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[551,25,926,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CARBON ENERGY-WILEY- 11 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[73,63,485,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,63,924,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"38. Tian Y,Yang C,Luo Y,et al.Understanding MXene-based “symmetric” supercapacitors and redox electrolyte energy storage.ACS Appl Energy Mater.2020;3(5):5006-5014. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,130,798,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUPPORTING INFORMATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,147,924,194]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Additional supporting information can be found online in the Supporting Information section at the end of this article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[534,231,904,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"How to cite this article: Huang Z, Qin J, Zhu Y, et al. Green and scalable electrochemical routes for cost-effective mass production of MXenes for supercapacitor electrodes. Carbon Energy.2023;5: e295. doi:10.1002/cey2.295 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,24,443,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 of 12 -WILEY-CARBON ENERGY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[847,28,922,37]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HUANG ET AL. ","text_format":null,"text_level":null,"type":"discarded"}],"string":"[\n {\n \"bbox\": \"[75,138,712,222]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Green and scalable electrochemical routes for cost-effective mass production of MXenes for supercapacitor electrodes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,250,773,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Zimo Huang1 $\\\\textcircled { 1 0 }$ 丨Jiadong $\\\\mathbf { Q i n } ^ { 1 } \\\\left( \\\\mathbb { D } \\\\right)$ |Yuxuan Zhu1 | Kelin He1 $\\\\textcircled{1}$ 一 Hao Chen² $\\\\textcircled{1}$ 丨Hui Ying $\\\\mathbf { H o h } ^ { 2 } \\\\mathbf { \\\\mathbb { \\\\oplus } }$ |Munkhbayar Batmunkh1 $\\\\textcircled{1}$ 一 Tania M.Benedetti1 $\\\\textcircled{1}$ | Qitao Zhang³ $\\\\textcircled{1}$ Chenliang $\\\\mathbf { S u } ^ { 3 } \\\\oplus$ 一 Shanqing Zhang² ① |Yu Lin Zhong1 D \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,352,931,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"QueenslandicrodanotecolgCetre,holofnviontandience,GiithUniversityuensnd,atatalia 2Centre forCatalysisandClean EnergyShoolofEnvironmentand Sience,GrifithUniversityQuensland,GoldCoast,Austral InteratioalClbatiebratorfaterafotoelectroeeholstryucatiostiutele Optoelectronics,Shenzhen University, Shenzhen, China \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,445,178,455]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Correspondence \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,457,321,554]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Chenliang Su,International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education,Institute of Microscale Optoelectronics,Shenzhen University,518060 Shenzhen,China. Email: chmsuc@szu.edu.cn \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,560,317,629]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Yu Lin Zhong, Queensland Micro-and Nanotechnology Centre,School of Environment and Science,Griffith University,Nathan,QLD 41ll,Australia. Email: y.zhong@griffith.edu.au \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,645,211,658]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,662,319,801]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Australian Research Council, \\nGrant/Award Numbers:DP190100120, FT200loool5;National Key Research and Development Program, \\nGrant/Award Number:2021YFA1600800; Shenzhen Science and Technology \\nProgram,Grant/Award Numbers: \\nRCJC20200714114434086, \\nJCYJ20190808142001745, \\nJCYJ20200812160737002,20180921273B \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[351,453,420,468]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[351,473,914,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the most unique properties of two-dimensional carbides and nitrides of transition metals (MXenes） is their excellent water dispersibility and yet possessing superior electrical conductivity but their industrial-scale applica-tion is limited by their costly chemical synthesis methods. In this work, the niche feature of MXenes was capitalized in the packed-bed electrochemical reactor to produce MXenes at an unprecedented reaction rate and yield with minimal chemical waste. A simple $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ solution was employed as the green electrolyte, which could be used repeatedly without any loss in its efficacy. Surprisingly, both fluoride and ammonium were found to play critical roles in the electrochemical etching, functionalization, and expansion of the layered parent materials (MAXs) through which the liberation of ammonia gas was observed. The electrochemically produced MXenes with excellent conductivity, applied as supercapacitor electrodes, could deliver an ultrahigh volumetric capacity $( 1 4 0 8 \\\\mathrm { F } \\\\mathrm { c m } ^ { - 3 } )$ and a volumetric energy density $( 7 5 . 8 \\\\mathrm { W h } \\\\mathrm { L } ^ { - 1 } )$ ). This revolutionary green, energy-efficient, and scalable electrochemical route will not only pave the way for industrial-scale production of MXenes but also open up a myriad of versatile electrochemical modifications for improved functional MXenes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[351,831,453,842]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KEYWORDS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[349,847,873,860]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"packed-bed electrochemical reactor, electrochemical etching, MXene, supercapacitor \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,956,238,980]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Carbon Energy.2023;5:e295. https://doi.org/10.1002/cey2.295 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[73,905,926,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"iisei the original work is properly cited. $\\\\circledcirc$ 2023 The Authors.Carbon Energy published by Wenzhou University and John Wiley& Sons Australia,Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[870,0,998,19]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[665,956,922,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"wileyonlinelibrary.com/journal/cey2 丨1of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[75,54,191,65]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DOI: 10.1002/cey2.295 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[72,34,532,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 29 August 2022 Revised: 20 September 2022丨Accepted: 4 October 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[75,86,278,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[638,78,922,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CARBON ENERGY WILEY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[75,61,319,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1|INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,95,485,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Benefiting from their unique structure,2D materials are endowed with many extraordinary properties, exceeding their parent bulk materials.1-4 Since 20ll， the twodimensional (2D) transition metal carbides,first discovered by Naguib and Gogotsi et al.,have rapidly become a rising star material amongst the burgeoning 2D materials.The family of 2D transition metal carbides,and the subsequent nitrides and borides (MXenes)，exhibits excellent electrical conductivity,hydrophilicity,diverse chemical functionality, structure,and thickness controllability，which promoted their utilization in a large number of applications, including energy conversion, catalysis,electromagnetic interference shielding,water desalination，biosensor， neural electrodes，andso forth.5-9 To date,over 30 different types of MXenes with varying chemical and physical properties have been synthesized.1° MXenes can be represented by a general formula $\\\\mathbf { M } _ { n + 1 } \\\\mathbf { X } _ { n } \\\\mathbf { T } _ { x }$ $( n = 1 - 3$ )，where M represents early transition metals such as Ti,V, Ta, Cr,Mo,and so forth, and X represents C,N,and B,and $\\\\mathrm { T } _ { x }$ denotes various surface terminations such as -OH, $- \\\\mathrm { F }$ ，and O.5,9,11 MXenes are typically prepared by selective etching of the A atomic layer in MAX $\\\\left( \\\\mathbf { M } _ { n + 1 } \\\\mathbf { A X } _ { n } \\\\right)$ phase precursors, where A is typically a Group 13 or 14 element of the periodic table.12 The multivalent A atom efectively supports the stable parent MAX structure but posts a challenge in its selective removal.13,14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,547,485,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Up to now, following the work of Gogotsi's research team in 2011,15 the use of hydrofluoric acid (HF) or in situ-generated HF solutions to prepare MXenes is still the most preferred synthesis method.However, the cost of managing highly toxic and corrosive HF and its associated chemical waste may be highly challenging at the industrial scale. Although streamlined pilot-scale production of MXenes， with comprehensive safety controls,16-18 has been demonstrated, there is still a strong motivation toward a safe, environmentally friendly,and cost-effective method to reduce the toxic chemical waste,drive down the production cost of MXenes,and realize their wide industrial applicability. In 2020,Lietal.19reported theuseof hightemperature molten salt to selectively etch the A atomic layer. However,due to the lack of hydrophilic functional groups $\\\\left( - \\\\mathrm { O H } / \\\\mathrm { - O } \\\\right)$ ，delaminating the multilayer MXenes prepared by the molten salt method could be a very difficult task.In addition, the high energy consumption and risk associated with high-temperature treatment need to be carefully considered.Concurrently，the electrochemical production route for MXenes has also been preliminarily studied by Pang et al. and Yang et al. where the electrochemical etching of MXenes in acidic and alkaline electrolytes was reported.20,21 Nevertheless, the low production yield and small-scale demonstration with preformed MAX electrodes would not be viable for industrial-scale production. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,62,924,127]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,130,924,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Herein,we report a green,cost-effective,and scalable electrochemical production of MXenes (eMXenes） with high yield,utilizing only aqueous ammonium fluoride $\\\\mathrm { ( N H } _ { 4 } \\\\mathrm { F ) }$ as the electrolyte in a simple two-electrode packedbed electrochemical reactor (PBER). Owing to the conductive nature of MXenes (even after functionalization), the PBER was remarkably successful for MXene production in terms of reaction yield $( 7 2 . 3 \\\\% )$ and rate $( 2 0 6 \\\\mathrm { m g h } ^ { - 1 } )$ . Moreover， we demonstrated the recyclability ofthe electrolyte, the versatility toward Nb-based MXenes, the unintuitive electrochemical etching mechanismwith undissociated $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ ，the scalability of the PBER with inexpensive graphite electrodes,and the application of eMXenes as superior supercapacitor electrodes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,393,875,410]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2| EXPERIMENTAL SECTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,427,677,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1| Materials\",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,461,924,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MAX phase powders $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ ,200 mesh, ${ \\\\tt 2 9 9 \\\\% }$ ， $\\\\mathrm { N b } _ { 2 } \\\\mathrm { A l C }$ and $\\\\mathrm { N b } _ { 4 } \\\\mathrm { A l C } _ { 3 }$ ，200 mesh, $2 9 8 \\\\%$ ）were purchased from Laizhou KaiXi Ceramic material Co., Ltd. Tetramethylammonium hydroxide (TMAOH, $2 5 \\\\mathrm { w t . } \\\\%$ aqueous solutions） and ammonium fluoride $( \\\\mathrm { N H } _ { 4 } \\\\mathrm { F } , \\\\geq 9 8 \\\\% )$ ）were purchased from Sigma-Aldrich.The materials were used directly without any further purification. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,609,794,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2| Synthesis of eMXenes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,644,924,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"eMXenes were synthesized in a PBER under constant current,as first demonstrated in our previous work,2 22 where the conductive boron-doped diamond (BDD)- coated niobium electrode (Diaccon GmBH） was employed as the working electrode and the MAX powder was packed against the BDD under an applied pressure $( 1 \\\\mathrm { k g }$ top load for the small reactor and $2 \\\\mathrm { k g }$ top load for the large reactor). A $\\\\mathrm { P t }$ wire ( $\\\\mathrm { 0 . 2 5 ~ m m }$ diameter) with a length of $3 3 \\\\mathrm { c m }$ (purity $9 9 . 9 9 \\\\%$ ；Goodfellow）was employed as the counter electrode,and the two electrodes were separated by a hydrophilic MCE membrane (pore size $0 . 4 5 \\\\mu \\\\mathrm { m }$ ,MF; Millipore).As a proof of concept on industrial scalability, the BDD and Pt electrodes in large PBER could be replaced by a graphite plate (anode, $1 0 0 \\\\mathrm { m m } \\\\times 2 0 \\\\mathrm { m m } \\\\times 2 \\\\mathrm { m m } )$ and graphite rod (cathode, length: $1 8 0 \\\\mathrm { m m }$ ，diameter: $6 \\\\mathrm { m m }$ ),respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,911,924,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the small PBER,a fixed amount of MAX powder (from 0.1 to $^ { 1 \\\\mathrm { g } ) }$ and $4 \\\\mathrm { m L }$ of the $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ aqueous electrolyte of a specified concentration was pipetted into the reactor. The exposed surface area of the BDD electrode was measured to be $1 . 5 4 \\\\mathrm { c m } ^ { 2 }$ .For the large PBER,a greater quantity of MAX powder (from 1 to $2 0 \\\\mathrm { g }$ was fed in a single batch,with $4 0 \\\\mathrm { m L }$ of the added electrolyte and the exposed surface area of BDD of $8 . 0 0 \\\\mathrm { c m } ^ { 2 }$ . A CHI760E electrochemical workstation （CH Instruments) was employed for the galvanostatic charging (GC) with the limiting voltage set at $3 \\\\mathrm { V }$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[847,29,922,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[72,24,438,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 12 -WILEY-CARBON ENERGY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[75,63,485,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,213,485,310]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The as-synthesized eMXene was dispersed in deionized water with agitation and followed by copious rising through a hydrophilic polyvinylidene difluoride (PVDF) membrane (pore size $0 . 2 2 \\\\mu \\\\mathrm { m }$ ,MF;Millipore). Immediately after rising,the eMXene cake was freeze-dried to remove the residual water. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,343,398,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.3l Delamination of eMXenes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,379,485,742]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The freeze-dried eMXene $\\\\left( 0 . 1 { \\\\bf g } \\\\right)$ was redispersed in $5 0 \\\\mathrm { m L }$ of deionized water,which was subsequently deaerated with argon for $3 0 \\\\mathrm { { m i n } }$ .After that, delamination was achieved by adding $0 . 3 9 3 \\\\mathrm { m L }$ of TMAOH solution (the intercalating agent) and stirring at $3 0 0 \\\\mathrm { r p m }$ for $1 2 \\\\mathrm { h }$ at room temperature. The delaminated product was collected under high-speed centrifugation $( 1 0 , 0 0 0 ~ \\\\mathrm { { r p m } }$ for $1 0 \\\\mathrm { { m i n } } ,$ )，and the clear supernatant was discarded. The sediment was further rinsed twice with centrifuge-wash cycles ( $\\\\mathrm { 1 0 , 0 0 0 ~ r p m }$ for $1 0 \\\\mathrm { { m i n } } ,$ ); it was redispersed in $5 0 \\\\mathrm { m L }$ of deionized water and subjected to sonication in an ice bath under argon protection for $3 0 \\\\mathrm { { m i n } }$ . After sonication, the solution was centrifuged ( $3 5 0 0 ~ \\\\mathrm { r p m }$ for $3 0 \\\\mathrm { m i n } )$ ）and the dispersed eMXene supernatant solution was collected and vacuumfiltered using a hydrophilic PVDF membrane. The eMXene film was freeze-dried and removed from the PVDF membrane for further material characterizations (i.e., X-ray difraction [XRD], X-ray photoemission spectroscopy [XPS],Raman and sheet resistivity measurement).The yield of the delaminated eMXene (DE-MXene) nanosheets was calculated based on the weight ratio of the freestanding eMXene film to the MAX precursor. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,776,315,794]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.4l Characterizations \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,810,484,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The XRD patterns were obtained from a Bruker D8 Advance diffractometer. The step size and the time per step were fixed at $0 . 0 1 ^ { \\\\circ }$ and 5 s，respectively. The morphology and element compositions of MAX phases and eMXenes were characterized using a JEOL JSM-7500FA SEM equipped with an EDS detector (Oxford EDS). The transmission electron microscopy (TEM) photographs were collected from a JEOL F200 electron microscope with energy-dispersive X-ray spectroscopy (EDS). The atomic force microscopy (AFM) characterization was carried out with a Bruker Dimension Icon atomic force microscope in tapping mode. The scanning electron microscopy (SEM) and AFM samples were prepared by spin-coating eMXenes onto a conductive $\\\\mathrm { S i } / \\\\mathrm { S i O } _ { 2 }$ wafer. The X-ray photoelectron spectroscopy (XPS) data was collected using a Kratos Axis Ultra with a monochromatized Al $K _ { \\\\alpha }$ X-ray source.The electrical conductivity of MXene films was measured using a Jandel RM30oo four-point probe system.Raman spectroscopy was performed on a LabRAM HR Evolution Raman microscope equipped with a $5 3 2 \\\\mathrm { n m }$ laser. The gas chromatogram was carried out with Agilent 7890B. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,63,924,294]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,327,852,345]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.5l Activated carbon electrodes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,361,924,478]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The activated carbon electrodes were prepared by mixing YP-50 activated carbon powder (Kuraray） and the polytetrafluoroethylene (PTFE) binder in a 95:5 weight ratio in ethanol. The resultant thick slurry could be continuously rolled into a self-supporting flexible film, the average mass loading of which was measured to be about 12 mg cm-2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,508,781,526]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.6| Electrochemical test \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,544,924,842]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The free-standing $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ MXene film was cut into a discshaped electrode (average active mass loading was between 3.0 and $4 . 2 \\\\mathrm { m g } \\\\mathrm { c m } ^ { - 2 } .$ ）witha diameter of $6 \\\\mathrm { m m }$ The electrochemical performance test was carried out in a Swagelok three-electrode configuration where glassy carbon electrodes were employed as current collectors for the three electrodes, namely, the MXene working electrode, the activated carbon counter electrode,and reference electrode $( \\\\mathrm { A g / A g C l }$ in $\\\\mathrm { { 1 m o l } L ^ { - 1 } \\\\ K C l \\\\mathrm { { } } }$ .For the fabrication of twoelectrode symmetric supercapacitors, two free-standing $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ MXene films of the same size served as electrodes, which were separated by a Celgard 350l membrane. $\\\\mathrm { H } _ { 2 } \\\\mathrm { S O } _ { 4 }$ solution $\\\\left( 3 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\right)$ was adopted as the electrolyte for both types of supercapacitor tests. The electrochemical characterizations, including cyclic voltammetry (CV)，galvanostatic charge-discharge (GCD)，and long-term cycling performance，were also acquired using the CHI760E electrochemical workstation at room temperature. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,843,924,893]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gravimetric capacitance $( C _ { \\\\mathrm { g } } , \\\\ \\\\mathrm { F } \\\\mathrm { g } ^ { - 1 } )$ of the working electrodes can be calculated from the CV profiles using the following equation: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[668,900,766,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0995/eadbdfc7ef6af083b6deb6c6f0f5c589175c1bbf4384b8ed713199b642059647.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nC _ { \\\\mathrm { g } } = { \\\\frac { \\\\displaystyle \\\\int I d V } { \\\\displaystyle \\\\Delta V m s } } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[75,29,151,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[557,25,926,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CARBON ENERGY-WILEY- 3 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[73,62,485,111]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $I ( \\\\mathbf { A } )$ is the current, $m$ is the mass of the electrodes, $s ( \\\\mathrm { V ~ s } ^ { - 1 } )$ is the scan rate,and $\\\\Delta V ( \\\\mathbf { V } )$ is the potential window. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,112,484,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The volumetric capacitance $( C _ { \\\\mathrm { v } } , \\\\ \\\\mathrm { ~ F ~ c m } ^ { - 3 } )$ can be calculated according to the following equation: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[242,158,317,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0843/b48dd3b9c57d717a50555c041c5c55b9476baa5a423def2b54fadc91127b49c6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nC _ { \\\\mathrm { v } } = \\\\rho C _ { \\\\mathrm { g } } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[73,195,484,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\rho ( \\\\mathbf { g } \\\\thinspace \\\\mathrm { c m } ^ { - 3 } )$ is the density of the eMXene film electrode. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,228,485,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Energy density $( E _ { \\\\mathrm { g } } , \\\\mathrm { W h } \\\\mathrm { k g } ^ { - 1 }$ and $E _ { \\\\mathrm { v } }$ ， $\\\\mathrm { W h ~ L ^ { - 1 } }$ ）and power density ( $( P _ { \\\\mathrm { { g } } }$ $\\\\mathbf { \\\\Sigma } _ { \\\\mathrm { g } } ^ { } , \\\\mathbf { W } \\\\mathbf { k g } ^ { - 1 }$ and $P _ { \\\\mathbf { V } }$ ， $\\\\mathrm { ~ W ~ L ~ } ^ { - 1 }$ ）of the two-electrode symmetric supercapacitorscanbe calculated from GCD profiles according to the following equations: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[216,329,342,460]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0809/ff96135346cc55482a133ef72a03caac6ecd62ba2c6a82e1d1695408bc31a402.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { c } { E _ { \\\\mathrm { g } } = \\\\displaystyle \\\\int V I d t / M , } \\\\\\\\ { E _ { \\\\mathrm { v } } = \\\\rho E _ { \\\\mathrm { g } } , } \\\\\\\\ { P _ { \\\\mathrm { g } } = 3 6 0 0 E _ { \\\\mathrm { g } } / \\\\Delta t , } \\\\\\\\ { P _ { \\\\mathrm { v } } = \\\\rho P _ { \\\\mathrm { g } } , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[73,478,485,526]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $V ( \\\\mathbf { V } )$ is the discharge voltage window, $\\\\Delta t$ (s) is the discharge time,and $M ( { \\\\mathrm { m g } } )$ is the total weight of electrode materials. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,560,453,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3I RESULTS AND DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,593,413,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1| Electrochemical production of $\\\\mathbf { T i } _ { 3 } \\\\mathbf { C } _ { 2 } \\\\mathbf { T } _ { x }$ eMXenes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,644,485,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The electrochemical etching of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and its concomitant functionalization process were carried out in a two-electrode PBER,as depicted in Figure 1A (in the photos of Figure S1,the synthetic process is described in detail in the Experimental Section). The aqueous $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte( $\\\\mathrm { \\\\langle p H } = 6 . 2 9 \\\\mathrm { \\\\rangle }$ ）was chosen as the fluoride source due to its low cost and excellent water solubility,which can afford a broad concentration range for fundamental investigation. The typical GC curve (Figure 1C) for electrochemical etching of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ exhibits three distinct stages during the electrochemical reactions: intercalation of anions (Stage I,the initial sharp rise in voltage),etching/ functionalization of MAXs/MXenes (Stage II, the long intermediate plateau steadily climbing from 0.5 to 1.5 V),and water splitting (Stage II, the sharp rise to over $3 \\\\mathrm { V }$ at the end of the reaction). The linear sweep voltammetry of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ MAXs performed at $1 \\\\mathrm { m V s } ^ { - 1 }$ (Figure S2A) revealed that the anodic etching reaction in the $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte could proceed at an increasing rate with increasing voltage from O.5 to $2 \\\\mathrm { v }$ (corresponding to Stage II in the GC curve)，while the etching current dropped sharply above $2 \\\\mathrm { v }$ (at Stage III, water splitting outweighed the etching reaction). The as-prepared eMXene product (denoted as $\\\\mathrm { E } { - } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } )$ showed dark black color in contrast to the metallic color of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ $\\\\mathrm { E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ was further delaminated with TMAOH to obtain a monolayer or a few-layer delaminated eMXene (Dl $\\\\mathrm { E } { \\\\cdot } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } )$ sheets. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,62,924,260]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,294,892,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2 Optimization of key parameters in the electrochemical reaction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,345,924,443]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To achieve a better understanding of the electrochemical reactions,the key experimental parameters (electrolyte concentration,applied current density,and MAX loading) were investigated and optimized in our current PBERs, relying on XRD characterization and the yield of exfoliated MXene flakes as the evaluation criteria.23,24 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,439,924,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The GC plots (Figure S3) in a wide range of $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte concentrations (from 2 to $1 8 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 }$ ）under the same constant current density $( 7 . 8 0 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 } )$ displayed similar charging profiles but with differences in the plateau voltages and total charges consumed. Notably，forlowerconcentrationsof $2 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 }$ (Figure S3), their plateau voltages were higher and the total charge consumed was smaller compared with that of the more concentrated electrolytes $( > 6 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } )$ . These imply that a higher level of electrochemical resistance and incomplete electrochemical reaction may be associated with using lower electrolyte concentrations.Evidently, the XRD patterns of the as-produced products (Figure 2A） showed a significant residual parent MAX phase (at $2 \\\\theta = 3 9 ^ { \\\\circ }$ ）and the yields of exfoliated MXenes (Figure S4) were lower for the lower electrolyte concentrations. When higher electrolyte concentrations $\\\\left( \\\\mathsf { z 6 m o l L } ^ { - 1 } \\\\right)$ ）were employed, successful etching of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ into $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ could be achieved as evidenced by the significant reduction of the parent MAX phase and the shift of the (O02) XRD peak from $9 . 6 ^ { \\\\circ }$ to $7 . 1 ^ { \\\\circ }$ . The XRD peaks at $2 \\\\theta = 3 9 ^ { \\\\circ }$ of the unetched $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ are minimal at concentrations from $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 }$ onwards. In addition, the use of $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ could achieve the highest yield of exfoliated MXenes of $7 2 . 3 \\\\%$ (Figure S4)，which is comparable to the currently reported MXenesynthesis methods.17,23-25 Hence, $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ was selected as the optimal electrolyte condition in this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,24,436,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 12 -WILEY-CARBON ENERGY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[847,28,922,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[142,63,865,418]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE1Schematicdiagramand typical galvanostaticchargingcureof theelectrochemicalproductionofeMXenes.(A)Schematic drawing of the small PBER used to prepare eMXenes in which the parent $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ MAX material was anodically etched and functionalized in the $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ electrolyte under the galvanostatic charging. (B) Schematic drawing of the large PBER and ${ 2 0 \\\\\\\\mathrm { g } }$ freeze-dried $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene product prepared by the large PBER. (C) Typical galvanostatic charging curve for electrochemical etching $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ with three distinct stages, i: intercalationof electrolyte ions,i: etching and functionalization,andi: water spliting on BDDat voltage over $_ { 3 \\\\\\\\mathrm { V } }$ (parameter: small PBER, $_ { 0 . 1 \\\\\\\\mathrm { g } }$ of starting $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ ， $1 0 \\\\\\\\mathrm { m o l } \\\\\\\\mathrm { L } ^ { - 1 } \\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ electrolyte and $7 . 8 0 \\\\\\\\mathrm { m A } \\\\\\\\mathrm { c m } ^ { - 2 }$ constant current density). BDD,boron-doped diamond; $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F } ,$ ，ammonium fluoride; PBER, packed-bed electrochemical reactor. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0225/02b6893237d1d7c676c0c06372e47a8703bc950a76fe6bddd5e508389116f39e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,580,485,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To study the effect of current densities,a series of constant current densities,ranging from 1.30 to $6 4 . 9 6 \\\\mathrm { m A c m } ^ { - 2 }$ ,were employed in our small PBER with $_ { 0 . 1 \\\\mathrm { g } }$ of MAXs $( 0 . 0 7 \\\\mathrm { g } \\\\mathrm { c m } ^ { - 2 } )$ . The corresponding charging curves (Figure S5） share similar cell voltage profiles, consisting of a stable etching voltage plateau followed by a sharp voltage rise, but with varying charge consumed. The XRD results (Figure S6） suggest that efective electrochemical etching could be achieved in this bench-scale PBER (small PBER) when the currents were between 1.30 and $1 9 . 4 9 \\\\mathrm { m A c m } ^ { - 2 }$ .In this range，the production rate of eMXenes (Figure 2B) in our small PBER shows a positive correlation with the applied current, achieving around $2 0 \\\\mathrm { m g h ^ { - 1 } }$ with a good yield $( > 6 0 \\\\% )$ at the current density of $1 9 . 4 9 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 }$ The product yield decreased significantly when the current density exceeded $1 9 . 4 9 \\\\mathrm { m A c m } ^ { - 2 }$ ,and is possibly due to the limitation in electrolyte diffusion in the small PBER and the transition to the water-splitting reaction prematurely. Based on the highest product yield achieved， the current density of $7 . 8 0 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 }$ was selected as the optimum for our small PBER. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,576,848,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3l Characterization of $\\\\mathbf { T i } _ { 3 } \\\\mathbf { C } _ { 2 } \\\\mathbf { T } _ { x }$ eMXenes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,627,924,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The morphological, physical,and chemical properties of the eMXene produced using the optimized parameters (small PBER, $_ { 0 . 1 \\\\mathrm { g } }$ or $0 . 0 7 \\\\mathrm { g c m } ^ { - 2 }$ MAXs, $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 }$ $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ and $7 . 8 0 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 }$ current density) were further investigated. The (O02) characteristic peak of DE- $\\\\mathbf { \\\\nabla } \\\\cdot \\\\mathrm { T i } _ { 3 } \\\\mathbf { C } _ { 2 } \\\\mathbf { T } _ { x }$ in XRD broadened and shifted from $7 . 1 ^ { \\\\circ }$ to $6 . 1 ^ { \\\\circ }$ (Figure S7),indicating the increase in the interlayer spacing of the adjacent $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 }$ layers. The SEM image shows that the $\\\\mathrm { E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ (Figure 3A) had a typical accordion-like morphology, similar to those prepared by chemically etching with HF.7 After delamination, the aqueous dispersion of $\\\\mathrm { D E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ shows Tyndall effect (Figure S8b） and negative zeta potential $( - 4 9 . 3 4 \\\\mathrm { m V }$ ， Figure S8C) lower than those of the products synthesized by using HF to chemically etch,indicative of highly stable colloidal dispersion. The DE- $\\\\mathbf { \\\\nabla } \\\\cdot \\\\mathrm { T i } _ { 3 } \\\\mathbf { C } _ { 2 } \\\\mathrm { T } _ { x }$ solution was vacuum-filtrated into a thin film (Figure S9A) composed of highly aligned, face-to-face packed sheets as seen in the cross-sectional SEM images (Figure S9B-D). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,29,151,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[557,25,926,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CARBON ENERGY-WILEY- 5 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[72,63,631,506]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0671/5c35a21750d2807aff5a2816baf49be957c833a61329387286f79f01788024ef.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[653,60,926,335]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"FIGURE 2Parameter optimization for the electrochemical reaction. (A) XRD patterns of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXene products etched with $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte concentrations range from 2 to $1 8 \\\\mathrm { m o l L } ^ { - 1 }$ (parameter: small PBER, $_ { 0 . 1 \\\\mathrm { g } }$ of the starting material $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and $7 . 8 0 \\\\mathrm { m A } \\\\mathrm { c m } ^ { - 2 }$ constant current density).(B) Yields and production rates of delaminated eMXene $\\\\left( \\\\mathrm { D E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x } \\\\right)$ samples etched with various constant current densities (parameter for small PBER: $_ { 0 . 1 \\\\mathrm { g } }$ of the starting material $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte; parameter for large PBER: $_ { 1 \\\\mathrm { g } }$ of the starting material $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and $1 0 \\\\mathrm { m o l L } ^ { - 1 }$ $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte). $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ ，ammonium fluoride;PBER,packed-bed electrochemical reactor;XRD,X-ray diffraction. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,544,484,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The freeze-dried D $\\\\mathrm { \\\\mathrm { F } { \\\\cdot } T i _ { 3 } C _ { 2 } T } _ { x }$ film has an excellent conductivity $( 1 0 , 4 7 0 \\\\mathrm { S c m } ^ { - 1 } )$ ） slightly higher than those prepared with HF.26,27 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,594,485,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The TEM image in Figure 3B shows the ultrathin nature of DE- $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ flakes,and the insignificant presence of Al from the EDS mapping indicates the successful removal of the Al layers from the parent MAX (Figure S1oA,B). The high-resolution transmission electron microscopy (HRTEM） image (Figure S10C） and its corresponding selected area diffraction (SEAD） pattern (the inset in Figure 3B) confirm that the DE- $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ nanosheets preserved the hexagonal lattice structure during the electrochemical etching and the following delamination. The AFM image (Figure S1l） shows bilayered or trilayered DE $\\\\mathbf { \\\\cdot } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ MXene flakes with a thickness of about $4 \\\\mathrm { n m }$ . The absence of the Al 2p signal in the X-ray photoelectron spectroscopy (XPS） spectra for $\\\\mathrm { E - T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ (Figure 3C and Figure S12A) again confirms the successful electrochemical etching of Al. Deconvolution of the XPS Ti 2p band for $\\\\mathrm { E } { \\\\cdot } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ (Figure S12B and details in Table S1) reveals the presence of several oxidation states of $\\\\mathrm { T i }$ atoms,which were bonded to $\\\\mathrm { T } _ { x }$ $\\\\left( - \\\\mathrm { O } / \\\\mathrm { - O H } \\\\right)$ and $- \\\\mathrm { F }$ termination.28 XPS spectra of C 1s and O 1s confirm the existence of C-Ti-O and C-Ti-OH bonds,and that of F 1s indicates ${ } _ { - \\\\mathrm { F } }$ termination group covalently bonded to $\\\\mathrm { E } { \\\\cdot } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ (Figure Sl2C-E). These results are all consistent with the XPS signal of Ti 2p. Raman spectra of starting materials $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ and $\\\\mathrm { E } { \\\\cdot } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ MXenes show that after electrochemical etching, the characteristic peaks $( \\\\omega _ { 1 } , \\\\omega _ { 2 } ,$ and $\\\\omega _ { 3 , }$ ）of the starting material $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ disappear with the appearance of new characteristic peaks $( \\\\omega _ { 4 } , \\\\omega _ { 5 }$ and $\\\\omega _ { 6 , - }$ from the $\\\\mathrm { E } { \\\\cdot } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\mathrm { x } }$ MXene sample (Figure S13). The emergence of new characteristic peaks can be attributed to the changes in the chemical states of Ti and C atomic layers associated with the removal of Al and the introduction of various termination groups during the electrochemical reaction.29 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,543,924,792]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,826,852,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.4| Electrochemical production of Nb-based eMXenes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,877,924,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Beyond $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\mathrm { x } } ,$ our electrochemical method can be applied to effectively etch $\\\\mathrm { N b } _ { 2 } \\\\mathrm { A l C }$ and $\\\\mathrm { N b } _ { 4 } \\\\mathrm { A l C } _ { 3 }$ MAXs to \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[847,28,922,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[72,25,438,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 12 -WILEY-CARBON ENERGY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[137,65,855,515]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 3Characterization of $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ and $\\\\\\\\mathrm { N b } _ { 4 } \\\\\\\\mathrm { C } _ { 3 } \\\\\\\\mathrm { T } _ { x }$ eMXenes. (A) SEM image of as-produced eMXenes $\\\\\\\\left( \\\\\\\\mathrm { E - T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x } \\\\\\\\right)$ . (B) TEM image of delaminated eMXene (DE- $\\\\\\\\mathrm { T i } _ { 3 } C _ { 2 } \\\\\\\\mathrm { T } _ { x } )$ nanosheets and corresponding SEAD images.(C) High-resolution XPS spectra of Al 2p of $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ and $\\\\\\\\mathrm { E - T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x } .$ (D) XRD patterns of $\\\\\\\\mathrm { N b } _ { 4 } \\\\\\\\mathrm { A l C } _ { 3 }$ MAXs and $\\\\\\\\mathrm { N b } _ { 4 } \\\\\\\\mathrm { C } _ { 3 } \\\\\\\\mathrm { T } _ { x }$ eMXenes (the inset shows the SEM image of as-produced $\\\\\\\\mathrm { N b } _ { 4 } \\\\\\\\mathrm { C } _ { 3 } \\\\\\\\mathrm { T } _ { x }$ eMXenes with a $2 \\\\\\\\mu \\\\\\\\mathrm { m }$ scale bar).SEAD,selected areadifraction; SEM,scanning electronmicroscopy;TEM,transmision electronmicroscopy; XRD, X-ray diffraction. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0327/f2fb91a4f0afea4931b08e7ba92c7c2452a3e86252f70479ad66ab1f3a8fd21b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,644,485,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2D MXenes (the corresponding charging curves are shown in Figure S14)，which typically require high concentrations of HF $( 4 8 \\\\% - 5 1 \\\\% )$ ，long reaction time (more than $9 6 \\\\mathrm { h }$ ),and heating.30-32 Similar to the Tibased MAX, the successful selective etching of both Nbbased MAXs was achieved,as indicated by the disappearance of the sharp XRD peaks of the parent MAX phases and the broadening and weakening of the remaining XRD peaks (see Figure 3D and Figure S15). The electrochemically prepared $\\\\mathrm { N b } _ { 2 } \\\\mathrm { C T } _ { \\\\boldsymbol { x } }$ and ${ \\\\mathrm { N b } } _ { 4 } { \\\\mathrm { C } } _ { 3 } { \\\\mathrm { T } } _ { x }$ MXenes displayed a typical accordion-like morphology in the SEM images (insets in Figure 3D and Figure S15), also consistent with the previous reports of the successful synthesis of $\\\\mathrm { N b } _ { 2 } \\\\mathrm { C T } _ { { \\\\boldsymbol { x } } }$ and $\\\\mathrm { N b } _ { 4 } \\\\mathrm { C } _ { 3 } \\\\mathrm { T } _ { x }$ MXenes.30.32 The elemental analysis by EDS (Figures S16 and S17） and XPS (Figures S18 and S19,Tables S2 and S3) further confirmed that the Al element was successfully removed from the starting materials $\\\\mathrm { N b } _ { 2 } \\\\mathrm { A l C }$ and $\\\\mathrm { N b } _ { 4 } \\\\mathrm { A l C } _ { 3 }$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,643,902,676]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.5l Cost-effectiveness and scalability of PBER \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,695,924,892]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to the huge versatility of PBER,its costeffectiveness and scalability were examined next.At the end of each experiment, the electrolyte from the PBER can be easily recovered, without contamination from the packed MXene product.As a proof of concept, the same $1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\ \\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ electrolyte was recovered and reused for at least five times with a similar level of high reaction yield $( > 7 0 \\\\% )$ maintained (Figure 4A and Figure S20). In addition to the energy efficiency of room temperature electrochemical reaction, the recyclability of the electrolyte is a major green chemistry feature,which will greatly reduce the pollution and cost of chemical wastes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,895,924,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Next, the scalability of the PBER (up to $2 0 \\\\mathrm { g }$ ina single batch） was demonstrated in a laterally upscaled PBER (as shown in Figure 1B and Figure S21). By conductingthe same systematic investigationof current density (Figures S22 and S23) and MAX loading (Figure S24) on the product yield and production rate (Figure 2B), it was found that applying $6 . 2 5 \\\\mathrm { m A c m } ^ { - 2 }$ to the large PBER containing $_ { 1 \\\\mathrm { g } }$ of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ $( 0 . 1 2 5 \\\\mathrm { g c m } ^ { - 2 } )$ could produce the highest yield $( 7 0 . 1 \\\\% )$ of MXene at the rate of $4 3 . 1 \\\\mathrm { m g h } ^ { - 1 }$ . Furthermore, the large PBER could allow the etching of $2 0 \\\\mathrm { g }$ of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ $( 2 . 5 \\\\mathrm { g c m } ^ { - 2 } )$ with similar efectiveness as the small PBER,as evidenced by XRD and SEM (Figures S24 and S25);and the high product yields were maintained ( $6 8 \\\\%$ for $5 { \\\\mathrm { g } }$ and $6 3 \\\\%$ for $2 0 \\\\mathrm { g }$ of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 } ,$ ). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,29,151,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[557,25,926,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CARBON ENERGY-WILEY- 7 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[193,66,800,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 4(A) Yield of $\\\\\\\\mathrm { D E - T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ MXenes prepared by electrochemically etching $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ with different-cycle-time electrolytes or graphite electrodes. (B) Large PBER with graphite electrodes (anode and cathode). (C) XRD patterns of $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene products etched with BBD/graphite electrodes (parameter: large PBER, $_ { 1 \\\\\\\\mathrm { g } }$ and $_ { 2 0 \\\\\\\\mathrm { ~ g ~ } }$ of the starting material $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ ， $1 0 \\\\\\\\mathrm { m o l } \\\\\\\\mathrm { L } ^ { - 1 } \\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ electrolyte and 12. $5 0 \\\\\\\\mathrm { m A } \\\\\\\\mathrm { c m } ^ { - 2 }$ constantcurrentdensity).BDD,boron-dopeddamond;eMXene,electrochemicallyproducedcarbidesandnitridesoftrasition metals; $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ ,ammonium fluoride; PBER,packed-bed electrochemical reactor; XRD,X-ray diffraction. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0705/12f5b054272f06b06838276a8255f5169756e42e4ebdc07404fc59f6161e692f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,595,485,792]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,795,485,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To reduce the cost of PBER and ensure its scalability, the costly BDD and Pt electrodes were replaced by graphite electrodes (plate for anode and rod for cathode, see Figure 4B) in the large PBER. Owing to the relatively low etching potential of MAXs (cell voltage plateau ${ < } 1 . 5 \\\\mathrm { V } )$ ,the graphite electrodes were intact even after repeated use.More importantly，the XRD and SEM results of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXenes ( $_ { 1 \\\\mathrm { g } }$ and $2 0 \\\\mathrm { g }$ ）prepared with graphite electrodes are consistent with those of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ eMXenes prepared with Pt and BDD electrodes (Figure 4C and Figure S25). In addition，eMXenes prepared by graphite electrodes still maintained a high yieldlevel ( $7 2 . 1 \\\\%$ for $_ { 1 \\\\mathrm { g } }$ and $6 7 . 4 \\\\%$ for $2 0 \\\\mathrm { g }$ of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ ， see Figure 4A). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,594,924,694]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,726,820,759]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.6| Electrochemical etching mechanism \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,778,924,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the standard electrode potential series (Table S4)，the selective electrochemical etching of aluminum $\\\\left( E ^ { \\\\mathrm { o } } = - 1 . 6 7 7 \\\\mathrm { V } \\\\right)$ ）with fluoride is thermodynamically more favorable compared with the etching of titanium $( E ^ { 0 } = - 1 . 3 7 0 \\\\mathrm { V } )$ or niobium $( E ^ { 0 } = - 0 . 8 0 0 \\\\mathrm { V } )$ . The electrochemical etching reaction would involve the intercalation and etching of aluminum by the fluoride anion $\\\\left( z = 3 \\\\right)$ in the positively charged MAX electrode:21 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[847,28,922,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[72,25,436,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 of 12 -WILEY-CARBON ENERGY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[141,60,420,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0411/1607504df4b1ff7819572db674fe7ffb841ef3feea128fb215f046c279e5fc18.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 } + 3 \\\\mathrm { F } ^ { - } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } + \\\\mathrm { A l F } _ { 3 } + 3 \\\\mathrm { e } ^ { - }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[73,95,484,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Subsequently， the etched MXene could be elctrochemically fluorinated or oxidized with hydroxyl groups $( z \\\\approx 2 )$ ： \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,158,445,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0219/1aab223e4ae0516243a0844ed416adf139a001b9dbadb5e5fac4bb894f3f5700.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } + x \\\\mathrm { F } ^ { - } + y \\\\mathrm { O H } ^ { - } \\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } ( \\\\mathrm { O H } ) _ { y } \\\\mathrm { F } _ { x } + z \\\\mathrm { e } ^ { - }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[75,213,485,643]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This process is accompanied by expected hydrogen evolution reaction at the Pt cathode (Figure S26 and Table S5) and an unexpected gas from the MAX anode (as evident from the gas bubble evolution), the expansion of MAX packed-bed (Figure S27),and the accordion-like structure of the as-produced product (Figure 3A). In contrast to the well-known role of the fluoride anion, the role of the ammonium cation was surprisingly found to be critical in the electrochemical process as similar concentration $( 1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } )$ of the KF electrolyte was unable to promote the electrochemical etching of MAXs (Figure S28). It was found that ammonia gas $\\\\left( \\\\mathrm { N H } _ { 3 } \\\\right)$ was produced from the MAX electrode,as evident from the increased $\\\\mathsf { p H }$ of the electrolyte and evolution of alkaline gas(only from the MAX electrode) during the electrochemical etching process (Figure S26 and Video S1). Our proposed mechanism is summarized in Figure 5 where there is a significant presence of undissociated ammonium fluoride $( \\\\mathrm { { \\\\sim } 1 . 6 \\\\ m o l \\\\ L ^ { - 1 } }$ ； $K _ { \\\\mathrm { s p } } = 4 4 . 1 7 $ ）in sufficiently concentrated $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ $\\\\left( 1 0 \\\\mathrm { m o l } \\\\mathrm { L } ^ { - 1 } \\\\right) ,$ ),which could be intercalated into the positively charged MAX anode in its uncharged form.In a concerted event following the bond forming between Al and $\\\\mathrm { F ^ { - } }$ (electrochemical） and breaking of the Al-Ti bond, the Ti is expected to extract a proton from $\\\\mathrm { N H } _ { 4 } \\\\mathrm { F }$ ， thus liberating ammonia gas. Progressively，Al would be electrochemically etched away in the form of $\\\\mathrm { A l F } _ { 3 }$ and the etched MAX could be subjected to further electrochemical functionalization as suggested in Equation (2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,62,924,111]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,144,852,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.7lSupercapacitor applications of $\\\\mathbf { T i } _ { 3 } \\\\mathbf { C } _ { 2 } \\\\mathbf { T } _ { x }$ eMXenes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,195,924,644]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\mathrm { x } }$ free-standing membrane was directly utilized as a binder-free electrode for supercapacitors. In a three-electrode setup，the CV of the eMXene electrode at various scan rates (Figure 6A） shows pseudocapacitive charge storage as evident from a pair of broad redox peaks relating to the redox reactions of Ti atoms of multiple valence states.25,26 The GCD profiles of the eMXene electrode at various current densities $( 2 { - } 5 0 \\\\mathrm { A g ^ { - 1 } } )$ also confirm the pseudocapacitive behavior from the nonlinear dependence of voltage with time at constant current (Figure 6B). The eMXene electrode exhibited an ultrahigh gravimetric capacitanceof $3 4 0 . 9 \\\\mathrm { F } \\\\ : \\\\mathrm { g } ^ { - 1 }$ and a volumetric capacitance of $1 4 0 7 . 9 \\\\mathrm { F }$ $\\\\mathrm { c m } ^ { - 3 }$ (Figure S3O) at a scan rate of $2 \\\\mathrm { m V s } ^ { - 1 }$ and even retained excellent gravimetric capacitance $( 1 3 2 . 3 \\\\mathrm { F } \\\\mathrm { g } ^ { - 1 } )$ and volumetric capacitance $( 5 4 6 . 3 \\\\mathrm { F } \\\\mathrm { c m } ^ { - 3 } )$ at a high scan rate of $1 \\\\mathrm { V } \\\\mathrm { s } ^ { - 1 }$ . The long-term cycling test at $2 0 \\\\mathrm { A g } ^ { - 1 }$ ,as shown in Figure 6C,demonstrates that the high capacitance of the eMXene electrode was maintained with a high Coulombic efficiency $( > 9 0 \\\\% )$ over at least 15,000 cycles.When applied to a two-electrode symmetric supercapacitor， the eMXene-based electrode could maintain its excellent energy storage performance (as depicted in Figure 6D and Figures S31-S33), including high volumetric capacitance $\\\\left( 3 2 5 \\\\mathrm { F c m } ^ { - 3 } \\\\right.$ at $2 \\\\mathrm { m V s } ^ { - 1 } )$ and volumetric energy densities across a broad range of powerdensities(seeFigure 6D). Thesuperior electrochemical performances of the eMXene electrode are attributed to the larger interlayer spacing in the freestanding eMXene membrane $( 1 . 4 3 \\\\mathrm { n m } )$ compared with those chemically etched by HF $( 1 . 3 6 \\\\mathrm { n m } )$ ,23 resulting in more accessible and faster movement of ions during the charge and discharge processes. In addition, the high electrical conductivity of the eMXene electrode also contributed to the rapid charge transfer. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,675,894,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG URE 5Electrochemical etching mechanism.(A) Initial state with dissociated and undissociated $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ on the $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { A l C } _ { 2 }$ surface. (B) Anodic etching reaction, $\\\\\\\\mathrm { F ^ { - } }$ ion bond with Al with electron transfer and concerted extraction of H from undissociated $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ by Ti. (C) Bond breaking between Al-Ti and $_ \\\\\\\\mathrm { N - H }$ resulted in liberation of $\\\\\\\\mathrm { N H } _ { 3 }$ gas.(D) Subsequent progression of concerted electrochemical etching with $\\\\\\\\mathrm { F ^ { - } }$ ions and proton transfer from undissociated $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ $\\\\\\\\mathrm { N H } _ { 3 }$ ,ammonia; $\\\\\\\\mathrm { N H } _ { 4 } \\\\\\\\mathrm { F }$ ，ammonium fluoride. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0880/aa34cbc3b87bbee89237b6835a07c3b2cf1010b41dcbd2ebfbd153114e7a8cb8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,28,151,38]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[557,24,926,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CARBON ENERGY-WILEY- 9 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[151,63,848,492]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 6Electrochemical performance of $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene electrodes in supercapacitors.(A) CV curves of the $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene electrode in asymmetric supercapacitors at different scan rates. (B) Galvanostatic charge/discharge curves of the $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene electrode in asymmetric supercapacitors at different current densities.(C) Cycling performance of the $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene electrode in asymmetric supercapacitors at a current density of $2 0 \\\\\\\\mathrm { A g ^ { - 1 } }$ .(D) Ragone plot showing volumetric energy and power densities of the $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ eMXene two-electrodesymmetric supercapacitor in comparison withdata reported in theliterature: $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x }$ and $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x } / \\\\\\\\mathrm { r G O } , ^ { 2 }$ wavy $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { \\\\\\\\boldsymbol { x } _ { 3 } } { } ^ { 3 }$ 3 $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x } /$ conducting polymer,34 $\\\\\\\\mathrm { T i } _ { 3 } { \\\\\\\\bf C } _ { 2 } \\\\\\\\mathrm { T } _ { x } / { \\\\\\\\bf K } _ { 2 } { \\\\\\\\bf S } { \\\\\\\\bf O } _ { 4 } .$ 35 $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { x } /$ mesoporous carbon,36 macroporous $\\\\\\\\mathrm { T i } _ { 3 } \\\\\\\\mathrm { C } _ { 2 } \\\\\\\\mathrm { T } _ { \\\\\\\\boldsymbol { x } , } { } ^ { 3 7 }$ and $\\\\\\\\mathrm { T i _ { 3 } C _ { 2 } T _ { \\\\\\\\it x } / H _ { 2 } S O _ { 4 } + K I }$ .38 cV, cyclic voltammetry. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0150/ae6f6a87dafa11c4a314d763e930793cebc842d56d74f9a51a742ec976241d5c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,661,484,792]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,661,924,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"instrumental for anodic etching, the role of ammonium is also crucial in supplying the hydride intermediate through the liberation of ammonia gas.The excellent quality of eMXenes has been extensively characterized, and its superior electrochemical properties in supercapacitor application have been demonstrated. It is noteworthy that the performance of our PBER can be further improved through the engineering of the electrochemical reactor, electrochemistry of the electrolyte,and advanced electrochemical techniques. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,826,289,842]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4l CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,860,485,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From our investigation,it is clear that the electrochemical approach in etching MAXs and producing functional MXenes in our PBER is promising for a truly green and cost-effective industrial-scale production.Although the fluoride anion in the electrolyte (ammonium fluoride) is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,845,741,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGEMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,861,924,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was financially supported by the Australian Research Council (FT200100015 and DP190100120), Griffith University PhD Scholarships，National Key Research and Development Program (2021YFA1600800), and Shenzhen Science and Technology Program (RCJC-\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[847,28,922,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[73,24,443,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 of 12 -WILEY-CARBON ENERGY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[73,63,487,94]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"20200714114434086，JCYJ20190808142001745，JCYJ2020- \\n0812160737002, 20180921273B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,112,329,126]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CONFLICTS OF INTEREST \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,130,393,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare no conflicts of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,163,139,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORCID \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,180,485,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Zimo Huang $\\\\textcircled{1}$ https://orcid.0rg/0000-0003-0048-8950 \\nJiadong Qin $\\\\textcircled{1}$ http://orcid.0rg/0000-0001-7648-0221 \\nKelin He $\\\\textcircled{1}$ https://orcid.0rg/0000-0003-1245-6868 \\nHao Chen $\\\\textcircled{1}$ https://orcid.0rg/0000-0002-0252-7530 \\nHui Ying Hoh $\\\\textcircled{1}$ https://orcid.0rg/0000-0001-8761-5523 \\nMunkhbayar Batmunkh $\\\\textcircled { 1 0 }$ https://orcid.org/0000-0002- \\n7493-4186 \\nTania M. Benedetti $\\\\textcircled{1}$ https://orcid.org/0000-0002- \\n4835-9384 \\nQitao Zhang $\\\\textcircled{1}$ https://orcid.0rg/0000-0002-8817-0033 \\nChenliang Su $\\\\textcircled{1}$ https://orcid.0rg/0000-0002-8453-1938 \\nShanqing Zhang $\\\\textcircled{1}$ http://orcid.0rg/0000-0001-5192-1844 \\nYu Lin Zhong $\\\\textcircled { 1 0 }$ http://orcid.0rg/0000-0001-6741-3609 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,413,205,427]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,428,489,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1．Xu M，Liang T,Shi M,Chen H.Graphene-like twodimensional materials. 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Chem Mater.2017;29(18):7633-7644. \\n8.Aslam MK,Niu Y,Xu M.MXenes for non-lithium-ion (Na,K, Ca,Mg,and Al) batteries and supercapacitors.Adv Energy Mater. 2021;11(2):2000681. \\n9. Gogotsi Y，Anasori B.The rise of MXenes.ACS Nano. 2019;13(8):8491-8494. \\n.0．NatuV,Pai R, Sokol M,Carey M,Kalra V,Barsoum MW.2D $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\mathrm { z } }$ MXene synthesized by water-free etching of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { A l C } _ { 2 }$ in polar organic solvents. Chem. 2020;6(3):616-630. \\n.1． Shahzad F,Alhabeb M,Hatter CB,et al.Electromagnetic interference shielding with 2D transition metal carbides (MXenes). Science.2016;353(6304):1137-1140. \\n.2. 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Safe synthesis of MAX and MXene: guidelines to reduce risk during synthesis. ACs Chem HealthSaf. 2021;28(5):326-338. \\n19．Li Y, Shao H, Lin Z,et al.A general Lewis acidic etching route for preparing MXenes with enhanced electrochemical performance in non-aqueous electrolyte.Nat Mater. 2020;19(8):894-899. \\n20．Pang S-Y,Wong Y-T, Yuan S,et al. Universal strategy for HFfree facile and rapid synthesis of two-dimensional MXenes as multifunctional energy materials. J Am Chem Soc. 2019; 141(24):9610-9616. \\n21. Yang S, Zhang P, Wang F, et al. Fluoride-free synthesis of twodimensional titanium carbide (MXene） using a binary aqueous system.Angew Chem Int Ed.2018;130(47):15717-15721. \\n22. Lowe SE, Shi G, Zhang Y,et al. Scalable production of graphene oxide using a 3D-printed packed-bed electrochemical reactor with a boron-doped diamond electrode. ACS Appl Nano Mater. 2019;2(2):867-878. \\n23.Huang X,Wu P.A facile,high-yield,and freeze-and-thaw-assisted approach to fabricate MXene with plentiful wrinkles and its application in on-chip micro-supercapacitors. Adv Funct Mater.2020;30(12):1910048. \\n24.Han F,Luo S,Xie L,et al. Boosting the yield of MXene 2D sheets via a facile hydrothermal-asssted intercalation.ACS Appl Mater Interfaces. 2019;11(8):8443-8452. \\n25． Ghidiu M, Lukatskaya MR, Zhao M-Q, Gogotsi Y,Barsoum MW. Conductive two-dimensional titanium carbide “clay'with high volumetric capacitance.Nature.2014;516(7529):78-81. \\n26.Yan J， Ren CE, Maleski K, et al. Flexible MXene/graphene films for ultrafast supercapacitors with outstanding volumetric capacitance.Adv Funct Mater.2017;27(30):1701264. \\n27．Wan S,Li X,Chen Y,etal.High-strength scalable MXene films throughbridging-induceddensification.Science. 2021; 374(6563):96-99. \\n28.Halim J,Cook KM,Naguib M,et al. X-ray photoelectron spectroscopy of select multi-layered transition metal carbides (MXenes).Appl Surf Sci. 2016;362:406-417. \\n29. Sarycheva A,Gogotsi Y. Raman spectroscopy analysis of the structure and surface chemistry of $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { x }$ MXene. Chem Mater. 2020;32(8):3480-3488. \\n30． Zhao S,Meng X, Zhu K,et al. Li-ion uptake and increase in interlayer spacing of $\\\\mathrm { N b } _ { 4 } \\\\mathrm { C } _ { 3 }$ MXene. Energy Stor Mater. 2017;8: 42-48. \\n31． Mashtalir O, Lukatskaya MR, Zhao MQ, Barsoum MW, Gogotsi Y. Amine-assisted delamination of $\\\\mathrm { N b } _ { 2 } \\\\mathrm { C }$ MXene for Li-ion energy storage devices.Adv Mater.2015;27(23):3501-3506. \\n32.Li X, Ma X, Hou Y,et al. Intrinsic voltage plateau of a $\\\\mathrm { N b } _ { 2 } \\\\mathrm { C T } _ { \\\\mathrm { x } }$ MXene cathode in an aqueous electrolyte induced by highvoltage scanning. Joule. 202l;5(11):2993-3005. \\n33.Li K,Wang X,Wang X,et al． All-pseudocapacitive asymmetric MXene-carbon-conducting polymer supercapacitors. Nano Energy. 2020;75:104971. \\n34.Li K,Wang X,Li S,et al. An ultrafast conducting polymer $@$ MXene positive electrode with high volumetric capacitance for advanced asymmetric supercapacitors. Small. 2020;16(4): \\n1906851. \\n35.Lukatskaya MR,Mashtalir O,Ren CE,etal. Cation intercalation and high volumetric capacitance of two-dimensional titanium carbide.Science.2013;341(6153):1502-1505. \\n36. Allah AE,Wang J，Kaneti YV，et al. Auto-programmed heteroarchitecturing: self-assembling ordered mesoporous carbon between two-dimensional $\\\\mathrm { T i } _ { 3 } \\\\mathrm { C } _ { 2 } \\\\mathrm { T } _ { \\\\mathrm { x } }$ MXene layers. Nano Energy.2019;65:103991. \\n37.Yao M,Chen Y,Wang Z,et al. Boosting gravimetric and volumetric energy density via engineering macroporous MXene films for supercapacitors. Chem Eng J. 2020;395: \\n124057. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,72,926,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,28,151,38]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[551,25,926,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CARBON ENERGY-WILEY- 11 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[73,63,485,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,63,924,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"38. Tian Y,Yang C,Luo Y,et al.Understanding MXene-based “symmetric” supercapacitors and redox electrolyte energy storage.ACS Appl Energy Mater.2020;3(5):5006-5014. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,130,798,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUPPORTING INFORMATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,147,924,194]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Additional supporting information can be found online in the Supporting Information section at the end of this article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[534,231,904,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"How to cite this article: Huang Z, Qin J, Zhu Y, et al. Green and scalable electrochemical routes for cost-effective mass production of MXenes for supercapacitor electrodes. Carbon Energy.2023;5: e295. doi:10.1002/cey2.295 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,24,443,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 of 12 -WILEY-CARBON ENERGY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[847,28,922,37]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HUANG ET AL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1002/cey2.295"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Chemistry/Materials Science and Engineering"},"sha256":{"kind":"string","value":"480206f849e659023f03443f64f75ce5f567207c153ca5ed8fefb573baaaa05b"},"title":{"kind":"string","value":"Green and scalable electrochemical routes for cost‐effective mass production of MXenes for supercapacitor electrodes"}}},{"rowIdx":149,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Yong Liu|Shusen Cheng|Tong Liu"},"content_list":{"kind":"list like","value":[{"bbox":"[70,84,880,137]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effects of Entrained Slag Droplets on Slag-Metal Interface in A Gas-Stirred Ladle ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,171,423,187]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Yong LIU, $^{1)}$ Shusen CHENG $^{1)*}$ and Tong LIU $^{2)}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,198,924,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1) School of Metallurgical and Ecological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing, 100083 P. R. China. \",\"2) School of Material Science and Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing, 100083 P. R. China. \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[144,256,845,282]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Received on April 2, 2022; accepted on March 10, 2023; J-STAGE Advance published date: March 21, 2023) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[129,316,868,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study explores the underlying mechanism between secondary refining efficiency, gas flow rate, and slag properties. The secondary refining efficiency is directly affected by the slag-metal interface area. Traditionally, the slag-metal interface has been limited to the liquid-liquid interface of the ladle cross-section and does not include the interface area between the entrained slag droplets and metal. To investigate the interface area with different slags and metals under various bottom blow rates, a physical model of a single-nozzle gas-stirred ladle was established using oil to simulate slag and water to simulate metal. The roles of relevant variables that affect the volume of entrained oil, the diameter of entrained droplets, and interface area were studied, as well as oil viscosity, interfacial tension, and oil thickness. Experimental data were collected using colorants and image processing techniques. Based on these findings, the increase in gas flow rate and oil layer thickness increased the volume of entrained oil and interface area, while the increase in oil viscosity and interfacial tension decreased these parameters. When the gas flow rate increased, the mean diameter of droplets first increased and then decreased. However, the specific surface area of droplets revealed the opposite trend. Furthermore, the mean diameter and specific surface area increased and decreased with increasing oil-layer thickness. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[129,508,865,536]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KEY WORDS: secondary refining; slag-metal interface; physical model; entrained slag droplets; specific surface area. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,605,194,618]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,626,480,697]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the secondary refining process, desulfurization is mainly dominated by the slag-metal interaction, $^{1-3)}$ which determines the area of the slag-metal interface and subsequently, affects the slag forming rate and desulfurization efficiency. $^{4)}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,697,480,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The desulfurization rate as given by Ahindra<sup>5)</sup> is revealed as Eq. (1) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[169,733,480,766]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n- \\frac {d [ W _ {S} ]}{d t} = k _ {S} \\frac {A}{V} \\left([ W _ {S} ] - \\frac {(W _ {S})}{L _ {S}}\\right) \\dots \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[68,769,480,856]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $[W_{s}]$ and $(W_{s})$ refer to the sulfur content in metal and slag (wt%), respectively, $k_{s}$ is the mass transfer coefficient of sulfur $(\\mathrm{m / s})$ , $A$ is the interface area $(\\mathrm{m}^2)$ , $V$ is the volume of metal $(\\mathrm{m}^3)$ , and $L_{s}$ is the distribution coefficient of sulfur. Equation (1) indicates that the desulfurization rate[6,7] is directly proportional to the interfacial area when the slag ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,599,675,612]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"has suitable properties. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,612,926,812]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Several researchers $^{1-3)}$ have attributed this to desulfurization, which mainly occurs at the initial slag-metal interface. However, owing to the influence of force imbalance, Kelvin-Helmholtz instability and Rayleigh-Taylor instability, the slag-metal boundary can become unbalanced, resulting in slag droplets entering the molten metal. Generally, the interface area can be increased by increasing the intensity of interface fluctuation and entrainment volume in the ladle. Mainly, the slag-metal interface fluctuation and entrainment phenomenon in the ladle cause an increase in the interface area. Moreover, Mietz et al. $^{8,9)}$ demonstrated that droplet emulsification was responsible for the acceleration of mass transfer. The entrainment phenomenon in the ladle directly led to improves desulfurization refining efficiency. $^{10)}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,812,926,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the 1850s, entrainment was proven to occur as slag droplets were found in molten metal.[11] Currently, the research on the entrainment phenomenon in the ladle is mainly performed with the help of industrial practice, physical simulations, and numerical simulations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[586,28,926,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6, pp. 1017-1024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[573,43,926,57]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.2355/isijinternational.ISIJINT-2022-164 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,873,426,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"* Corresponding author: E-mail: chengsusu@metall.ustb.edu.cn ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[70,910,178,938]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CC BY NC ND ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[189,912,820,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Iron and Steel Institute of Japan. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs license (https://creativecommons.org/licenses/by-nc-nd/4.0/). ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[480,956,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1017 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[68,70,482,468]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the cold model research, Iguchi et al. $^{12)}$ established an empirical relationship for ladle entrained slag. This relationship is affected by the phase physical properties, ladle size, and gas flow rate. In addition, it was demonstrated that the kinematic viscosity of the slag has a significant effect on the critical velocity required for entrainment. $^{13)}$ Jönsson et al. $^{14)}$ further proved that slag viscosity is a key factor affecting slag entrainment. By establishing a cold model of the water-oil system, Dayal and Du et al. $^{15,16)}$ found that the shear force between the liquid slag and liquid steel played an important role in the slag metal mixing process. Industrial experiments revealed that, slag droplets appeared in the molten metal, and a thin metal film was present around the slag. It was once again proven that the slag droplets can be entrained into the molten metal. $^{15)}$ Simultaneously, a sphere-bed phenomenon appeared near the open-eye and affected the removal methods of inclusions. $^{16)}$ Petri and Jari et al. $^{17,18)}$ used a simplified physical model of a water-oil system to study the entrainment behavior in the ladle. The mean droplet size in the system is $2 - 3\\mathrm{mm}$ . The critical velocity required for emulsification and the diameter of the entrained oil droplets increased as the oil viscosity, interfacial tension, and oil layer thickness increased. An increase in the density difference caused the critical velocity and droplet diameter to increase and decrease, respectively. The critical speed findings were also confirmed by Kitamura. $^{19)}$ In addition Visuri et al. $^{20)}$ reported that the droplets were smaller than the bubbles. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,470,480,669]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Numerical simulations have been increasingly applied in research studies with advancements in calculation methods and capabilities.[21,22] For example, several researchers[17,23-27) have used the Volume of Fluid (VOF) to capture the slagmetal interface. Singh et al.[28) found that the interfacial area first increased and then decreased with the increase in gas flow rate. Petri and Visuri et al.[25) identified that the droplets Sauter diameter was between 4 and $6\\mathrm{mm}$ and the generation rate of the interfacial area between 0.2 and $0.6\\mathrm{m}^2\\cdot \\mathrm{s}^{-1}$ . With numerical simulation methods (VOF), it can be difficult to reproduce the entrainment phenomenon, and large model scales have the difficulty of limited computing powers or numerical methods. Through water-oil system experiments, similarities in the physical sense can be achieved. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,670,482,771]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thus, this report aims to contribute to understanding the main factors that influence slag-metal interactions during the secondary refining process. A physical model was developed to study the influence of slag layer thickness, gas flow rate, slag viscosity and interfacial tension on entrainment volume, diameter distribution of entrained slag, interfacial area, and specific interface area. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,791,205,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Experimental ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,812,203,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1. Experiment ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,827,482,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study was carried out using a physical model, developed based on the similarity principle according to a refining 120 t ladle used in practice. The dimensions of the 1:6 scaled-down model and fluid were determined based on the modified Froude.[29] Equation (3) was used to determine the gas flow in the current model with one tuyere. The dimensions of the cold model and experimental setup are displayed in Fig. 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[658,76,926,111]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF r ^ {\\prime} = \\frac {\\rho_ {l}}{\\rho_ {l} - \\rho_ {g}} \\frac {v ^ {2}}{g H}. \\tag {2}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[581,127,926,175]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nQ _ {m} = \\left[ \\left(\\frac {\\rho_ {g , p}}{\\rho_ {g , m}}\\right) \\left(\\frac {\\rho_ {l , m}}{\\rho_ {l , p}}\\right) \\left(\\frac {d _ {m}}{d _ {p}}\\right) ^ {4} \\left(\\frac {H _ {m}}{H _ {p}}\\right) \\right] ^ {\\frac {1}{2}} Q _ {p} \\dots \\dots \\dots \\tag {3}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,185,926,298]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $Fr'$ is the modified Froude number, $\\rho_l$ and $\\rho_g$ are the densities of liquid and gas respectively $(\\mathrm{kg} / \\mathrm{m}^3)$ , $\\nu$ is the gas velocity $(\\mathrm{m} / \\mathrm{s})$ , $g$ is the acceleration due to gravity $(\\mathrm{m} / \\mathrm{s}^2)$ , $H$ is the characteristic length $(\\mathrm{m})$ , $d$ is the diameter of tuyere $(\\mathrm{m})$ , $Q$ is the gas flow, and the subscripts $m$ and $p$ refer to the model and prototype, respectively. The maximum gas flow rate used in the cold model is 9 L/min. The flow interval used in the experiment was 1 L/min. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,299,927,429]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A high-speed camera with a resolution of $1280 \\times 1024$ and a maximum frame rate of 200 FPS (frames per second) was used for experimental recording. The data were saved at 15 FPS. Before starting the experiment, the mixture of water and oil was allowed to stand to ensure that the water and oil did not dissolve in each other. The gas flow rate in each experiment was controlled by a gas flowmeter. The camera started recording when the bottom blow and the bath flow were stable. Each experiment was repeated five times. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,441,752,456]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1.1. Area Analysis of Slag-eye ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,456,926,586]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open-eye formation in a gas stirred ladle has been the subject of many studies, including physical $^{30-32}$ and numerical modeling studies. $^{31,33}$ Ten pictures were recorded using the camera when the open-eye shape was relatively stable. Image processing and a non-dimensionalized process were used to obtain the resulting differential open-eye area. The open-eye area was evaluated using the ImageJ software, and an example of a processed image is displayed in Fig. 2. The open-eye ratio was calculated using the following equation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[690,592,926,621]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nR _ {e} = \\frac {S _ {e}}{S _ {a}} \\dots \\tag {4}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,626,927,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Where $S_{e}$ and $S_{a}$ are the open-eye area and total area of the oil layer surface, respectively. For a certain gas flow rate, the average was recorded as the final open-eye rate, reducing experimental errors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,697,860,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1.2. Droplets Analysis of the Entrainment Slag ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,712,926,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Different droplet sizes were formed when the slag was entrained into the metal phase during blowing. To analyze the size distribution of the droplets in the bath, ImageJ was used to determine the droplet diameter, $d_{i}$ . The mean diameter can be written as Eq. (5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[673,790,926,822]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nd _ {m} = \\frac {1}{n} \\sum_ {i = 1} ^ {n} d _ {i} \\dots \\tag {5}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,826,927,870]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $d_{m}$ is the mean diameter, and $i$ is the number of statistical droplets. The average number can be expressed by Eq. (6). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[663,875,926,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn = \\operatorname {I N T} \\left(\\frac {6 V _ {e}}{\\pi d _ {m} ^ {3}}\\right) \\dots \\tag {6}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,910,927,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $V_{e}$ is the volume of entrained oil, which is measured indirectly using the drawer principle. A circular baffle was ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[359,38,636,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,954,161,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[480,954,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1018 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[144,71,853,304]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \",\"(b) \"]","image_footnote":"[]","img_path":"images/0978/05476df1c2dee4e08fa909bbc86a1899b3771247b57b55cc0364173fde7eb177.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[142,370,319,498]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. (a) cold model size and (b) experiment setup. \"]","image_footnote":"[]","img_path":"images/0119/ab587aee610b99072edf53cc89338a8cce6e967a5e9ba5c2f8f1112b57fe9db0.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[327,370,504,498]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0163/0f4d18c4aba9f94b13c7e24ad6b60c03a97eedab430d1f1b07c8a22ee8971e61.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[510,374,675,495]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0135/729786012ff193f36c1f684029520d510333b3e5f5d74a9dda1d27fdeff1ef1d.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[684,372,855,495]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \",\"(b) \",\"Fig. 2. The contour of eye-opening image processing for the oil layer thickness is $15\\\\mathrm{mm}$ when the gas flow rate are (a) $1\\\\mathrm{L / min}$ and (b) $3\\\\mathrm{L / min}$ . \"]","image_footnote":"[]","img_path":"images/0176/8691778ef26a0c1e5d5cd2de3ab1001bc022e554b7dbf1cc5788c14a833022c9.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[216,594,781,688]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0521/4c152acabce1419e2035e560eb0b882a520aa57f6adee4224bff06ded7ec6a42.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>Parameters</td><td>Water</td><td>3# white oil</td><td>100# white oil</td><td>200# white oil</td></tr><tr><td>Density, g·cm-3</td><td>0.98</td><td>0.76</td><td>0.80</td><td>0.81</td></tr><tr><td>Viscosity, mPa·s</td><td>3</td><td>8.9</td><td>93.3</td><td>193.5</td></tr><tr><td>Surface tension, mN·m-1</td><td>72.75</td><td>33.10</td><td>35.24</td><td>34.38</td></tr><tr><td>Water-oil interfacial tension, mN·m-1</td><td>-</td><td>40.02</td><td>42.05</td><td>47.25</td></tr></table>","table_caption":"[\"Table 1. Physical property of the fluids. \"]","table_footnote":"[\"Note: measured value \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[68,727,480,769]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"installed on one side of the ladle at the water-oil interface. Under quasi-stable conditions, the oil layer separated from the entrainment droplets when the baffle was quickly pushed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,770,480,827]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The total surface area of the droplets can be approximated by using Eq. (7). To evaluate the chemical reaction rate or mass transfer rate, the specific surface area was utilized. The specific surface area is represented by Eq. (8). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[236,834,480,850]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nA _ {d} = n \\pi d _ {m} ^ {2}. \\tag {7}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[247,864,480,892]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\na = \\frac {A _ {d}}{V _ {e}} \\dots \\tag {8}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[68,897,480,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Where $A_{d}$ is the interface area of the slag droplets $(\\mathrm{dm}^2)$ , and $a$ is the specific interface area $(\\mathrm{dm}^2/\\mathrm{L})$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,727,794,740]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2. Physical Property Measurement ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,741,926,810]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The physical property parameters used to simulate the metal phase, and slag phase are illustrated in Table 1. To ensure the precision of test, the experiment was carried out by performing the following points at a room temperature of $25^{\\circ}\\mathrm{C}$ : ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,812,926,840]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1) To precisely control the temperature of the liquid to be tested, often a water bath. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,840,926,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"2) Ensure the uniformity of liquid. \",\"3) Ensure the cleanness of the structure of the instrument. 4) Judge the measurement result by the standard sample. \",\"The densities of fluids used in the current study were measured by the balance measuring cylinder method. Due to the importance of viscosity and interfacial tension of fluids, the measurement details were thus focused. The \"]","page_idx":"2","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[361,38,636,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[480,956,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1019 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,956,924,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,71,480,112]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MZ-NDJ-5S rotary viscosimeter was used to measure the fluid viscosity in the experiment. When measuring, carries on the operating steps. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,114,480,255]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1) The measured liquid, ready to put measured liquid, is not less than $60~\\\\mathrm{mm}$ in diameter, height not less than 120 mm beaker. \",\"2) On the rotor protection, after carefully adjusting the level of the instrument, ensure instrument in the level of work state. \",\"3) Reference range table, select the adaptation of rotor screwing in rotor connecting head. \",\"4) Slowly adjust elevator knob, and adjust the rotor in the measured liquid level. \"]","page_idx":"3","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[68,256,480,311]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Also, based on the du Noüy ring method, the interfacial tension was measured by the DCAT21 tensiometer. In interfacial tension measurements, the main steps need to be followed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,313,480,426]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1) The ring is first immersed in the denser phase which is water. Then the less dense liquid is poured on top. \",\"2) Care must not contaminate the ring when pouring the liquid. \",\"3) The measurement is then started, and the sample stage with the liquid container is moved down. \",\"4) When the ring is at the interface, the software will detect that automatically and continue to move the stage \"]","page_idx":"3","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[514,71,818,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"down until the detected force starts to drop. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,105,714,118]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results and Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,128,843,141]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. Physical Property Measurement Result ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,143,926,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Measurements were repeated five times to reduce errors, and the average value was calculated. The measurement error bar of physical property parameters is illustrated in Fig. 3. Overall, the results of this measurement suggest excellent reliability and acceptable measurement errors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,228,786,241]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Slag Entrainment Phenomenon ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,242,926,428]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the experiment, the oil was dyed red to facilitate analysis. Interestingly, many oil droplets were formed in the water phase due to shear effects at the interface. Furthermore, a sphere-bed of entrained droplets was formed when the droplets floated up to the interface, as depicted in Fig. 4. This phenomenon was reported in a study by Kang et al. (16) (Fig. 4(c)). When droplet formation, combination, and breakage are balanced, the sphere-bed maintains its thickness during the blowing process. The sphere-bed formation not only sharply increased the interfacial area but also changed the morphology of the water-oil interface. In addition, at a gas flow rate of $6\\mathrm{L / min}$ , a water droplet wrapped with an oil film was observed in the water-oil ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[161,458,489,642]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0386/38ed5f2acb9948199ad47290c28e1400588cfb258fa1b33ef5f236215d98ad55.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[514,455,836,643]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0277/3a7e8f228a5948dbb2b80d1516733a7f386ce234c0f0d4aab704e697265c6502.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[171,690,480,879]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0973/715c6a5ca210871c156cafb49e1eef50bf3ec73a6d5edf00ba2f4ceb682f085f.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,690,830,879]","code_body":null,"code_caption":null,"image_caption":"[\"(d) \",\"Fig. 3. Physical property parameters measurement error bar. (a) Density, (b) viscosity, (c) surface tension, (d) water-oil interfacial tension. \"]","image_footnote":"[]","img_path":"images/0637/91381bc62d721770d72c9156f898b92477b3555f5af6d82a776d8061b6dcdbc4.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[359,38,636,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,954,161,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[480,954,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1020 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[157,71,381,200]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0969/d7088143d624df3b0913fc6ebd389a109342e4896e39c7c0d75b594aaa90f52b.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[383,71,608,200]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0323/9706047bc3320f0409f390dae0f2d0f98021e3e1d0677a3dd08dfd84b594da58.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[611,71,836,199]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \",\"Fig. 4. Entrainment and sphere-bed phenomenon. (Online version in color.) \"]","image_footnote":"[]","img_path":"images/0410/7028243d6311bb2c4fa9c43b3ce747e882dd42dc341fcff96a86eaba62760312.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[68,269,482,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"system (Fig. 4(b)). It provided almost twice the interfacial area than oil droplets of the same size. However, it was noted that the water droplet did not appear when the gas flow rate was relatively small (Fig. 4(a)) $3\\mathrm{L / min}$ ). In reality, the interface interaction and mass transfer efficiency between slag and molten metal would be further increased if the metal droplets were wrapped by slag, but this was not favorable for yield. As a result, metal entrainment into the slag should be controlled carefully in different stages of the refining process, given the factors discussed in the following section. Furthermore, the experiment demonstrated that the bubbles generated by bottom blowing caused quasi-periodic tangential pulsation of liquid metal at the oil-water interface (Fig. 4(b)). Slag-metal interface instability occurred when the bubbles indirectly went through the interface and broke up at the air surface. This fluctuation phenomenon also causes the appearance of water droplets. Further research is required to investigate the complexity of this instability. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,541,186,555]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. Open-eye ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[72,556,482,843]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To investigate the open-eye formed by the bottom blowing plume, the flow rates, and slag layer thickness were considered, as displayed in Fig. 5. Generally, the open- eye ratio is an increasing function of flow rate. This view is supported by many researchers.[34-36] According to the results, the ratio of open-eye increased by $21\\%$ when the gas flow rate increased from 1 to $5\\mathrm{L / min}$ for the slag layer thickness of $15~\\mathrm{mm}$ . However, the ratio only increased by $3\\%$ when the gas flow rate increased from 5 to $9\\mathrm{L / min}$ . Based on similar trends in the results of other layer thicknesses, the flow rate is no longer the major factor influencing the open eye if it is higher than a critical value. In addition, the openeye ratio decreased as the oil layer thickness increased. The ratio of open-eye decreased by $42\\%$ and $59\\%$ when the oil layer thickness increased by $67\\%$ and $134\\%$ , respectively. In comparison, the oil layer thickness was $15~\\mathrm{mm}$ , and the gas flow rate was $5\\mathrm{L / min}$ . Generally, the open-eye ratio is significantly affected by the gas flow rate when the slag layer is thin. However, a further increase in the oil-layer thickness inhibited the influence of the gas flow rate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,854,349,869]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.4. Volume of the Slag Entrainment ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,869,480,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although the entrainment phenomenon is conducive to removing impurities in liquid steel, it is not recommended for clean steel. The total slag entrainment volume is important for realizing a secondary refining control process. Figure 6 displays the effects of the gas flow rate and oil layer thick-","text_format":null,"text_level":null,"type":"text"},{"bbox":"[532,269,910,480]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5. The ratio of open-eye with different gas flow rate and oil thickness. \"]","image_footnote":"[]","img_path":"images/0689/8d3907ef571bb01a243769a91130c6f1ac16cce2e0dcd6b4a413dab15460e334.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[526,533,915,739]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 6. The volume of entrained oil as function of gas flow rate and oil thickness. \"]","image_footnote":"[]","img_path":"images/0382/9afcae8c66086a016ee2cd229233a57ff0e1d61caa7180932cb9add5818046b7.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[512,797,927,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ness on the entrainment volume. It can be seen from Fig. 6 that the volume of entrained oil increased with the increasing gas flow rate and decreased when the slag layer became thicker. It should be noted that an increase in the gas flow rate increased the volume of entrained oil only up to a certain level. Subsequently, a further increase in the gas flow rate had a weaker effect on the volume of entrained oil. At an oil layer thickness of $25\\mathrm{mm}$ , the volume of entrained oil increased by $106\\%$ , $212\\%$ , and $212\\%$ when the gas flow rate was increased from 2 to 4, 6, and $8\\mathrm{L / min}$ , respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[361,38,636,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[480,956,515,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1021 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,956,924,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,70,480,112]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At a gas flow rate of $9\\mathrm{L / min}$ , the volume of entrained oil decreased by $51\\%$ and $103\\%$ when the oil layer thickness increased from 15 to 25 and $35~\\mathrm{mm}$ , respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,112,480,243]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 7 illustrates the relationship between entrained oil and the total volume of oil. Compared with the results in Fig. 6, a similar trend was noted in that the ratio was an increasing function of the gas flow rate. In addition, the entrainment ratio was $33\\%$ for a slag thickness of $15\\mathrm{mm}$ , compared to a ratio of $28\\%$ for a slag thickness of $35\\mathrm{mm}$ . This finding indicates that entrainment slag is not proportional to the total slag volume. The entrainment ratio remained below $35\\%$ regardless of flow rate and slag thickness. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,256,326,269]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.5. Size of the Slag Entrainment ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,269,480,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The interaction between molten steel and slag is influenced not only by the entrained slag volume, but also by the size of the slag droplets. Accordingly, the effects of oil layer thickness and gas flow rate on the mean oil diameter were investigated and are presented in Fig. 8. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,341,480,399]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Generally, the mean diameter decreases with increasing oil layer thickness. Figure 8 also depicts that the increase in gas flow rate increased the mean diameter of entrained droplets when the gas flow rate was relatively small, and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,70,927,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"then further increases in gas flow rate displayed a decreasing tendency. At an oil layer thickness of $25\\mathrm{mm}$ , the mean oil droplet diameter increased by $22\\%$ when the gas flow rate was increased from 2 to $4\\mathrm{L / min}$ . The mean diameter decreased by $11\\%$ and $33\\%$ when the gas flow rate increased from 2 to 6 and $8\\mathrm{L / min}$ , respectively. A more intense force was formed at the water-oil interface when the gas flow rate was increased. As a result, more oil was pulled down into the water phase owing to the shear stress, which led to the formation of larger oil droplets. As the flow intensity increased, the large oil droplets formed were broken into smaller oil droplets. In this blowing stage, the higher flow rates produced smaller droplets. These results are not similar to studies by Kang, Frohberg, and Wei et al. $^{15,32,33)}$ According to Kang, Frohberg and Wei et al., $^{16,37,38)}$ an increase in the gas flow rate decreases the mean oil diameter. The main reason for this variation is that the range of gas flow studied was inconsistent, or the shear velocity was different. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,341,678,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.6. Interfacial Area ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,356,927,399]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When slag possesses good properties in the secondary refining process, the interface area directly affects the desulfurization rate. According to the experiments (Fig. 9(a)), the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,429,487,645]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 7. The volume ratio of entrained oil as function of gas flow rate and oil thickness. \"]","image_footnote":"[]","img_path":"images/0967/42d818e6fde199ba7164a6b6964a6d47821be479bf0d3590d61851d49c69cdf6.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[526,432,915,645]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 8. The mean oil droplets diameter as function of gas flow rate and oil thickness. \"]","image_footnote":"[]","img_path":"images/0407/76b79f888651f5e1753277481412342e64f5c3d21d6162d9806177a53ab49bee.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[121,696,497,891]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0513/458472131056e24ce359b8eeb5490bdf0e29696bdbec06e17749c59847865102.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[500,696,875,891]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \",\"Fig. 9. The interfacial area (a) as well as specific interface area (b) as function of gas flow rate and oil thickness. \"]","image_footnote":"[]","img_path":"images/0113/9a9d24a840bf8bd496d2653a65b8040c12c1f2293b78c63f64bd6929639b2b30.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[359,38,636,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,954,161,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[480,954,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1022 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[176,71,500,273]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0199/83e816e80904dec0a32f4470c869a5e1034c24477c261f3cb63e5ee4e04d43fc.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[526,71,821,271]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \",\"Fig. 10. Effect of oil viscosity on the volume of entrained oil (a) and mean droplets (b) diameter under the gas flow rate is $4\\\\mathrm{L / min}$ and the oil layer thickness is $25~\\\\mathrm{mm}$ . (Online version in color.) \"]","image_footnote":"[]","img_path":"images/0006/deb6d239ad1ef077e2922b22276fae6e3f7e1de339614db2d814249642a85ee6.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[68,356,480,441]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"interfacial area of the formed droplets was positively associated with gas flow rate at less than $8\\mathrm{L / min}$ . However, the interfacial area was almost the same for different oil layer thicknesses when the gas flow rate was $2 - 6\\mathrm{L / min}$ . When the gas flow rate was higher than $6\\mathrm{L / min}$ , the effect of oil layer thickness was more prominent. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,441,482,741]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The interfacial reaction efficiency is not only related to the interfacial area of the droplets but also requires the evaluation of specific interfacial areas. The functions of reservoir thickness, gas flow and specific interface area are demonstrated in Fig. 9(b). Compared with the Figs. 8, 9(b) reveals the opposite trend. The specific interface area decreased as the slag layer thickness increased. At a gas flow rate of $9\\mathrm{L / min}$ , the specific interface area decreased by $17\\%$ and $29\\%$ when the oil layer thickness increased from 15 to 25 and $35~\\mathrm{mm}$ , respectively. At an oil layer thickness of $25\\mathrm{mm}$ , the specific interface area increased by $25\\%$ when the gas flow rate increased from 2 to $3\\mathrm{L / min}$ . Furthermore, the specific interface area increased by $51\\%$ and $101\\%$ when the gas flow rate increased from 3 to 6 and $8\\mathrm{L / min}$ , respectively. When strong stirring was performed, the size of entrained droplets decreased, and the specific interface area, as well as interfacial area, increased. Therefore, the droplet breakage effect is the key to influencing the specific interface area. The smaller the mean diameter of generated droplets, the more the specific interface area increases when the gas flow rate reaches a certain value. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,755,352,768]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.7. Viscosity and Interfacial Tension ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,769,482,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study focused not only on the gas flow rate and oil layer thickness but also on the physical properties of the oil, such as the oil-water interfacial tension and viscosity. Considering viscosity, the interfacial tension between water and oil differed when different oils were applied. At a gas flow rate of $4\\mathrm{L / min}$ and an oil layer thickness of $25\\mathrm{mm}$ , the entrained volume of oil decreased, and the diameter of the mean droplets decreased when the oil viscosity and interfacial tension were increased, as demonstrated in Fig. 10. This suggests that a more intense force of shear stress at the interface is required if more slag is entrained into the steel phase, or droplets of smaller diameter are expected to form ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,356,927,414]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"if the slag viscosity or interfacial tension is increased. To clearly understand the percentage significance of the physical properties on entrainment in the studied parameter range, the experimental scheme needs to be further optimized. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,434,636,447]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,455,926,526]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study aimed to evaluate the effects of the gas flow rate, slag viscosity, interfacial tension, and slag layer thickness on the entrained volume, droplet diameter, interfacial area, and specific interface area. Based on these findings, the following conclusions can be drawn: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,527,926,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"(1) The bottom-blowing process leads to the formation of oil droplets. The spherical bed consisted of entrained droplets that floated up to the traditional liquid-liquid interface for buoyancy and interfacial tension. Remarkably, water droplets were observed in the water phase. Water droplets wrapped in oil films appeared at relatively high flow rates and provided almost twice the interfacial area compared with oil droplets of the same size. The number of oil droplets in the water phase was much greater than the number of water droplets. \",\"(2) When the gas flow rate or oil thickness increases, the volume of entrained oil and the number of oil droplets also increase. However, these values decrease with increasing oil viscosity and interfacial tension. \",\"(3) As the oil-layer thickness increased, the mean diameter of entrained droplets decreased. The increase in the gas flow rate increased the mean diameter when the gas flow rate was relatively small, and further increases in the gas flow rates depicted a decreasing tendency. At an oil layer thickness of $25\\\\mathrm{mm}$ , the mean oil droplet diameter increased by $22\\\\%$ when the gas flow rate increased from 2 to $4\\\\mathrm{L / min}$ . Conversely, the mean diameter decreased by $11\\\\%$ and $33\\\\%$ when the gas flow rate increased from 2 to 6 and $8\\\\mathrm{L / min}$ , respectively. \",\"(4) The specific surface area of oil droplets demonstrated an opposite trend to that of the mean diameter. At the same oil layer thickness, the specific interface area increased by $25\\\\%$ when the gas flow rate increased from 2 to $3\\\\mathrm{L / min}$ . Moreover, the specific interface area increased by $51\\\\%$ and \"]","page_idx":"6","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[361,38,636,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[480,956,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1023 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,956,924,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,71,480,112]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$101\\%$ when the gas flow rate increased from 3 to 6 and 8 L/min, respectively. In addition, the specific surface area decreased as the oil-layer thickness increased. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,114,480,228]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(5) For the open-eye process, the increase in the gas flow rate or decrease in the oil layer thickness led to the open-eye growing bigger in size. Specifically, the eye-opening increased by $21\\%$ when the gas flow rate increased from 1 to $5\\mathrm{L / min}$ , while the slag layer thickness was 15 mm. Furthermore, when the oil layer thickness increased by $67\\%$ , the eye-opening decreased by $56\\%$ to that of the $15\\mathrm{mm}$ oil layer. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,244,215,256]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,256,480,330]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present work was funded by China Funding Agency National for National Natural Science (62071034) and JISCO Iron & Steel Co., Ltd. We would also like to express our gratitude to Mr. Hu Zheng and Mr. Li Shi Wang for their help during the experimental part of the study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[221,343,329,355]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,363,480,637]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1) M. A. Andersson, L. T. Jonsson and P. G. Jonsson: ISIJ Int., 40 (2000), 1080. https://doi.org/10.2355/isijinternational.40.1080 \",\"2) P. G. Jonsson and L. T. Jonsson: ISIJ Int., 41 (2001), 1289. https://doi.org/10.2355/isijinternational.41.1289 \",\"3) M. Andersson, M. Hallberg, L. Jonsson and P. Jonsson: Ironmaking Steel-making, 29 (2002), 224. https://doi.org/10.1179/030192302225004106 \",\"4) A. M. B. Silva, M. A. Oliveira, J. J. M. Peixoto and C. A. da Silva: Metall. Mater. Trans. 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B, 53 (2022), 999. https://doi.org/10.1007/s11663-021-02355-8 \",\"33) Q. Cao and L. Nastac: Ironmaking Steelmaking, 47 (2019), 873. https://doi.org/10.1080/03019233.2019.1629155 \",\"34) A. M. Amaro-Villeda, M. A. Ramirez-Argaez and A. N. Conejo: ISIJ Int., 54 (2014), 1. https://doi.org/10.2355/isijinternational.54.1 \",\"35) K. Yonezawa and K. Schwertfeger: Metall. Mater. Trans. B, 30 (1999), 411. https://doi.org/10.1007/s11663-999-0073-y \",\"36) A. Maruyama and M. Iguchi: J. Jpn. Soc. Exp. Mech., 12 (2012), s7. https://doi.org/10.11395/jjsem.12.s7 \",\"37) M. G. Frohberg, F. Gerlach and G. Handschuh: Steel Res., 61 (1990), 151. https://doi.org/10.1002/srin.199000322 \",\"38) T. Wei and F. Oeters: Steel Res. Int., 63 (1992), 60. https://doi.org/10.1002/srin.199200471 \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[361,39,635,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISIJ International, Vol. 63 (2023), No. 6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[72,956,161,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 ISIJ ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[480,956,517,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1024 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[70,84,880,137]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effects of Entrained Slag Droplets on Slag-Metal Interface in A Gas-Stirred Ladle \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,171,423,187]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Yong LIU, $^{1)}$ Shusen CHENG $^{1)*}$ and Tong LIU $^{2)}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,198,924,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1) School of Metallurgical and Ecological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing, 100083 P. R. China. \\\",\\\"2) School of Material Science and Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing, 100083 P. R. China. \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[144,256,845,282]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Received on April 2, 2022; accepted on March 10, 2023; J-STAGE Advance published date: March 21, 2023) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[129,316,868,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study explores the underlying mechanism between secondary refining efficiency, gas flow rate, and slag properties. The secondary refining efficiency is directly affected by the slag-metal interface area. Traditionally, the slag-metal interface has been limited to the liquid-liquid interface of the ladle cross-section and does not include the interface area between the entrained slag droplets and metal. To investigate the interface area with different slags and metals under various bottom blow rates, a physical model of a single-nozzle gas-stirred ladle was established using oil to simulate slag and water to simulate metal. The roles of relevant variables that affect the volume of entrained oil, the diameter of entrained droplets, and interface area were studied, as well as oil viscosity, interfacial tension, and oil thickness. Experimental data were collected using colorants and image processing techniques. Based on these findings, the increase in gas flow rate and oil layer thickness increased the volume of entrained oil and interface area, while the increase in oil viscosity and interfacial tension decreased these parameters. When the gas flow rate increased, the mean diameter of droplets first increased and then decreased. However, the specific surface area of droplets revealed the opposite trend. Furthermore, the mean diameter and specific surface area increased and decreased with increasing oil-layer thickness. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[129,508,865,536]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KEY WORDS: secondary refining; slag-metal interface; physical model; entrained slag droplets; specific surface area. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,605,194,618]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,626,480,697]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the secondary refining process, desulfurization is mainly dominated by the slag-metal interaction, $^{1-3)}$ which determines the area of the slag-metal interface and subsequently, affects the slag forming rate and desulfurization efficiency. $^{4)}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,697,480,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The desulfurization rate as given by Ahindra<sup>5)</sup> is revealed as Eq. (1) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[169,733,480,766]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n- \\\\frac {d [ W _ {S} ]}{d t} = k _ {S} \\\\frac {A}{V} \\\\left([ W _ {S} ] - \\\\frac {(W _ {S})}{L _ {S}}\\\\right) \\\\dots \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[68,769,480,856]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $[W_{s}]$ and $(W_{s})$ refer to the sulfur content in metal and slag (wt%), respectively, $k_{s}$ is the mass transfer coefficient of sulfur $(\\\\mathrm{m / s})$ , $A$ is the interface area $(\\\\mathrm{m}^2)$ , $V$ is the volume of metal $(\\\\mathrm{m}^3)$ , and $L_{s}$ is the distribution coefficient of sulfur. Equation (1) indicates that the desulfurization rate[6,7] is directly proportional to the interfacial area when the slag \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,599,675,612]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"has suitable properties. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,612,926,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Several researchers $^{1-3)}$ have attributed this to desulfurization, which mainly occurs at the initial slag-metal interface. However, owing to the influence of force imbalance, Kelvin-Helmholtz instability and Rayleigh-Taylor instability, the slag-metal boundary can become unbalanced, resulting in slag droplets entering the molten metal. Generally, the interface area can be increased by increasing the intensity of interface fluctuation and entrainment volume in the ladle. Mainly, the slag-metal interface fluctuation and entrainment phenomenon in the ladle cause an increase in the interface area. Moreover, Mietz et al. $^{8,9)}$ demonstrated that droplet emulsification was responsible for the acceleration of mass transfer. The entrainment phenomenon in the ladle directly led to improves desulfurization refining efficiency. $^{10)}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,812,926,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the 1850s, entrainment was proven to occur as slag droplets were found in molten metal.[11] Currently, the research on the entrainment phenomenon in the ladle is mainly performed with the help of industrial practice, physical simulations, and numerical simulations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[586,28,926,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6, pp. 1017-1024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[573,43,926,57]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.2355/isijinternational.ISIJINT-2022-164 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,873,426,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"* Corresponding author: E-mail: chengsusu@metall.ustb.edu.cn \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[70,910,178,938]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CC BY NC ND \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[189,912,820,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Iron and Steel Institute of Japan. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs license (https://creativecommons.org/licenses/by-nc-nd/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[480,956,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1017 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[68,70,482,468]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the cold model research, Iguchi et al. $^{12)}$ established an empirical relationship for ladle entrained slag. This relationship is affected by the phase physical properties, ladle size, and gas flow rate. In addition, it was demonstrated that the kinematic viscosity of the slag has a significant effect on the critical velocity required for entrainment. $^{13)}$ Jönsson et al. $^{14)}$ further proved that slag viscosity is a key factor affecting slag entrainment. By establishing a cold model of the water-oil system, Dayal and Du et al. $^{15,16)}$ found that the shear force between the liquid slag and liquid steel played an important role in the slag metal mixing process. Industrial experiments revealed that, slag droplets appeared in the molten metal, and a thin metal film was present around the slag. It was once again proven that the slag droplets can be entrained into the molten metal. $^{15)}$ Simultaneously, a sphere-bed phenomenon appeared near the open-eye and affected the removal methods of inclusions. $^{16)}$ Petri and Jari et al. $^{17,18)}$ used a simplified physical model of a water-oil system to study the entrainment behavior in the ladle. The mean droplet size in the system is $2 - 3\\\\mathrm{mm}$ . The critical velocity required for emulsification and the diameter of the entrained oil droplets increased as the oil viscosity, interfacial tension, and oil layer thickness increased. An increase in the density difference caused the critical velocity and droplet diameter to increase and decrease, respectively. The critical speed findings were also confirmed by Kitamura. $^{19)}$ In addition Visuri et al. $^{20)}$ reported that the droplets were smaller than the bubbles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,470,480,669]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Numerical simulations have been increasingly applied in research studies with advancements in calculation methods and capabilities.[21,22] For example, several researchers[17,23-27) have used the Volume of Fluid (VOF) to capture the slagmetal interface. Singh et al.[28) found that the interfacial area first increased and then decreased with the increase in gas flow rate. Petri and Visuri et al.[25) identified that the droplets Sauter diameter was between 4 and $6\\\\mathrm{mm}$ and the generation rate of the interfacial area between 0.2 and $0.6\\\\mathrm{m}^2\\\\cdot \\\\mathrm{s}^{-1}$ . With numerical simulation methods (VOF), it can be difficult to reproduce the entrainment phenomenon, and large model scales have the difficulty of limited computing powers or numerical methods. Through water-oil system experiments, similarities in the physical sense can be achieved. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,670,482,771]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thus, this report aims to contribute to understanding the main factors that influence slag-metal interactions during the secondary refining process. A physical model was developed to study the influence of slag layer thickness, gas flow rate, slag viscosity and interfacial tension on entrainment volume, diameter distribution of entrained slag, interfacial area, and specific interface area. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,791,205,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Experimental \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,812,203,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1. Experiment \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,827,482,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study was carried out using a physical model, developed based on the similarity principle according to a refining 120 t ladle used in practice. The dimensions of the 1:6 scaled-down model and fluid were determined based on the modified Froude.[29] Equation (3) was used to determine the gas flow in the current model with one tuyere. The dimensions of the cold model and experimental setup are displayed in Fig. 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[658,76,926,111]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF r ^ {\\\\prime} = \\\\frac {\\\\rho_ {l}}{\\\\rho_ {l} - \\\\rho_ {g}} \\\\frac {v ^ {2}}{g H}. \\\\tag {2}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[581,127,926,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nQ _ {m} = \\\\left[ \\\\left(\\\\frac {\\\\rho_ {g , p}}{\\\\rho_ {g , m}}\\\\right) \\\\left(\\\\frac {\\\\rho_ {l , m}}{\\\\rho_ {l , p}}\\\\right) \\\\left(\\\\frac {d _ {m}}{d _ {p}}\\\\right) ^ {4} \\\\left(\\\\frac {H _ {m}}{H _ {p}}\\\\right) \\\\right] ^ {\\\\frac {1}{2}} Q _ {p} \\\\dots \\\\dots \\\\dots \\\\tag {3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,185,926,298]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $Fr'$ is the modified Froude number, $\\\\rho_l$ and $\\\\rho_g$ are the densities of liquid and gas respectively $(\\\\mathrm{kg} / \\\\mathrm{m}^3)$ , $\\\\nu$ is the gas velocity $(\\\\mathrm{m} / \\\\mathrm{s})$ , $g$ is the acceleration due to gravity $(\\\\mathrm{m} / \\\\mathrm{s}^2)$ , $H$ is the characteristic length $(\\\\mathrm{m})$ , $d$ is the diameter of tuyere $(\\\\mathrm{m})$ , $Q$ is the gas flow, and the subscripts $m$ and $p$ refer to the model and prototype, respectively. The maximum gas flow rate used in the cold model is 9 L/min. The flow interval used in the experiment was 1 L/min. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,299,927,429]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A high-speed camera with a resolution of $1280 \\\\times 1024$ and a maximum frame rate of 200 FPS (frames per second) was used for experimental recording. The data were saved at 15 FPS. Before starting the experiment, the mixture of water and oil was allowed to stand to ensure that the water and oil did not dissolve in each other. The gas flow rate in each experiment was controlled by a gas flowmeter. The camera started recording when the bottom blow and the bath flow were stable. Each experiment was repeated five times. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,441,752,456]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1.1. Area Analysis of Slag-eye \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,456,926,586]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open-eye formation in a gas stirred ladle has been the subject of many studies, including physical $^{30-32}$ and numerical modeling studies. $^{31,33}$ Ten pictures were recorded using the camera when the open-eye shape was relatively stable. Image processing and a non-dimensionalized process were used to obtain the resulting differential open-eye area. The open-eye area was evaluated using the ImageJ software, and an example of a processed image is displayed in Fig. 2. The open-eye ratio was calculated using the following equation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[690,592,926,621]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nR _ {e} = \\\\frac {S _ {e}}{S _ {a}} \\\\dots \\\\tag {4}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,626,927,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Where $S_{e}$ and $S_{a}$ are the open-eye area and total area of the oil layer surface, respectively. For a certain gas flow rate, the average was recorded as the final open-eye rate, reducing experimental errors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,697,860,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1.2. Droplets Analysis of the Entrainment Slag \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,712,926,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Different droplet sizes were formed when the slag was entrained into the metal phase during blowing. To analyze the size distribution of the droplets in the bath, ImageJ was used to determine the droplet diameter, $d_{i}$ . The mean diameter can be written as Eq. (5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[673,790,926,822]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nd _ {m} = \\\\frac {1}{n} \\\\sum_ {i = 1} ^ {n} d _ {i} \\\\dots \\\\tag {5}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,826,927,870]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $d_{m}$ is the mean diameter, and $i$ is the number of statistical droplets. The average number can be expressed by Eq. (6). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[663,875,926,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn = \\\\operatorname {I N T} \\\\left(\\\\frac {6 V _ {e}}{\\\\pi d _ {m} ^ {3}}\\\\right) \\\\dots \\\\tag {6}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,910,927,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $V_{e}$ is the volume of entrained oil, which is measured indirectly using the drawer principle. A circular baffle was \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[359,38,636,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,954,161,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[480,954,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1018 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[144,71,853,304]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\",\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0978/05476df1c2dee4e08fa909bbc86a1899b3771247b57b55cc0364173fde7eb177.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[142,370,319,498]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. (a) cold model size and (b) experiment setup. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0119/ab587aee610b99072edf53cc89338a8cce6e967a5e9ba5c2f8f1112b57fe9db0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[327,370,504,498]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0163/0f4d18c4aba9f94b13c7e24ad6b60c03a97eedab430d1f1b07c8a22ee8971e61.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[510,374,675,495]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0135/729786012ff193f36c1f684029520d510333b3e5f5d74a9dda1d27fdeff1ef1d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[684,372,855,495]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\",\\\"(b) \\\",\\\"Fig. 2. The contour of eye-opening image processing for the oil layer thickness is $15\\\\\\\\mathrm{mm}$ when the gas flow rate are (a) $1\\\\\\\\mathrm{L / min}$ and (b) $3\\\\\\\\mathrm{L / min}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0176/8691778ef26a0c1e5d5cd2de3ab1001bc022e554b7dbf1cc5788c14a833022c9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[216,594,781,688]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0521/4c152acabce1419e2035e560eb0b882a520aa57f6adee4224bff06ded7ec6a42.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Parameters</td><td>Water</td><td>3# white oil</td><td>100# white oil</td><td>200# white oil</td></tr><tr><td>Density, g·cm-3</td><td>0.98</td><td>0.76</td><td>0.80</td><td>0.81</td></tr><tr><td>Viscosity, mPa·s</td><td>3</td><td>8.9</td><td>93.3</td><td>193.5</td></tr><tr><td>Surface tension, mN·m-1</td><td>72.75</td><td>33.10</td><td>35.24</td><td>34.38</td></tr><tr><td>Water-oil interfacial tension, mN·m-1</td><td>-</td><td>40.02</td><td>42.05</td><td>47.25</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Physical property of the fluids. \\\"]\",\n \"table_footnote\": \"[\\\"Note: measured value \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[68,727,480,769]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"installed on one side of the ladle at the water-oil interface. Under quasi-stable conditions, the oil layer separated from the entrainment droplets when the baffle was quickly pushed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,770,480,827]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The total surface area of the droplets can be approximated by using Eq. (7). To evaluate the chemical reaction rate or mass transfer rate, the specific surface area was utilized. The specific surface area is represented by Eq. (8). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[236,834,480,850]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nA _ {d} = n \\\\pi d _ {m} ^ {2}. \\\\tag {7}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[247,864,480,892]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\na = \\\\frac {A _ {d}}{V _ {e}} \\\\dots \\\\tag {8}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[68,897,480,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Where $A_{d}$ is the interface area of the slag droplets $(\\\\mathrm{dm}^2)$ , and $a$ is the specific interface area $(\\\\mathrm{dm}^2/\\\\mathrm{L})$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,727,794,740]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2. Physical Property Measurement \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,741,926,810]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The physical property parameters used to simulate the metal phase, and slag phase are illustrated in Table 1. To ensure the precision of test, the experiment was carried out by performing the following points at a room temperature of $25^{\\\\circ}\\\\mathrm{C}$ : \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,812,926,840]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1) To precisely control the temperature of the liquid to be tested, often a water bath. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,840,926,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"2) Ensure the uniformity of liquid. \\\",\\\"3) Ensure the cleanness of the structure of the instrument. 4) Judge the measurement result by the standard sample. \\\",\\\"The densities of fluids used in the current study were measured by the balance measuring cylinder method. Due to the importance of viscosity and interfacial tension of fluids, the measurement details were thus focused. The \\\"]\",\n \"page_idx\": \"2\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[361,38,636,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[480,956,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1019 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,956,924,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,71,480,112]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MZ-NDJ-5S rotary viscosimeter was used to measure the fluid viscosity in the experiment. When measuring, carries on the operating steps. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,114,480,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1) The measured liquid, ready to put measured liquid, is not less than $60~\\\\\\\\mathrm{mm}$ in diameter, height not less than 120 mm beaker. \\\",\\\"2) On the rotor protection, after carefully adjusting the level of the instrument, ensure instrument in the level of work state. \\\",\\\"3) Reference range table, select the adaptation of rotor screwing in rotor connecting head. \\\",\\\"4) Slowly adjust elevator knob, and adjust the rotor in the measured liquid level. \\\"]\",\n \"page_idx\": \"3\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[68,256,480,311]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Also, based on the du Noüy ring method, the interfacial tension was measured by the DCAT21 tensiometer. In interfacial tension measurements, the main steps need to be followed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,313,480,426]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1) The ring is first immersed in the denser phase which is water. Then the less dense liquid is poured on top. \\\",\\\"2) Care must not contaminate the ring when pouring the liquid. \\\",\\\"3) The measurement is then started, and the sample stage with the liquid container is moved down. \\\",\\\"4) When the ring is at the interface, the software will detect that automatically and continue to move the stage \\\"]\",\n \"page_idx\": \"3\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[514,71,818,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"down until the detected force starts to drop. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,105,714,118]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results and Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,128,843,141]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. Physical Property Measurement Result \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,143,926,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Measurements were repeated five times to reduce errors, and the average value was calculated. The measurement error bar of physical property parameters is illustrated in Fig. 3. Overall, the results of this measurement suggest excellent reliability and acceptable measurement errors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,228,786,241]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Slag Entrainment Phenomenon \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,242,926,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the experiment, the oil was dyed red to facilitate analysis. Interestingly, many oil droplets were formed in the water phase due to shear effects at the interface. Furthermore, a sphere-bed of entrained droplets was formed when the droplets floated up to the interface, as depicted in Fig. 4. This phenomenon was reported in a study by Kang et al. (16) (Fig. 4(c)). When droplet formation, combination, and breakage are balanced, the sphere-bed maintains its thickness during the blowing process. The sphere-bed formation not only sharply increased the interfacial area but also changed the morphology of the water-oil interface. In addition, at a gas flow rate of $6\\\\mathrm{L / min}$ , a water droplet wrapped with an oil film was observed in the water-oil \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[161,458,489,642]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0386/38ed5f2acb9948199ad47290c28e1400588cfb258fa1b33ef5f236215d98ad55.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[514,455,836,643]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0277/3a7e8f228a5948dbb2b80d1516733a7f386ce234c0f0d4aab704e697265c6502.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[171,690,480,879]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0973/715c6a5ca210871c156cafb49e1eef50bf3ec73a6d5edf00ba2f4ceb682f085f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[515,690,830,879]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) \\\",\\\"Fig. 3. Physical property parameters measurement error bar. (a) Density, (b) viscosity, (c) surface tension, (d) water-oil interfacial tension. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0637/91381bc62d721770d72c9156f898b92477b3555f5af6d82a776d8061b6dcdbc4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[359,38,636,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,954,161,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[480,954,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[157,71,381,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0969/d7088143d624df3b0913fc6ebd389a109342e4896e39c7c0d75b594aaa90f52b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[383,71,608,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0323/9706047bc3320f0409f390dae0f2d0f98021e3e1d0677a3dd08dfd84b594da58.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[611,71,836,199]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\",\\\"Fig. 4. Entrainment and sphere-bed phenomenon. (Online version in color.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0410/7028243d6311bb2c4fa9c43b3ce747e882dd42dc341fcff96a86eaba62760312.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[68,269,482,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"system (Fig. 4(b)). It provided almost twice the interfacial area than oil droplets of the same size. However, it was noted that the water droplet did not appear when the gas flow rate was relatively small (Fig. 4(a)) $3\\\\mathrm{L / min}$ ). In reality, the interface interaction and mass transfer efficiency between slag and molten metal would be further increased if the metal droplets were wrapped by slag, but this was not favorable for yield. As a result, metal entrainment into the slag should be controlled carefully in different stages of the refining process, given the factors discussed in the following section. Furthermore, the experiment demonstrated that the bubbles generated by bottom blowing caused quasi-periodic tangential pulsation of liquid metal at the oil-water interface (Fig. 4(b)). Slag-metal interface instability occurred when the bubbles indirectly went through the interface and broke up at the air surface. This fluctuation phenomenon also causes the appearance of water droplets. Further research is required to investigate the complexity of this instability. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,541,186,555]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. Open-eye \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,556,482,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To investigate the open-eye formed by the bottom blowing plume, the flow rates, and slag layer thickness were considered, as displayed in Fig. 5. Generally, the open- eye ratio is an increasing function of flow rate. This view is supported by many researchers.[34-36] According to the results, the ratio of open-eye increased by $21\\\\%$ when the gas flow rate increased from 1 to $5\\\\mathrm{L / min}$ for the slag layer thickness of $15~\\\\mathrm{mm}$ . However, the ratio only increased by $3\\\\%$ when the gas flow rate increased from 5 to $9\\\\mathrm{L / min}$ . Based on similar trends in the results of other layer thicknesses, the flow rate is no longer the major factor influencing the open eye if it is higher than a critical value. In addition, the openeye ratio decreased as the oil layer thickness increased. The ratio of open-eye decreased by $42\\\\%$ and $59\\\\%$ when the oil layer thickness increased by $67\\\\%$ and $134\\\\%$ , respectively. In comparison, the oil layer thickness was $15~\\\\mathrm{mm}$ , and the gas flow rate was $5\\\\mathrm{L / min}$ . Generally, the open-eye ratio is significantly affected by the gas flow rate when the slag layer is thin. However, a further increase in the oil-layer thickness inhibited the influence of the gas flow rate. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,854,349,869]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.4. Volume of the Slag Entrainment \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,869,480,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although the entrainment phenomenon is conducive to removing impurities in liquid steel, it is not recommended for clean steel. The total slag entrainment volume is important for realizing a secondary refining control process. Figure 6 displays the effects of the gas flow rate and oil layer thick-\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[532,269,910,480]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5. The ratio of open-eye with different gas flow rate and oil thickness. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0689/8d3907ef571bb01a243769a91130c6f1ac16cce2e0dcd6b4a413dab15460e334.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[526,533,915,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 6. The volume of entrained oil as function of gas flow rate and oil thickness. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0382/9afcae8c66086a016ee2cd229233a57ff0e1d61caa7180932cb9add5818046b7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,797,927,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ness on the entrainment volume. It can be seen from Fig. 6 that the volume of entrained oil increased with the increasing gas flow rate and decreased when the slag layer became thicker. It should be noted that an increase in the gas flow rate increased the volume of entrained oil only up to a certain level. Subsequently, a further increase in the gas flow rate had a weaker effect on the volume of entrained oil. At an oil layer thickness of $25\\\\mathrm{mm}$ , the volume of entrained oil increased by $106\\\\%$ , $212\\\\%$ , and $212\\\\%$ when the gas flow rate was increased from 2 to 4, 6, and $8\\\\mathrm{L / min}$ , respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[361,38,636,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[480,956,515,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,956,924,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,70,480,112]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At a gas flow rate of $9\\\\mathrm{L / min}$ , the volume of entrained oil decreased by $51\\\\%$ and $103\\\\%$ when the oil layer thickness increased from 15 to 25 and $35~\\\\mathrm{mm}$ , respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,112,480,243]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 7 illustrates the relationship between entrained oil and the total volume of oil. Compared with the results in Fig. 6, a similar trend was noted in that the ratio was an increasing function of the gas flow rate. In addition, the entrainment ratio was $33\\\\%$ for a slag thickness of $15\\\\mathrm{mm}$ , compared to a ratio of $28\\\\%$ for a slag thickness of $35\\\\mathrm{mm}$ . This finding indicates that entrainment slag is not proportional to the total slag volume. The entrainment ratio remained below $35\\\\%$ regardless of flow rate and slag thickness. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,256,326,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.5. Size of the Slag Entrainment \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,269,480,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The interaction between molten steel and slag is influenced not only by the entrained slag volume, but also by the size of the slag droplets. Accordingly, the effects of oil layer thickness and gas flow rate on the mean oil diameter were investigated and are presented in Fig. 8. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,341,480,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Generally, the mean diameter decreases with increasing oil layer thickness. Figure 8 also depicts that the increase in gas flow rate increased the mean diameter of entrained droplets when the gas flow rate was relatively small, and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,70,927,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"then further increases in gas flow rate displayed a decreasing tendency. At an oil layer thickness of $25\\\\mathrm{mm}$ , the mean oil droplet diameter increased by $22\\\\%$ when the gas flow rate was increased from 2 to $4\\\\mathrm{L / min}$ . The mean diameter decreased by $11\\\\%$ and $33\\\\%$ when the gas flow rate increased from 2 to 6 and $8\\\\mathrm{L / min}$ , respectively. A more intense force was formed at the water-oil interface when the gas flow rate was increased. As a result, more oil was pulled down into the water phase owing to the shear stress, which led to the formation of larger oil droplets. As the flow intensity increased, the large oil droplets formed were broken into smaller oil droplets. In this blowing stage, the higher flow rates produced smaller droplets. These results are not similar to studies by Kang, Frohberg, and Wei et al. $^{15,32,33)}$ According to Kang, Frohberg and Wei et al., $^{16,37,38)}$ an increase in the gas flow rate decreases the mean oil diameter. The main reason for this variation is that the range of gas flow studied was inconsistent, or the shear velocity was different. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,341,678,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.6. Interfacial Area \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,356,927,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When slag possesses good properties in the secondary refining process, the interface area directly affects the desulfurization rate. According to the experiments (Fig. 9(a)), the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,429,487,645]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 7. The volume ratio of entrained oil as function of gas flow rate and oil thickness. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0967/42d818e6fde199ba7164a6b6964a6d47821be479bf0d3590d61851d49c69cdf6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[526,432,915,645]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 8. The mean oil droplets diameter as function of gas flow rate and oil thickness. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0407/76b79f888651f5e1753277481412342e64f5c3d21d6162d9806177a53ab49bee.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[121,696,497,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0513/458472131056e24ce359b8eeb5490bdf0e29696bdbec06e17749c59847865102.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[500,696,875,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\",\\\"Fig. 9. The interfacial area (a) as well as specific interface area (b) as function of gas flow rate and oil thickness. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0113/9a9d24a840bf8bd496d2653a65b8040c12c1f2293b78c63f64bd6929639b2b30.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[359,38,636,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,954,161,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[480,954,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[176,71,500,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0199/83e816e80904dec0a32f4470c869a5e1034c24477c261f3cb63e5ee4e04d43fc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[526,71,821,271]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\",\\\"Fig. 10. Effect of oil viscosity on the volume of entrained oil (a) and mean droplets (b) diameter under the gas flow rate is $4\\\\\\\\mathrm{L / min}$ and the oil layer thickness is $25~\\\\\\\\mathrm{mm}$ . (Online version in color.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0006/deb6d239ad1ef077e2922b22276fae6e3f7e1de339614db2d814249642a85ee6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[68,356,480,441]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"interfacial area of the formed droplets was positively associated with gas flow rate at less than $8\\\\mathrm{L / min}$ . However, the interfacial area was almost the same for different oil layer thicknesses when the gas flow rate was $2 - 6\\\\mathrm{L / min}$ . When the gas flow rate was higher than $6\\\\mathrm{L / min}$ , the effect of oil layer thickness was more prominent. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,441,482,741]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The interfacial reaction efficiency is not only related to the interfacial area of the droplets but also requires the evaluation of specific interfacial areas. The functions of reservoir thickness, gas flow and specific interface area are demonstrated in Fig. 9(b). Compared with the Figs. 8, 9(b) reveals the opposite trend. The specific interface area decreased as the slag layer thickness increased. At a gas flow rate of $9\\\\mathrm{L / min}$ , the specific interface area decreased by $17\\\\%$ and $29\\\\%$ when the oil layer thickness increased from 15 to 25 and $35~\\\\mathrm{mm}$ , respectively. At an oil layer thickness of $25\\\\mathrm{mm}$ , the specific interface area increased by $25\\\\%$ when the gas flow rate increased from 2 to $3\\\\mathrm{L / min}$ . Furthermore, the specific interface area increased by $51\\\\%$ and $101\\\\%$ when the gas flow rate increased from 3 to 6 and $8\\\\mathrm{L / min}$ , respectively. When strong stirring was performed, the size of entrained droplets decreased, and the specific interface area, as well as interfacial area, increased. Therefore, the droplet breakage effect is the key to influencing the specific interface area. The smaller the mean diameter of generated droplets, the more the specific interface area increases when the gas flow rate reaches a certain value. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,755,352,768]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.7. Viscosity and Interfacial Tension \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,769,482,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study focused not only on the gas flow rate and oil layer thickness but also on the physical properties of the oil, such as the oil-water interfacial tension and viscosity. Considering viscosity, the interfacial tension between water and oil differed when different oils were applied. At a gas flow rate of $4\\\\mathrm{L / min}$ and an oil layer thickness of $25\\\\mathrm{mm}$ , the entrained volume of oil decreased, and the diameter of the mean droplets decreased when the oil viscosity and interfacial tension were increased, as demonstrated in Fig. 10. This suggests that a more intense force of shear stress at the interface is required if more slag is entrained into the steel phase, or droplets of smaller diameter are expected to form \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,356,927,414]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"if the slag viscosity or interfacial tension is increased. To clearly understand the percentage significance of the physical properties on entrainment in the studied parameter range, the experimental scheme needs to be further optimized. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,434,636,447]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,455,926,526]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study aimed to evaluate the effects of the gas flow rate, slag viscosity, interfacial tension, and slag layer thickness on the entrained volume, droplet diameter, interfacial area, and specific interface area. Based on these findings, the following conclusions can be drawn: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,527,926,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"(1) The bottom-blowing process leads to the formation of oil droplets. The spherical bed consisted of entrained droplets that floated up to the traditional liquid-liquid interface for buoyancy and interfacial tension. Remarkably, water droplets were observed in the water phase. Water droplets wrapped in oil films appeared at relatively high flow rates and provided almost twice the interfacial area compared with oil droplets of the same size. The number of oil droplets in the water phase was much greater than the number of water droplets. \\\",\\\"(2) When the gas flow rate or oil thickness increases, the volume of entrained oil and the number of oil droplets also increase. However, these values decrease with increasing oil viscosity and interfacial tension. \\\",\\\"(3) As the oil-layer thickness increased, the mean diameter of entrained droplets decreased. The increase in the gas flow rate increased the mean diameter when the gas flow rate was relatively small, and further increases in the gas flow rates depicted a decreasing tendency. At an oil layer thickness of $25\\\\\\\\mathrm{mm}$ , the mean oil droplet diameter increased by $22\\\\\\\\%$ when the gas flow rate increased from 2 to $4\\\\\\\\mathrm{L / min}$ . Conversely, the mean diameter decreased by $11\\\\\\\\%$ and $33\\\\\\\\%$ when the gas flow rate increased from 2 to 6 and $8\\\\\\\\mathrm{L / min}$ , respectively. \\\",\\\"(4) The specific surface area of oil droplets demonstrated an opposite trend to that of the mean diameter. At the same oil layer thickness, the specific interface area increased by $25\\\\\\\\%$ when the gas flow rate increased from 2 to $3\\\\\\\\mathrm{L / min}$ . Moreover, the specific interface area increased by $51\\\\\\\\%$ and \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[361,38,636,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[480,956,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,956,924,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,71,480,112]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$101\\\\%$ when the gas flow rate increased from 3 to 6 and 8 L/min, respectively. In addition, the specific surface area decreased as the oil-layer thickness increased. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,114,480,228]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(5) For the open-eye process, the increase in the gas flow rate or decrease in the oil layer thickness led to the open-eye growing bigger in size. Specifically, the eye-opening increased by $21\\\\%$ when the gas flow rate increased from 1 to $5\\\\mathrm{L / min}$ , while the slag layer thickness was 15 mm. Furthermore, when the oil layer thickness increased by $67\\\\%$ , the eye-opening decreased by $56\\\\%$ to that of the $15\\\\mathrm{mm}$ oil layer. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,244,215,256]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,256,480,330]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The present work was funded by China Funding Agency National for National Natural Science (62071034) and JISCO Iron & Steel Co., Ltd. We would also like to express our gratitude to Mr. Hu Zheng and Mr. Li Shi Wang for their help during the experimental part of the study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[221,343,329,355]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,363,480,637]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1) M. A. Andersson, L. T. Jonsson and P. G. Jonsson: ISIJ Int., 40 (2000), 1080. https://doi.org/10.2355/isijinternational.40.1080 \\\",\\\"2) P. G. Jonsson and L. T. 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Padmanabhan and A. K. Singh: Metall. Mater. Trans. B, 47 (2016), 1804. https://doi.org/10.1007/s11663-016-0620-2 \\\",\\\"29) D. Mazumdar: Metall. Mater. Trans. B, 21 (1990), 925. https://doi.org/10.1007/BF02657818 \\\",\\\"30) E. K. Ramasetti, V. V. Visuri, P. Sulasalmi, R. Mattila and T. Fabritius: Steel Res. Int., 90 (2019), 1800365. https://doi.org/10.1002/srin.201800365 \\\",\\\"31) E. K. Ramasetti, V. V. Visuri, P. Sulasalmi, T. Palovaara, A. K. Gupta and T. Fabritius: Steel Res. Int., 90 (2019), 1900088. https://doi.org/10.1002/srin.201900088 \\\",\\\"32) A. N. Conejo and W. Feng: Metall. Mater. Trans. B, 53 (2022), 999. https://doi.org/10.1007/s11663-021-02355-8 \\\",\\\"33) Q. Cao and L. Nastac: Ironmaking Steelmaking, 47 (2019), 873. https://doi.org/10.1080/03019233.2019.1629155 \\\",\\\"34) A. M. Amaro-Villeda, M. A. Ramirez-Argaez and A. N. Conejo: ISIJ Int., 54 (2014), 1. https://doi.org/10.2355/isijinternational.54.1 \\\",\\\"35) K. Yonezawa and K. Schwertfeger: Metall. Mater. Trans. B, 30 (1999), 411. https://doi.org/10.1007/s11663-999-0073-y \\\",\\\"36) A. Maruyama and M. Iguchi: J. Jpn. Soc. Exp. Mech., 12 (2012), s7. https://doi.org/10.11395/jjsem.12.s7 \\\",\\\"37) M. G. Frohberg, F. Gerlach and G. Handschuh: Steel Res., 61 (1990), 151. https://doi.org/10.1002/srin.199000322 \\\",\\\"38) T. Wei and F. Oeters: Steel Res. Int., 63 (1992), 60. https://doi.org/10.1002/srin.199200471 \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[361,39,635,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISIJ International, Vol. 63 (2023), No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[72,956,161,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 ISIJ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[480,956,517,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.2355/isijinternational.isijint-2022-164"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"nl"},"sci_category":{"kind":"string","value":"Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"e84cce6591941f7d83b9d80d15512b01a7382754183342295ab910ae6e9c3217"},"title":{"kind":"string","value":"Effects of Entrained Slag Droplets on Slag-Metal Interface in A Gas-Stirred Ladle"}}},{"rowIdx":150,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Isaac H Solomon|Shibani Mukerji|Farrah J Mateen|Sarah I Collens|Douglas R Wilcox"},"content_list":{"kind":"list like","value":[{"bbox":"[85,54,430,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0664/30f8b44ed1b3310aeb159ea7d3dc964dae9b5096c22379f0c4b38e8e07e342f9.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":"<table><tr><td>Variables</td><td>No of cases</td><td>Percentage, %</td><td>Median (SD)</td><td>Relative Risk (95% CI)</td><td>P-value</td></tr><tr><td colspan=\"6\">Comorbidities</td></tr><tr><td>Acquired immunodeficiency syndrome</td><td>122</td><td>18.31</td><td rowspan=\"10\"></td><td>Reference</td><td></td></tr><tr><td>Cancer</td><td>190</td><td>28.52</td><td>1.41 (1.15-1.72)</td><td>0.0008*</td></tr><tr><td>Cerebrovascular accidents</td><td>387</td><td>58.10</td><td>3.17 (2.66-3.77)</td><td><0.0001*</td></tr><tr><td>Chronic obstructive pulmonary disease</td><td>278</td><td>41.74</td><td>2.27 (1.89-2.73)</td><td><0.0001*</td></tr><tr><td>Congestive heart failure</td><td>249</td><td>37.38</td><td>2.04 (1.69-2.46)</td><td><0.0001*</td></tr><tr><td>Diabetes mellitus</td><td>299</td><td>44.89</td><td>2.45 (2.04-2.93)</td><td><0.0001*</td></tr><tr><td>Hypertension</td><td>305</td><td>45.79</td><td>2.50 (2.08-2.99)</td><td><0.0001*</td></tr><tr><td>Liver disease</td><td>205</td><td>30.78</td><td>1.68 (1.38-2.04)</td><td><0.0001*</td></tr><tr><td>Peripheral vascular disease</td><td>307</td><td>46.09</td><td>2.51 (2.10-3.01)</td><td><0.0001*</td></tr><tr><td>Renal disease</td><td>290</td><td>43.54</td><td>2.37 (1.98-2.85)</td><td><0.0001*</td></tr><tr><td colspan=\"6\">Charlson Comorbidity Index Score</td></tr><tr><td>1-4</td><td>163</td><td>24.47</td><td rowspan=\"6\">10.90 (9.52)</td><td>Reference</td><td></td></tr><tr><td>5-9</td><td>260</td><td>39.03</td><td>1.59 (1.35-1.87)</td><td><0.0001*</td></tr><tr><td>10-14</td><td>109</td><td>16.36</td><td>0.66 (0.53-0.83)</td><td>0.0003*</td></tr><tr><td>15-19</td><td>15</td><td>2.25</td><td>0.90 (0.05-0.15)</td><td><0.0001*</td></tr><tr><td>21-29</td><td>50</td><td>7.50</td><td>0.30 (0.22-0.41)</td><td><0.0001*</td></tr><tr><td>30-33</td><td>69</td><td>10.36</td><td>0.41 (0.32-0.54)</td><td><0.0001*</td></tr></table>","table_caption":"[\"Table 2: Comorbidities and Charlson Comorbidity Index score of patients with brain abscess and cerebritis at Mayo Clinic, 2009-2019. \"]","table_footnote":"[\"Abbreviations: CI, confidence interval; No, number; SD, standard deviation; $\\\\alpha$ , Chi-Square Test; $\\\\mu$ , Anova \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[77,219,485,260]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion: Male, White Non-Hispanics, and elderly patients seem to be the most prevalent patient population at risk for brain abscess or cerebritis. This investigation provides clinicians the demographic data needed to identify potentially complex patients with brain abscesses. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,260,484,282]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclosures: M. Rizwan Sohail, MD, Aziyo Biologics (Consultant)Medtronic Inc (Consultant, Research Grant or Support) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,300,467,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"345. Early Oral Therapy for Streptococcus anginosus Purulent Brain Infections: A Single Center Experience ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,320,458,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniel S. Dodson, MD, MS $^{1}$ ; Heather R. Heizer, Physician Assistant $^{1}$ ; James Gaensbauer, MD $^{2}$ ; Children's Hospital Colorado, Aurora, CO; Children's Hospital Colorado and Denver Health, Denver, Colorado ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,356,218,365]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Session: P-11. CNS Infection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,372,484,411]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: Pediatric Streptococcus anginosus intracranial pyogenic are commonly treated with prolonged intravenous (IV) antibiotics, exposing patients to risks of a long-term central catheter. Antibiotics with high oral bioavailability, such as levofloxacin, may allow early oral transition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,411,485,484]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: To characterize patients with S. anginosus intracranial infections transitioned to oral therapy, we performed a retrospective review at Children's Hospital Colorado from 1/2004 to 2/2019. Inclusion criteria were radiologic evidence of an infected parenchymal, subdural, or epidural fluid collection AND a positive culture for S. anginosus from an intracranial source, specific extracranial sources (sinus, scalp, orbit), or blood. The primary endpoint was oral antibiotic failure defined as worsening infection on oral therapy. Comparisons were done using Fisher's exact test. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,484,485,597]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: 94 patients met inclusion criteria, 57 of whom were transitioned to oral therapy during treatment. Oral levofloxacin was used in 54 of the 57. $12\\%$ of oral transitions occurred in the first 14 days of therapy (range 3-8 days), and $35\\%$ in the first 28 days. Patients transitioned in the first 28 days were more likely to have an epidural collection $(p < 0.01)$ , and less likely to have a subdural collection (p: 0.03) or brain abscess $(p < 0.01)$ . Of the 57, none had oral antibiotic failure. Contributing reasons for oral transition included central line complications $(18\\%)$ , IV medication reaction $(18\\%)$ , hematologic abnormality presumed secondary to IV antibiotics $(33\\%)$ , and provider judgement $(56\\%)$ . Two patients required re-introduction of IV therapy for reasons other than clinical failure (one for medication non-adherence and one for adverse reaction to levofloxacin). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,613,478,838]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0277/2c420eb363bfeb06472c9887813392b79abcc316b45bbff92fead3920b8afe0d.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":"<table><tr><td colspan=\"2\">Race (percent)</td><td colspan=\"2\">Co-Pathogens Present</td></tr><tr><td>Asian</td><td>4%</td><td>Methicillin sensitive Staphylococcus aureus</td><td>16%</td></tr><tr><td>Black or African American</td><td>7%</td><td>Methicillin resistant Staphylococcus aureus</td><td>0%</td></tr><tr><td>White</td><td>74%</td><td>Coagulase negative Staphylococci</td><td>25%</td></tr><tr><td>Other</td><td>12%</td><td>Other Streptococcus species</td><td>11%</td></tr><tr><td>Unknown</td><td>4%</td><td>Gram negative aerobic bacteria</td><td>14%</td></tr><tr><td colspan=\"2\">Ethnicity (percent)</td><td>Anaerobic bacteria</td><td>14%</td></tr><tr><td>Hispanic</td><td>18%</td><td>Candida species</td><td>4%</td></tr><tr><td>non-Hispanic</td><td>77%</td><td colspan=\"2\">Number of Source Control Procedures</td></tr><tr><td>Other</td><td>2%</td><td>Zero</td><td>32%</td></tr><tr><td>Unknown</td><td>4%</td><td>One</td><td>51%</td></tr><tr><td>Age (average years)</td><td>11.1</td><td>Two</td><td>14%</td></tr><tr><td>Sex (percent female)</td><td>35%</td><td>Three</td><td>4%</td></tr><tr><td colspan=\"2\">Intracranial Diagnosis</td><td colspan=\"2\">Laboratory Data</td></tr><tr><td>Brain Abscess</td><td>30%</td><td>Average highest C-reactive protein (mg/dl)</td><td>14.7</td></tr><tr><td>Subdural Abscess/Empyema</td><td>40%</td><td>Average C-reactive protein before oral transition (mg/dl)</td><td>0.9</td></tr><tr><td>Epidural Abscess/Empyema</td><td>60%</td><td>Average highest Erythrocyte sedimentation rate</td><td>66</td></tr><tr><td colspan=\"2\">Presumed Source of Infection</td><td>Average erythrocyte sedimentation rate before oral transition</td><td>18</td></tr><tr><td>Sinogenic</td><td>72%</td><td colspan=\"2\">Contributing reasons for oral transition</td></tr><tr><td>Otogenic</td><td>7%</td><td>Complication with central catheter</td><td>18%</td></tr><tr><td>Trauma</td><td>4%</td><td>Medication reaction/allergy</td><td>18%</td></tr><tr><td>Hematogenous/unknown</td><td>18%</td><td>Hematologic abnormalities</td><td>33%</td></tr><tr><td colspan=\"2\">Co-Diagnoses</td><td>Provider Judgement</td><td>56%</td></tr><tr><td>Orbital Abscess</td><td>16%</td><td>Length of IV therapy (average days)</td><td>37</td></tr><tr><td>Osteomyelitis</td><td>25%</td><td>Length of total therapy (average days)</td><td>84</td></tr><tr><td>Sinus Thrombosis</td><td>16%</td><td></td><td></td></tr></table>","table_caption":"[\"Table 1: Characteristics of patients transitioned to oral therapy (n= 57) \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[521,61,907,179]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1: Outcomes of oral transition versus timing of oral transition. \"]","image_footnote":"[]","img_path":"images/0478/3d4e8bca053244c78f8172ca253446cdc9dd11f657d9ee17ddc1065ace293490.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[521,210,907,349]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2: Reason for transition to oral therapy versus timing of oral transition. Note that single patients may have had more than one documented reason for transition to oral therapy. \"]","image_footnote":"[]","img_path":"images/0685/32ddee1123faa9532f58e54b42e0f0c4c099e3f32f39ae6619cee4dfb4f8f168.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,356,917,428]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion: We observed success and tolerance of levofloxacin-based oral therapy for pediatric pyogenic intracranial S. anginosus brain infections and confirmed the frequent occurrence of adverse events associated with IV treatment. Transition to oral therapy should be considered, particularly if complications of IV therapy arise in treatment of an epidural infection. A subset of patients in our study transitioned within the first 14 days of therapy; prospective studies are needed to characterize the safety of such very early transition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[526,428,778,438]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclosures: All Authors: No reported disclosures ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,457,878,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"346. Eastern Equine Encephalitis and Use of Intravenous Immunoglobulin Therapy and High-Dose Steroids ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,476,905,539]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sarah I. Collens, n/a; Douglas R. Wilcox, MD, PhD $^{2}$ ; Shibani Mukerji, MD, PhD $^{1}$ ; Farrah J. Mateen, MD, PhD $^{3}$ ; Isaac H. Solomon, MD, PhD $^{4}$ ; Massachusetts General Hospital, Boston, Massachusetts; Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Brigham and Women's Hospital, Boston, Massachusetts ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,544,650,554]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Session: P-11. CNS Infection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,558,917,599]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: Eastern equine encephalitis (EEE) is a mosquito-borne viral infection with significant neurological morbidity and mortality. The clinical presentation and patient outcomes after treatment with IVIG, high-dose steroids, or standard of care alone in EEE remains unclear. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,599,917,620]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: A retrospective observational study of patients admitted to two tertiary academic medical centers in Boston, Massachusetts with EEE from 2005 to 2019. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,620,917,732]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Of 17 patients (mean [SD] age, 50 [26] years; 10 (59%) male, and 16 (94%) White race), 17 patients had fever (100%), 15 had encephalopathy (88%), and 12 had headache (71%). Eleven of 14 patients with cerebrospinal fluid (CSF) cell count differential had a neutrophil predominance (mean [SD], 60.6% of white blood cells [22.8]) with an elevated protein level (mean [SD], $112\\mathrm{mg / dL}$ [48.8]). Affected neuroanatomical regions included the basal ganglia $(n = 9 / 17)$ , thalamus $(n = 7 / 17)$ , and mesial temporal lobe $(n = 7 / 17)$ . A total of 11 patients (65%) received IVIG; 8 (47%) received steroids. Of the patients who received IVIG, increased time from hospital admission to IVIG administration correlated with worse long-term disability as assessed by modified Rankin Score (mRS) $(r = 0.72, p = 0.02)$ ; steroid use was not associated with mRS score. The mortality was 12%. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,732,917,846]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 1. Imaging Characteristics: Typical Pattern of MRI Involvement and Affected Neuroanatomical Regions in Patients with Eastern Equine Encephalitis. All images displayed are the T2-FLAIR sequence. (A) Representative images of pattern of typical neuroanatomical region involved in one patient with demonstrated involvement of the temporal lobe and pons, temporal lobe and midbrain, and basal gangial by T2-FLAIR hyperintensity (panels left to right). (B) Representative images of patients with mild (mRS 0–2), moderate (mRS 3–4), and severe (mRS 5–6) disability score at discharge. (C) Representative images of one patient over course of hospitalization at days 1, 4, and 10 after admission. (D) Quantification of neuroanatomical region involvement in initial MRI of patients with EEE as determined by T2-FLAIR hyperintensity. An area was scored as abnormal only once per patient. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[954,240,974,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Downloaded from https://academic.oup.com/ofid/article/7/Supplement_1/S242/6058341 by guest on 25 May 2021 ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[78,933,363,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S242 OFID 2020:7 (Suppl 1) Poster Abstracts ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[87,49,473,228]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0575/00c8950a7d3d46810d0da457cb8bfacc6c697030d5160a5c154a27ce30c9ba68.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[87,278,478,451]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. Outcomes in Patients with Eastern Equine Encephalitis. Patient disability by modified Rankin Score (mRS) of EEE patients at admission to the hospital, discharge from the hospital, and last recorded follow-up (A). Time to IVIG administration compared to mRS at discharge (B), and most recent clinical follow-up (C). \"]","image_footnote":"[]","img_path":"images/0398/725fd45f5c5841b100388f2ed04af79f6a13952f7fd43ac8b80b2f00ddd6ee60.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,452,268,581]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0347/5f5b7e2337e1c88a3e5c3d96d1dd6a07e232ae3c5ef63a0681cee7ce6e8ff21e.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[287,452,470,580]","code_body":null,"code_caption":null,"image_caption":"[\"Table 1. Demographics, Clinical Characteristics, and Laboratory Data in Patients with Eastern Equine Encephalitis. Abbreviations: CSF = cerebrospinal fluid, WBC = white clood count, EEG = electroencephalogram, ALT = alanine aminotransferase, AST = aspartate transaminase. Demographic data was collected for all patients with confirmed EEE. Altered mental status included any description of encephalopathy, confusion, or difficulty with attention. Seizures were defined as clinical events with a high-degree of suspicion to be true seizures, and were entirely comprised of generalized tonic-clonic seizures. \"]","image_footnote":"[]","img_path":"images/0556/5ae360085e7f98baf82772c02235f058f3f1674c366b4210d8949a668eeab905.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[519,49,910,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0076/27d5102c5fdc4b06ac1ba736a310438e1427edc25d9bf00567f7791852facd1e.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":"<table><tr><td>Demographics</td><td>Overall Prevalence(n=17)</td><td>Received IVIG(n=11)</td><td>Did Not Receive IVIG(n=6)</td></tr><tr><td>Age, years (mean(SD))</td><td>50 (25)</td><td>55 (25)</td><td>41 (23)</td></tr><tr><td>Race, n (%)</td><td></td><td></td><td></td></tr><tr><td>White</td><td>16 (94)</td><td>11 (100)</td><td>5 (83)</td></tr><tr><td>Hispanic</td><td>1 (6)</td><td>0 (0)</td><td>1 (6)</td></tr><tr><td>Gender, n (%)</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>10 (59)</td><td>6 (55)</td><td>4 (67)</td></tr><tr><td>Female</td><td>7 (41)</td><td>5 (46)</td><td>2 (33)</td></tr><tr><td>Clinical Characteristics (n (%))</td><td></td><td></td><td></td></tr><tr><td>Fever</td><td>17 (100)</td><td>11 (100)</td><td>6 (100)</td></tr><tr><td>Altered Mental Status</td><td>15 (88)</td><td>10 (91)</td><td>5 (83)</td></tr><tr><td>Headache</td><td>12 (71)</td><td>7 (64)</td><td>5 (83)</td></tr><tr><td>Photophobia</td><td>3 (18)</td><td>1 (9)</td><td>2 (33)</td></tr><tr><td>Neck Stiffness</td><td>3 (18)</td><td>2 (18)</td><td>1 (17)</td></tr><tr><td>Nausea</td><td>5 (29)</td><td>2 (18)</td><td>3 (50)</td></tr><tr><td>Vomiting</td><td>6 (35)</td><td>2 (18)</td><td>4 (67)</td></tr><tr><td>Abdominal Pain</td><td>3 (18)</td><td>0 (0)</td><td>3 (50)</td></tr><tr><td>Respiratory Symptoms</td><td>2 (12)</td><td>1 (9)</td><td>1 (17)</td></tr><tr><td>Tremor</td><td>6 (35)</td><td>6 (55)</td><td>0 (0)</td></tr><tr><td>Seizures</td><td>7 (41)</td><td>5 (46)</td><td>2 (33)</td></tr><tr><td>Abnormal EEG</td><td>10 (59)</td><td>7 (64)</td><td>3 (50)</td></tr><tr><td>Prodrome, days, mean (range)</td><td>3 (0-9)</td><td>3 (0-7)</td><td>3 (0-9)</td></tr><tr><td colspan=\"4\">Laboratory Characteristics (mean(SD))</td></tr><tr><td>CSF WBC, cells, uL</td><td>645 (712)</td><td>601 (709)</td><td>726 (777)</td></tr><tr><td>CSF Glucose, mg/dL</td><td>71 (20)</td><td>70 (20)</td><td>68 (22)</td></tr><tr><td>CSF Total Protein, mg/dL</td><td>112 (47)</td><td>107 (48)</td><td>108 (50)</td></tr><tr><td>Serum WBC, K/uL</td><td>12 (5)</td><td>12 (5)</td><td>12 (6)</td></tr><tr><td>Sodium, mmol/L</td><td>135 (4)</td><td>135 (4)</td><td>136 (3)</td></tr><tr><td>Platelets, K/uL</td><td>181 (44)</td><td>181 (44)</td><td>194 (33)</td></tr><tr><td>ALT, U/L</td><td>45 (50)</td><td>41 (38)</td><td>56 (69)</td></tr><tr><td>AST, U/L</td><td>62 (79)</td><td>70 (87)</td><td>39 (27)</td></tr><tr><td>Alk Phos, U/L</td><td>94 (134)</td><td>111 (157)</td><td>56 (8)</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[509,333,917,384]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion: Clinicians should suspect EEE in immunocompetent patients with early subcortical neuroimaging abnormalities and CSF neutrophilic predominance. This study suggests a lower mortality than previously reported, but a high morbidity rate in EEE. IVIG as an adjunctive to standard of care may be considered early during hospitalization. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[527,386,776,397]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclosures: All Authors: No reported disclosures ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,414,855,434]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"347. Etiologies in a Cohort of Pediatric Patients Who Underwent CSF Metagenomic Next Generation Sequencing ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,434,915,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Molly Wilson-Murphy, MD<sup>1</sup>; Gabriella S. Lamb, MD, MPH<sup>2</sup>; Mark P. Gorman, MD<sup>3</sup>; Asim A. Ahmed, MD<sup>3</sup>; Boston Childrens Hospital, Needham, Massachusetts; Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Boston Children's Hospital, Boston, Massachusetts ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,480,650,491]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Session: P-11. CNS Infection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,496,917,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: The differential diagnosis in pediatric patients presenting with concern for CNS infections and/or autoimmune disorders is broad. Despite recent advances in diagnostic modalities, many cases may remain undiagnosed. For example, approximately $50\\%$ of pediatric patients with encephalitis do not have an identified etiology. Use of metagenomic next-generation sequencing (mNGS) may improve the diagnostic yield. This study evaluated etiologies in a cohort of pediatric patients who underwent CSF mNGS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,567,917,618]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: Retrospective cohort study of all hospitalized patients $< 21$ years-old who underwent CSF mNGS at a tertiary pediatric hospital from June, 2017 - February, 2020. Final diagnosis was assigned by two independent study physician reviewers (pediatric infectious disease and neurologist) based on documentation including discharge summaries, consult notes, and subsequent clinic notes where available. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,618,917,672]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Thirty-seven patients (59% female, median age 9 (1-17) years) were identified (21 with encephalitis). Twenty-six (70%) had a definite diagnosis - 10 (27%) infectious, 11 (30%) autoimmune, 5 (14%) other. The most common etiology was anti-MOG antibody associated meningoencephalitis $(n = 4, 11\\%)$ . Among infections, Powassan virus encephalitis $(n = 3, 8\\%)$ was most common; other infectious etiologies ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[954,240,974,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Downloaded from https://academic.oup.com/ofid/article/7/Supplement_1/S242/6058341 by guest on 25 May 2021 ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[633,933,872,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Poster Abstracts • OFID 2020:7 (Suppl 1) ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[880,934,915,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S243 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[85,54,430,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0664/30f8b44ed1b3310aeb159ea7d3dc964dae9b5096c22379f0c4b38e8e07e342f9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Variables</td><td>No of cases</td><td>Percentage, %</td><td>Median (SD)</td><td>Relative Risk (95% CI)</td><td>P-value</td></tr><tr><td colspan=\\\"6\\\">Comorbidities</td></tr><tr><td>Acquired immunodeficiency syndrome</td><td>122</td><td>18.31</td><td rowspan=\\\"10\\\"></td><td>Reference</td><td></td></tr><tr><td>Cancer</td><td>190</td><td>28.52</td><td>1.41 (1.15-1.72)</td><td>0.0008*</td></tr><tr><td>Cerebrovascular accidents</td><td>387</td><td>58.10</td><td>3.17 (2.66-3.77)</td><td><0.0001*</td></tr><tr><td>Chronic obstructive pulmonary disease</td><td>278</td><td>41.74</td><td>2.27 (1.89-2.73)</td><td><0.0001*</td></tr><tr><td>Congestive heart failure</td><td>249</td><td>37.38</td><td>2.04 (1.69-2.46)</td><td><0.0001*</td></tr><tr><td>Diabetes mellitus</td><td>299</td><td>44.89</td><td>2.45 (2.04-2.93)</td><td><0.0001*</td></tr><tr><td>Hypertension</td><td>305</td><td>45.79</td><td>2.50 (2.08-2.99)</td><td><0.0001*</td></tr><tr><td>Liver disease</td><td>205</td><td>30.78</td><td>1.68 (1.38-2.04)</td><td><0.0001*</td></tr><tr><td>Peripheral vascular disease</td><td>307</td><td>46.09</td><td>2.51 (2.10-3.01)</td><td><0.0001*</td></tr><tr><td>Renal disease</td><td>290</td><td>43.54</td><td>2.37 (1.98-2.85)</td><td><0.0001*</td></tr><tr><td colspan=\\\"6\\\">Charlson Comorbidity Index Score</td></tr><tr><td>1-4</td><td>163</td><td>24.47</td><td rowspan=\\\"6\\\">10.90 (9.52)</td><td>Reference</td><td></td></tr><tr><td>5-9</td><td>260</td><td>39.03</td><td>1.59 (1.35-1.87)</td><td><0.0001*</td></tr><tr><td>10-14</td><td>109</td><td>16.36</td><td>0.66 (0.53-0.83)</td><td>0.0003*</td></tr><tr><td>15-19</td><td>15</td><td>2.25</td><td>0.90 (0.05-0.15)</td><td><0.0001*</td></tr><tr><td>21-29</td><td>50</td><td>7.50</td><td>0.30 (0.22-0.41)</td><td><0.0001*</td></tr><tr><td>30-33</td><td>69</td><td>10.36</td><td>0.41 (0.32-0.54)</td><td><0.0001*</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2: Comorbidities and Charlson Comorbidity Index score of patients with brain abscess and cerebritis at Mayo Clinic, 2009-2019. \\\"]\",\n \"table_footnote\": \"[\\\"Abbreviations: CI, confidence interval; No, number; SD, standard deviation; $\\\\\\\\alpha$ , Chi-Square Test; $\\\\\\\\mu$ , Anova \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[77,219,485,260]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion: Male, White Non-Hispanics, and elderly patients seem to be the most prevalent patient population at risk for brain abscess or cerebritis. This investigation provides clinicians the demographic data needed to identify potentially complex patients with brain abscesses. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,260,484,282]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disclosures: M. Rizwan Sohail, MD, Aziyo Biologics (Consultant)Medtronic Inc (Consultant, Research Grant or Support) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,300,467,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"345. Early Oral Therapy for Streptococcus anginosus Purulent Brain Infections: A Single Center Experience \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,320,458,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniel S. Dodson, MD, MS $^{1}$ ; Heather R. Heizer, Physician Assistant $^{1}$ ; James Gaensbauer, MD $^{2}$ ; Children's Hospital Colorado, Aurora, CO; Children's Hospital Colorado and Denver Health, Denver, Colorado \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,356,218,365]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Session: P-11. CNS Infection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,372,484,411]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: Pediatric Streptococcus anginosus intracranial pyogenic are commonly treated with prolonged intravenous (IV) antibiotics, exposing patients to risks of a long-term central catheter. Antibiotics with high oral bioavailability, such as levofloxacin, may allow early oral transition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,411,485,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: To characterize patients with S. anginosus intracranial infections transitioned to oral therapy, we performed a retrospective review at Children's Hospital Colorado from 1/2004 to 2/2019. Inclusion criteria were radiologic evidence of an infected parenchymal, subdural, or epidural fluid collection AND a positive culture for S. anginosus from an intracranial source, specific extracranial sources (sinus, scalp, orbit), or blood. The primary endpoint was oral antibiotic failure defined as worsening infection on oral therapy. Comparisons were done using Fisher's exact test. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,484,485,597]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: 94 patients met inclusion criteria, 57 of whom were transitioned to oral therapy during treatment. Oral levofloxacin was used in 54 of the 57. $12\\\\%$ of oral transitions occurred in the first 14 days of therapy (range 3-8 days), and $35\\\\%$ in the first 28 days. Patients transitioned in the first 28 days were more likely to have an epidural collection $(p < 0.01)$ , and less likely to have a subdural collection (p: 0.03) or brain abscess $(p < 0.01)$ . Of the 57, none had oral antibiotic failure. Contributing reasons for oral transition included central line complications $(18\\\\%)$ , IV medication reaction $(18\\\\%)$ , hematologic abnormality presumed secondary to IV antibiotics $(33\\\\%)$ , and provider judgement $(56\\\\%)$ . Two patients required re-introduction of IV therapy for reasons other than clinical failure (one for medication non-adherence and one for adverse reaction to levofloxacin). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,613,478,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0277/2c420eb363bfeb06472c9887813392b79abcc316b45bbff92fead3920b8afe0d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td colspan=\\\"2\\\">Race (percent)</td><td colspan=\\\"2\\\">Co-Pathogens Present</td></tr><tr><td>Asian</td><td>4%</td><td>Methicillin sensitive Staphylococcus aureus</td><td>16%</td></tr><tr><td>Black or African American</td><td>7%</td><td>Methicillin resistant Staphylococcus aureus</td><td>0%</td></tr><tr><td>White</td><td>74%</td><td>Coagulase negative Staphylococci</td><td>25%</td></tr><tr><td>Other</td><td>12%</td><td>Other Streptococcus species</td><td>11%</td></tr><tr><td>Unknown</td><td>4%</td><td>Gram negative aerobic bacteria</td><td>14%</td></tr><tr><td colspan=\\\"2\\\">Ethnicity (percent)</td><td>Anaerobic bacteria</td><td>14%</td></tr><tr><td>Hispanic</td><td>18%</td><td>Candida species</td><td>4%</td></tr><tr><td>non-Hispanic</td><td>77%</td><td colspan=\\\"2\\\">Number of Source Control Procedures</td></tr><tr><td>Other</td><td>2%</td><td>Zero</td><td>32%</td></tr><tr><td>Unknown</td><td>4%</td><td>One</td><td>51%</td></tr><tr><td>Age (average years)</td><td>11.1</td><td>Two</td><td>14%</td></tr><tr><td>Sex (percent female)</td><td>35%</td><td>Three</td><td>4%</td></tr><tr><td colspan=\\\"2\\\">Intracranial Diagnosis</td><td colspan=\\\"2\\\">Laboratory Data</td></tr><tr><td>Brain Abscess</td><td>30%</td><td>Average highest C-reactive protein (mg/dl)</td><td>14.7</td></tr><tr><td>Subdural Abscess/Empyema</td><td>40%</td><td>Average C-reactive protein before oral transition (mg/dl)</td><td>0.9</td></tr><tr><td>Epidural Abscess/Empyema</td><td>60%</td><td>Average highest Erythrocyte sedimentation rate</td><td>66</td></tr><tr><td colspan=\\\"2\\\">Presumed Source of Infection</td><td>Average erythrocyte sedimentation rate before oral transition</td><td>18</td></tr><tr><td>Sinogenic</td><td>72%</td><td colspan=\\\"2\\\">Contributing reasons for oral transition</td></tr><tr><td>Otogenic</td><td>7%</td><td>Complication with central catheter</td><td>18%</td></tr><tr><td>Trauma</td><td>4%</td><td>Medication reaction/allergy</td><td>18%</td></tr><tr><td>Hematogenous/unknown</td><td>18%</td><td>Hematologic abnormalities</td><td>33%</td></tr><tr><td colspan=\\\"2\\\">Co-Diagnoses</td><td>Provider Judgement</td><td>56%</td></tr><tr><td>Orbital Abscess</td><td>16%</td><td>Length of IV therapy (average days)</td><td>37</td></tr><tr><td>Osteomyelitis</td><td>25%</td><td>Length of total therapy (average days)</td><td>84</td></tr><tr><td>Sinus Thrombosis</td><td>16%</td><td></td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1: Characteristics of patients transitioned to oral therapy (n= 57) \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[521,61,907,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1: Outcomes of oral transition versus timing of oral transition. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0478/3d4e8bca053244c78f8172ca253446cdc9dd11f657d9ee17ddc1065ace293490.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[521,210,907,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2: Reason for transition to oral therapy versus timing of oral transition. Note that single patients may have had more than one documented reason for transition to oral therapy. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0685/32ddee1123faa9532f58e54b42e0f0c4c099e3f32f39ae6619cee4dfb4f8f168.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,356,917,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion: We observed success and tolerance of levofloxacin-based oral therapy for pediatric pyogenic intracranial S. anginosus brain infections and confirmed the frequent occurrence of adverse events associated with IV treatment. Transition to oral therapy should be considered, particularly if complications of IV therapy arise in treatment of an epidural infection. A subset of patients in our study transitioned within the first 14 days of therapy; prospective studies are needed to characterize the safety of such very early transition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[526,428,778,438]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disclosures: All Authors: No reported disclosures \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,457,878,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"346. Eastern Equine Encephalitis and Use of Intravenous Immunoglobulin Therapy and High-Dose Steroids \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,476,905,539]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sarah I. Collens, n/a; Douglas R. Wilcox, MD, PhD $^{2}$ ; Shibani Mukerji, MD, PhD $^{1}$ ; Farrah J. Mateen, MD, PhD $^{3}$ ; Isaac H. Solomon, MD, PhD $^{4}$ ; Massachusetts General Hospital, Boston, Massachusetts; Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Brigham and Women's Hospital, Boston, Massachusetts \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,544,650,554]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Session: P-11. CNS Infection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,558,917,599]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: Eastern equine encephalitis (EEE) is a mosquito-borne viral infection with significant neurological morbidity and mortality. The clinical presentation and patient outcomes after treatment with IVIG, high-dose steroids, or standard of care alone in EEE remains unclear. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,599,917,620]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: A retrospective observational study of patients admitted to two tertiary academic medical centers in Boston, Massachusetts with EEE from 2005 to 2019. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,620,917,732]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Of 17 patients (mean [SD] age, 50 [26] years; 10 (59%) male, and 16 (94%) White race), 17 patients had fever (100%), 15 had encephalopathy (88%), and 12 had headache (71%). Eleven of 14 patients with cerebrospinal fluid (CSF) cell count differential had a neutrophil predominance (mean [SD], 60.6% of white blood cells [22.8]) with an elevated protein level (mean [SD], $112\\\\mathrm{mg / dL}$ [48.8]). Affected neuroanatomical regions included the basal ganglia $(n = 9 / 17)$ , thalamus $(n = 7 / 17)$ , and mesial temporal lobe $(n = 7 / 17)$ . A total of 11 patients (65%) received IVIG; 8 (47%) received steroids. Of the patients who received IVIG, increased time from hospital admission to IVIG administration correlated with worse long-term disability as assessed by modified Rankin Score (mRS) $(r = 0.72, p = 0.02)$ ; steroid use was not associated with mRS score. The mortality was 12%. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,732,917,846]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 1. Imaging Characteristics: Typical Pattern of MRI Involvement and Affected Neuroanatomical Regions in Patients with Eastern Equine Encephalitis. All images displayed are the T2-FLAIR sequence. (A) Representative images of pattern of typical neuroanatomical region involved in one patient with demonstrated involvement of the temporal lobe and pons, temporal lobe and midbrain, and basal gangial by T2-FLAIR hyperintensity (panels left to right). (B) Representative images of patients with mild (mRS 0–2), moderate (mRS 3–4), and severe (mRS 5–6) disability score at discharge. (C) Representative images of one patient over course of hospitalization at days 1, 4, and 10 after admission. (D) Quantification of neuroanatomical region involvement in initial MRI of patients with EEE as determined by T2-FLAIR hyperintensity. An area was scored as abnormal only once per patient. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[954,240,974,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Downloaded from https://academic.oup.com/ofid/article/7/Supplement_1/S242/6058341 by guest on 25 May 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[78,933,363,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S242 OFID 2020:7 (Suppl 1) Poster Abstracts \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[87,49,473,228]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0575/00c8950a7d3d46810d0da457cb8bfacc6c697030d5160a5c154a27ce30c9ba68.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[87,278,478,451]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. Outcomes in Patients with Eastern Equine Encephalitis. Patient disability by modified Rankin Score (mRS) of EEE patients at admission to the hospital, discharge from the hospital, and last recorded follow-up (A). Time to IVIG administration compared to mRS at discharge (B), and most recent clinical follow-up (C). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0398/725fd45f5c5841b100388f2ed04af79f6a13952f7fd43ac8b80b2f00ddd6ee60.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,452,268,581]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0347/5f5b7e2337e1c88a3e5c3d96d1dd6a07e232ae3c5ef63a0681cee7ce6e8ff21e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[287,452,470,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Table 1. Demographics, Clinical Characteristics, and Laboratory Data in Patients with Eastern Equine Encephalitis. Abbreviations: CSF = cerebrospinal fluid, WBC = white clood count, EEG = electroencephalogram, ALT = alanine aminotransferase, AST = aspartate transaminase. Demographic data was collected for all patients with confirmed EEE. Altered mental status included any description of encephalopathy, confusion, or difficulty with attention. Seizures were defined as clinical events with a high-degree of suspicion to be true seizures, and were entirely comprised of generalized tonic-clonic seizures. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0556/5ae360085e7f98baf82772c02235f058f3f1674c366b4210d8949a668eeab905.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[519,49,910,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0076/27d5102c5fdc4b06ac1ba736a310438e1427edc25d9bf00567f7791852facd1e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Demographics</td><td>Overall Prevalence(n=17)</td><td>Received IVIG(n=11)</td><td>Did Not Receive IVIG(n=6)</td></tr><tr><td>Age, years (mean(SD))</td><td>50 (25)</td><td>55 (25)</td><td>41 (23)</td></tr><tr><td>Race, n (%)</td><td></td><td></td><td></td></tr><tr><td>White</td><td>16 (94)</td><td>11 (100)</td><td>5 (83)</td></tr><tr><td>Hispanic</td><td>1 (6)</td><td>0 (0)</td><td>1 (6)</td></tr><tr><td>Gender, n (%)</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>10 (59)</td><td>6 (55)</td><td>4 (67)</td></tr><tr><td>Female</td><td>7 (41)</td><td>5 (46)</td><td>2 (33)</td></tr><tr><td>Clinical Characteristics (n (%))</td><td></td><td></td><td></td></tr><tr><td>Fever</td><td>17 (100)</td><td>11 (100)</td><td>6 (100)</td></tr><tr><td>Altered Mental Status</td><td>15 (88)</td><td>10 (91)</td><td>5 (83)</td></tr><tr><td>Headache</td><td>12 (71)</td><td>7 (64)</td><td>5 (83)</td></tr><tr><td>Photophobia</td><td>3 (18)</td><td>1 (9)</td><td>2 (33)</td></tr><tr><td>Neck Stiffness</td><td>3 (18)</td><td>2 (18)</td><td>1 (17)</td></tr><tr><td>Nausea</td><td>5 (29)</td><td>2 (18)</td><td>3 (50)</td></tr><tr><td>Vomiting</td><td>6 (35)</td><td>2 (18)</td><td>4 (67)</td></tr><tr><td>Abdominal Pain</td><td>3 (18)</td><td>0 (0)</td><td>3 (50)</td></tr><tr><td>Respiratory Symptoms</td><td>2 (12)</td><td>1 (9)</td><td>1 (17)</td></tr><tr><td>Tremor</td><td>6 (35)</td><td>6 (55)</td><td>0 (0)</td></tr><tr><td>Seizures</td><td>7 (41)</td><td>5 (46)</td><td>2 (33)</td></tr><tr><td>Abnormal EEG</td><td>10 (59)</td><td>7 (64)</td><td>3 (50)</td></tr><tr><td>Prodrome, days, mean (range)</td><td>3 (0-9)</td><td>3 (0-7)</td><td>3 (0-9)</td></tr><tr><td colspan=\\\"4\\\">Laboratory Characteristics (mean(SD))</td></tr><tr><td>CSF WBC, cells, uL</td><td>645 (712)</td><td>601 (709)</td><td>726 (777)</td></tr><tr><td>CSF Glucose, mg/dL</td><td>71 (20)</td><td>70 (20)</td><td>68 (22)</td></tr><tr><td>CSF Total Protein, mg/dL</td><td>112 (47)</td><td>107 (48)</td><td>108 (50)</td></tr><tr><td>Serum WBC, K/uL</td><td>12 (5)</td><td>12 (5)</td><td>12 (6)</td></tr><tr><td>Sodium, mmol/L</td><td>135 (4)</td><td>135 (4)</td><td>136 (3)</td></tr><tr><td>Platelets, K/uL</td><td>181 (44)</td><td>181 (44)</td><td>194 (33)</td></tr><tr><td>ALT, U/L</td><td>45 (50)</td><td>41 (38)</td><td>56 (69)</td></tr><tr><td>AST, U/L</td><td>62 (79)</td><td>70 (87)</td><td>39 (27)</td></tr><tr><td>Alk Phos, U/L</td><td>94 (134)</td><td>111 (157)</td><td>56 (8)</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[509,333,917,384]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion: Clinicians should suspect EEE in immunocompetent patients with early subcortical neuroimaging abnormalities and CSF neutrophilic predominance. This study suggests a lower mortality than previously reported, but a high morbidity rate in EEE. IVIG as an adjunctive to standard of care may be considered early during hospitalization. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[527,386,776,397]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disclosures: All Authors: No reported disclosures \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,414,855,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"347. Etiologies in a Cohort of Pediatric Patients Who Underwent CSF Metagenomic Next Generation Sequencing \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,434,915,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Molly Wilson-Murphy, MD<sup>1</sup>; Gabriella S. Lamb, MD, MPH<sup>2</sup>; Mark P. Gorman, MD<sup>3</sup>; Asim A. Ahmed, MD<sup>3</sup>; Boston Childrens Hospital, Needham, Massachusetts; Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Boston Children's Hospital, Boston, Massachusetts \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,480,650,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Session: P-11. CNS Infection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,496,917,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: The differential diagnosis in pediatric patients presenting with concern for CNS infections and/or autoimmune disorders is broad. Despite recent advances in diagnostic modalities, many cases may remain undiagnosed. For example, approximately $50\\\\%$ of pediatric patients with encephalitis do not have an identified etiology. Use of metagenomic next-generation sequencing (mNGS) may improve the diagnostic yield. This study evaluated etiologies in a cohort of pediatric patients who underwent CSF mNGS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,567,917,618]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: Retrospective cohort study of all hospitalized patients $< 21$ years-old who underwent CSF mNGS at a tertiary pediatric hospital from June, 2017 - February, 2020. Final diagnosis was assigned by two independent study physician reviewers (pediatric infectious disease and neurologist) based on documentation including discharge summaries, consult notes, and subsequent clinic notes where available. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,618,917,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Thirty-seven patients (59% female, median age 9 (1-17) years) were identified (21 with encephalitis). Twenty-six (70%) had a definite diagnosis - 10 (27%) infectious, 11 (30%) autoimmune, 5 (14%) other. The most common etiology was anti-MOG antibody associated meningoencephalitis $(n = 4, 11\\\\%)$ . Among infections, Powassan virus encephalitis $(n = 3, 8\\\\%)$ was most common; other infectious etiologies \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[954,240,974,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Downloaded from https://academic.oup.com/ofid/article/7/Supplement_1/S242/6058341 by guest on 25 May 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[633,933,872,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Poster Abstracts • OFID 2020:7 (Suppl 1) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[880,934,915,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S243 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1093/ofid/ofaa439.541"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"62cc53d6501cae3ae09e713020d39f55b8cee4dfa50d988181ddc584c644acd9"},"title":{"kind":"string","value":"346. Eastern Equine Encephalitis and Use of Intravenous Immunoglobulin Therapy and High-Dose Steroids"}}},{"rowIdx":151,"cells":{"abstract":{"kind":"string","value":"A monomeric form of C-reactive protein (CRP) which precipitates with cell wall pneumococcal C polysaccharide (CWPS) and retains the ability to reversibly bind to its ligand phosphocholine has been produced through urea-induced dissociation at an optimized concentration of 3 M urea over a 10 weeks period. Dissociated samples were purified via size exclusion chromatography and characterized by western blot, phosphocholine affinity chromatography and CWPS precipitation. Human serum samples from patients with raised CRP levels (>100 mg/L as determined by the clinical laboratory assay) were purified by affinity and size exclusion chromatography and analyzed (n = 40) to determine whether circulating monomeric CRP could be detected ex vivo. All 40 samples tested positive for pentameric CRP via western blot and enzyme linked immunosorbent assay (ELISA) analysis. Monomeric C-reactive protein was also identified in all 40 patient samples tested, with an average level recorded of 1.03 mg/L (SE = ±0.11). Both the in vitro monomeric C-reactive protein and the human serum monomeric protein displayed a molecular weight of approximately 23 kDa, both were recognized by the same anti-CRP monoclonal antibody and both reversibly bound to phosphocholine in a calcium-dependent manner. In common with native pentameric CRP, the in vitro mCRP precipitated with CWPS. These overlapping characteristics suggest that a physiologically relevant, near-native monomeric CRP, which retains the structure and binding properties of native CRP subunits, has been produced through in vitro dissociation of pentameric CRP and also isolated from serum with markedly elevated CRP levels. This provides a clear route toward the in-depth study of the structure and function of physiological monomeric CRP."},"author":{"kind":"string","value":"Jennifer A. Moran|Trevor J. Greenhough|Annette K. Shrive|Jamie R. Littlejohn|Harry M. Williams|Robert D. Williams|Anthony A. Fryer"},"content_list":{"kind":"list like","value":[{"bbox":"[295,181,897,385]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric C-Reactive Protein in Serum With Markedly Elevated CRP Levels Shares Common Calcium-Dependent Ligand Binding Properties With an in vitro Dissociated Form of C-Reactive Protein ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[142,369,268,383]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[208,397,268,409]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Edited by: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[189,410,267,421]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Janos G. 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,827,268,839]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Serum With Markedly Elevated CRP ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[144,840,268,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Levels Shares Common ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,853,268,866]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Calcium-Dependent Ligand Binding ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,867,268,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Properties With an in vitro Dissociated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[124,879,268,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Form of C-Reactive Protein. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[142,892,268,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Front. Immunol. 11:115. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,903,268,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"doi: 10.3389/fimmu.2020.00115 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[292,403,862,433]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Robert D. Williams<sup>1†</sup>, Jennifer A. Moran<sup>1</sup>, Anthony A. Fryer<sup>2</sup>, Jamie R. Littlejohn<sup>1</sup>, Harry M. Williams<sup>1</sup>, Trevor J. Greenhough<sup>1</sup> and Annette K. Shrive<sup>1*</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[292,442,922,468]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"<sup>1</sup>School of Life Sciences, Keele University, Staffordshire, United Kingdom, <sup>2</sup>Department of Clinical Biochemistry, Institute for Applied Clinical Sciences, University Hospitals of North Midlands, Keele University, Staffordshire, United Kingdom ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[292,489,927,881]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A monomeric form of C-reactive protein (CRP) which precipitates with cell wall pneumococcal C polysaccharide (CWPS) and retains the ability to reversibly bind to its ligand phosphocholine has been produced through urea-induced dissociation at an optimized concentration of 3M urea over a 10 weeks period. Dissociated samples were purified via size exclusion chromatography and characterized by western blot, phosphocholine affinity chromatography and CWPS precipitation. Human serum samples from patients with raised CRP levels ( $>100\\mathrm{mg/L}$ as determined by the clinical laboratory assay) were purified by affinity and size exclusion chromatography and analyzed ( $n = 40$ ) to determine whether circulating monomeric CRP could be detected ex vivo. All 40 samples tested positive for pentameric CRP via western blot and enzyme linked immunosorbent assay (ELISA) analysis. Monomeric C-reactive protein was also identified in all 40 patient samples tested, with an average level recorded of $1.03\\mathrm{mg/L}$ ( $\\mathrm{SE} = \\pm 0.11$ ). Both the in vitro monomeric C-reactive protein and the human serum monomeric protein displayed a molecular weight of approximately $23\\mathrm{kDa}$ , both were recognized by the same anti-CRP monoclonal antibody and both reversibly bound to phosphocholine in a calcium-dependent manner. In common with native pentameric CRP, the in vitro mCRP precipitated with CWPS. These overlapping characteristics suggest that a physiologically relevant, near-native monomeric CRP, which retains the structure and binding properties of native CRP subunits, has been produced through in vitro dissociation of pentameric CRP and also isolated from serum with markedly elevated CRP levels. This provides a clear route toward the in-depth study of the structure and function of physiological monomeric CRP. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[292,890,924,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: monomeric C-reactive protein, serum C-reactive protein, dissociated C-reactive protein, calcium-dependent ligand binding, phosphocholine, C-polysaccharide, pentraxin, innate immunity ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,30,104,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[105,41,201,57]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiers ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[105,59,268,75]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in Immunology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[798,42,924,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORIGINAL RESEARCH ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[776,53,924,62]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"published: 04 February 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[757,64,924,74]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"doi: 10.3389/fimmu.2020.00115 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[875,91,924,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,948,302,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[492,949,504,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[722,948,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[73,75,230,89]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,103,485,367]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C-reactive protein (CRP) belongs to the family of proteins known as the pentraxins, which have been highly conserved throughout evolution and can be identified in species ranging from mammals and fish to the primitive Atlantic horseshoe crab, Limulus polyphemus (1). The human form of CRP displays a ring structure of five non-covalently bound subunits around a central pore, with each subunit containing 206 amino acids folded into two antiparallel $\\beta$ -sheets with a flattened jellyroll topology (2). Two calcium ions are contained within each promoter, forming the site for the binding of ligands such as phosphocholine (PCho) expressed on the surface structures of pathogens and dead or damaged cell membranes (2, 3). The primary role of CRP within the human body is believed to be the initiation of the innate immune response via the classical complement pathway, cytokine induced inflammation and interactions with antibodies. However, more complex roles for CRP have been described, including immune exacerbation, regulation and suppression (4-7). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,369,485,661]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In normal, healthy individuals, baseline levels of CRP range from 1 to $5\\mathrm{mg / L}$ (8). During infection, inflammation or tissue damage, CRP levels will rise acutely to elicit a sufficient immune response over a $24 - 72\\mathrm{h}$ period. Due to this rapid increase in serum levels of CRP, it is routinely measured as a clinical biomarker for infection or inflammation in the healthcare setting. Over recent years, evidence has emerged linking CRP to the development and progression of chronic, auto-inflammatory diseases such as cardiovascular disease (9, 10). It has been hypothesized that CRP exerts an alternative, pro-inflammatory role in disease development, with in vitro studies demonstrating up-regulation of cell adhesion molecules, activation of endothelial cells, deposition within atherosclerotic lesions and the increased production of inflammatory cytokines; all common features found in the pathophysiology of cardiovascular disease (8, 11-15). This evidence has led to the development of a high sensitivity CRP assay which can accurately measure CRP levels $< 3\\mathrm{mg / L}$ and assess an individual's risk of developing cardiovascular disease (9, 10). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,663,485,793]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although human pentameric CRP (pCRP) is extremely stable under physiological conditions, there is increasing evidence which suggests a biological role for a monomeric form of CRP, commonly denoted mCRP (16-19). A wide variety of in vitro and ex vivo monomeric CRP (mCRP) conformers have been reported, ranging from the in vitro denatured mCRP produced by high concentrations of urea (up to $8\\mathrm{M}$ ) (20) through reduced membrane bound mCRP (21) to the hybrid mCRP with near native structure (22). Monoclonal antibodies for the various ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,77,922,311]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"conformers have been generated, including those targeting neoepitopes revealed by pCRP subunit dissociation, and used to identify monomeric forms as distinct from pCRP (23-25). The urea dissociated mCRP of Potempa et al. (20) remains very much the prototypical mCRP, being used in a wide variety of studies for over 30 years. This mCRP displays a decrease in solubility (being insoluble in calcium concentrations as low as $0.05\\mathrm{mM}$ ) and isoelectric point and a loss of calcium-dependent binding to the prototypical CRP ligand C-polysaccharide (20). This monomer could not be re-associated back into its pentameric form, the dissociation being accompanied by significant changes in both structure and function (26). On the basis of reduction of the intrachain disulphide in this mCRP, but not in pCRP, by reducing agents such as dithiothreitol, several reports have shown discrimination between pentameric and monomeric CRP (21, 27, 28). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,313,922,649]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Several models suggesting a physiological mechanism for the formation of mCRP have been postulated within the literature. The most widely accepted involves dissociation through calcium-dependent binding of pCRP to cell membranes (17, 18, 25, 27-32) although a clear picture is yet to emerge of the nature and fate of the resulting mCRP conformer. Binding to microvesicles has been proposed to lead to pCRP structural changes that allow binding of C1q and hence complement activation (27). In addition, increasing experimental evidence within the literature suggests a pro-inflammatory role for mCRP (33) and a link between mCRP and the progression of certain auto-inflammatory diseases within the body. Similarly to that described previously for pCRP, mCRP displays an ability to stimulate cytokine production and up-regulate the production of adhesion molecules as well as induce thrombus growth formation and alter fibrin properties and tissue factor expression (18, 34). It has been hypothesized that circulating micro-particles, generated from lipid membranes, can not only induce pCRP dissociation, but also act as a mode of transport around the body to sites of intensified inflammation (30). The failure of standard clinical CRP tests, employed in a large proportion of healthcare laboratories, to detect mCRP that is bound to circulating microparticles has also been highlighted (35). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,650,922,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"More recently, the development of ELISA methods which can quantify mCRP in clinical serum and tissue samples down to $1\\mathrm{ng / ml}$ have been reported (24, 36). Zhang et al. (36) demonstrated a sandwich ELISA that detected mCRP in patients with skin-related autoimmune disorders, with a statistical difference in mCRP levels when compared to the control group, even when native, pentameric samples showed no such difference (35). Levels of serum mCRP reported by Zhang et al. (36) were in the $\\mathrm{ng / ml}$ range, as were those reported by Wang et al. (24) who employed a monoclonal antibody based on the C-terminal octapeptide of CRP, proposed to be exposed on pCRP dissociation by treatment with $8\\mathrm{M}$ urea, in a study of mCRP levels in acute myocardial infarction (AMI). The antibody was shown to recognize mCRP from denatured pCRP, but not pCRP itself. This study of patients $(n = 101)$ who had recently suffered with an AMI reported an average recorded mCRP serum level of $0.021\\mathrm{mg / L}$ (24), with six patients out of 42 with raised levels of pCRP ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,817,485,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abbreviations: CRP, human C-reactive protein; pCRP, pentameric human C-reactive protein; mCRP, monomeric human C-reactive protein; BSA, bovine serum albumin; PBS, phosphate buffered saline; TMB, 3, $3^{\\prime}$ , 5, $5^{\\prime}$ , tetramethylbenzidine; APC, $p$ -aminophenyl phosphoryl choline; FPLC, Fast Protein Liquid Chromatography; CWPS, Streptococcus pneumoniae cell wall C-polysaccharide; NRES, National Health Service Research Ethics Service; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme linked immunosorbent assay; tris, tris(hydroxymethyl)aminomethane; PCho, phosphocholine. ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[73,949,300,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[722,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[73,77,485,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(3-285 mg/L) displaying detectable mCRP levels of 0.0057 mg/L-0.1227 mg/L. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,107,485,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our aim was to generate, and find in serum with markedly elevated CRP levels, a near native mCRP that retains as far as possible the structure and binding of the monomer in the pentameric molecule. We describe the production, purification and characterization of in vitro mCRP, produced under milder dissociation conditions than those usually employed, alongside the analysis of human serum samples from patients exhibiting raised CRP levels $(>100\\mathrm{mg / L})$ by clinical assay. This analysis reveals an ex vivo form of mCRP in all patient samples analyzed. Both forms of mCRP were recognized by the same anti-CRP monoclonal antibody, both were soluble in tris buffered saline with $5 - 10\\mathrm{mM}$ $\\mathrm{CaCl}_2$ ,and both reversibly bound to PCho in a calcium-dependent manner. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,313,344,329]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MATERIALS AND METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,342,485,459]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Standard buffers used were as follows: buffer A: (storage buffer) $20\\mathrm{mM}$ tris(hydroxymethyl) aminomethane (tris), $280\\mathrm{mMNaCl}$ , $5\\mathrm{mM}\\mathrm{CaCl}_2$ , $0.01\\%$ sodium azide, $\\mathrm{pH}7.4$ ; buffer B: (elution buffer) $50\\mathrm{mM}$ tris, $150\\mathrm{mMNaCl}$ , $\\mathrm{pH}7.2$ ; buffer C: (equilibration buffer) $10\\mathrm{mM}\\mathrm{CaCl}_2$ , $50\\mathrm{mM}$ tris $\\mathrm{pH}7.4$ , $150\\mathrm{mMNaCl}$ , $0.01\\%$ sodium azide; buffer D: (chelating buffer) $10\\mathrm{mM}$ ethylenediaminetetraacetic acid (EDTA), $50\\mathrm{mM}$ tris $\\mathrm{pH}7.4$ , $150\\mathrm{mMNaCl}$ , $0.01\\%$ sodium azide. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,469,220,486]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ELISA Protocol ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,487,485,707]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The general procedures for ELISA were as follows: All ELISA analysis was carried out on a sterile, 96-well plate (Costar). $50~\\mu \\mathrm{l}$ of each sample was added to each well. Plates were blocked with $3\\%$ bovine serum albumin (BSA) and washed with phosphate buffered saline (PBS)-Tween (Sigma). The primary antibody used was a monoclonal anti-C-reactive protein antibody (CRP-8, Sigma) produced in a mouse; the secondary antibody was an antimouse IgG (whole molecule)-peroxidase antibody produced in rabbit (Sigma). Both were used at 1:40,000 dilution. Positive and negative controls were included in analysis and all samples were tested in triplicate. The developing substrate used was $3, 3^{\\prime}, 5, 5^{\\prime}$ , tetramethylbenzidine (TMB) liquid substrate (Sigma). ELISA plates were left to develop for $10\\mathrm{min}$ prior to addition of $2\\mathrm{M}$ sulfuric acid. Plates were read at $450\\mathrm{nm}$ on a BioTek EL800 plate reader using Gen5 software. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,718,389,750]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Production of in vitro Monomeric C-Reactive Protein ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,753,485,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Native pentameric human CRP (pCRP) was purchased from Scripps in storage buffer (buffer A). Dissociation was achieved through the addition of pCRP to a range of dissociation buffers $(20\\mathrm{mM}$ tris, $280\\mathrm{mMNaCl},$ 1 mM EDTA, and 2, 2.5, 3, and 4 M urea), followed by storage at $4^{\\circ}\\mathrm{C}$ for periods of up to 12 weeks. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,835,369,871]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Phosphocholine (PCho) Affinity Chromatography ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,872,485,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Immobilized $p$ -aminophenyl phosphoryl choline (APC) was purchased from Fisher Scientific in the form of a gel, crosslinked with $6\\%$ beaded agarose. The binding capacity of the APC ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,77,922,252]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"was $>3\\mathrm{mg}$ of CRP per $1\\mathrm{ml}$ of gel. All affinity chromatography experiments for both in vitro and ex vivo CRP were run using the Biologic LP Chromatography System (BioRad) with a flow rate of $0.5\\mathrm{ml / min}$ throughout. The absorbance was measured at $280~\\mathrm{nm}$ . Prior to samples being run through the column, the column was equilibrated with 20 column volumes of equilibration buffer (buffer C) and the UV absorbance baseline reading was then blanked to a value of 0 absorbance units (Au) prior to application of the sample. Once the entire sample had been applied, the column was re-equilibrated with 5 column volumes of buffer C followed by elution with the chelating buffer (buffer D) until the UV absorbance reading had returned to its baseline value of 0 Au. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,270,831,304]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Purification of in vitro Monomeric C-Reactive Protein (mCRP) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,305,922,480]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"mCRP and pCRP in the urea dissociated samples were separated and purified using the AKTA explorer 100 Fast Protein Liquid Chromatography (FPLC) system (GE Healthcare) with a HiLoad 16/60 Superdex $200~\\mathrm{pg}$ column. Calibration was performed using a Gel Filtration Calibration Kit (GE Healthcare), with the included molecular weight markers ferritin, aldolase, conalbumin, ovalbumin, and ribonuclease (elution buffer: buffer B). The void volume was determined using Blue Dextran (Sigma). Samples were injected onto the column via a $2\\mathrm{ml}$ sample injection loop and elution was monitored by UV absorbance at $280~\\mathrm{nm}$ at a flow rate of $0.5\\mathrm{ml / min}$ . Samples were eluted off and collected in $5\\mathrm{ml}$ fractions in the storage buffer A. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,496,897,532]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SDS PAGE and Western Blots of Purified pCRP and in vitro mCRP Samples ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,532,922,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Both purified dissociated CRP samples and CRP purified from human serum were confirmed to contain CRP through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and western blot analysis. Samples were run under non-reducing conditions on a $12.5\\%$ resolving and $4\\%$ stacking gel. All reagents were purchased from Sigma. SDS PAGE was run in a BioRad mini-Protein II cell at $200\\mathrm{V}$ for approximately $45 - 50\\mathrm{min}$ . All samples were run with positive and negative controls and molecular weight markers. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,664,922,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Western blot analysis was performed using the Mini TransBlot Electrophoretic Transfer Cell (BioRad), using nitrocellulose blotting paper or Polyvinylidene difluoride (PVDF) membrane. The transfer was run at $350\\mathrm{mA}$ for $1\\mathrm{h}$ at $4^{\\circ}\\mathrm{C}$ . Membranes were blocked with Marvel dried milk powder and washed with BLOTTO (Marvel dried milk, Triton-X 100 or Tween-20, and tris-buffered saline). The primary antibody, a monoclonal anti-C-reactive protein antibody (CRP-8, Sigma) produced in a mouse, was used at a 1:1,000 dilution except for the mCRP purified from human serum (1:400) and for the non-dissociated pCRP following treatment with urea (1:200). The secondary antibody, an anti-mouse IgG (whole molecule)-peroxidase antibody produced in rabbit (Sigma), was used at a 1:40,000 dilution except for the non-dissociated pCRP following treatment with urea (1:2,000). Clarity Western Enzyme Chemiluminescence substrate (BioRad) or Thermo Scientific™ SuperSignal™ West Pico Chemiluminescent Substrate diluted x4 was used to detect ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[73,77,485,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"protein bands which were visualized using a CCD digital image detector. Exposure time was approximately 30-60 min. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,116,334,152]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Binding of in vitro mCRP to Phosphocholine ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,152,485,240]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The calcium-dependent binding to PCho of the size exclusion purified mCRP from the 3M urea dissociation was assessed using PCho affinity chromatography as described above. Protein samples were prepared by diluting $500\\mu \\mathrm{l}$ $(250~\\mu \\mathrm{g})$ of the mCRP in $5\\mathrm{ml}$ of buffer C. Larger volumes of samples were used to prevent air bubbles entering the column whilst applying a sample. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,250,467,284]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Precipitation Studies With Streptococcus pneumoniae Cell Wall Polysaccharide ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[72,286,211,300]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ELISA Calibration ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,301,485,388]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$50~\\mu \\mathrm{l}$ of calcium buffer (buffer A) was added to columns 1-12, rows A-F of the ELISA plate. $50~\\mu \\mathrm{l}$ $(3.0~\\mu \\mathrm{g}$ in $50~\\mu \\mathrm{l}, 60~\\mathrm{mg / L})$ of pCRP (Scripps) was added to column 1, rows A-C, and mCRP (in vitro, purified following the $3\\mathrm{M}$ dissociation) to rows D-F. Serial dilution through to column 11, rows A-F was carried out leaving buffer A in column 12 rows A-F (negative control). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,400,268,415]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CRP/CWPS Precipitation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,415,485,650]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Native pCRP (Scripps) alongside mCRP (dissociated with $3\\mathrm{M}$ urea and purified by size exclusion), were incubated with varying amounts of Streptococcus pneumoniae cell wall C-polysaccharide (CWPS; Oxford Biosystems). CWPS quantities used were 0.1, 0.5, 1, 10, 20, 50, 100, 200, $300~\\mu \\mathrm{g}$ . Both CRP samples contained 20 $\\mu \\mathrm{g}$ in $400~\\mu \\mathrm{l}$ buffer A. All samples were incubated at $37^{\\circ}\\mathrm{C}$ for $1\\mathrm{h}$ whilst being gently agitated. The samples were then centrifuged at $6,500\\times \\mathrm{g}$ for $15\\mathrm{min}$ to pellet the precipitate and the supernatant from each sample was transferred to separate tubes. Precipitation levels were calculated based on the remaining concentration of protein within the supernatant via ELISA following the general procedures outlined above. CRP concentrations were determined using the calibration line equations and the total level of precipitation was calculated by subtracting the total amount of CRP remaining in solution post CWPS incubation from the initial amount $(20~\\mu \\mathrm{g})$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,661,467,677]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein Concentration and Quantification ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,679,485,840]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Eluted protein samples were stored for use at $4^{\\circ}\\mathrm{C}$ in the various elution buffers following concentration using a Vivaspin Centrifugal Concentrator (Fisher Scientific), $10\\mathrm{kDa}$ molecular weight cut off. The concentrator was initially primed with deionised water and spun at $1,000\\times \\mathrm{g}, 4^{\\circ}\\mathrm{C}$ for $10\\mathrm{min}$ . The protein sample was then spun at $1,000\\times \\mathrm{g}, 4^{\\circ}\\mathrm{C}$ for $15\\mathrm{min}$ or until the desired concentration had been achieved. The protein content of the CRP samples was determined from absorbance at UV $280\\mathrm{nm}$ . The extinction coefficient was calculated from the CRP sequence as 1.7 (Expasy, http://web.expasy.org/protparam/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,849,450,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ethical Application and Research Study Design ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[72,885,485,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ethical approval for the human serum samples pilot study was granted by UK National Health Service Research Ethics Service ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,77,922,237]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(NRES) Committee South Central—Oxford B (REC reference: 15/SC/0179). A total of 40 inpatients at the University Hospitals of North Midlands (UHNM), identified only by sample numbers, were recruited who were over the age of 18, were able to give informed consent, were due to undergo a routine blood test and who had a serum CRP level $>100\\mathrm{mg/L}$ as measured by immunoturbidimetry on the Siemens Advia 2400 assay (Siemens Healthcare Diagnostics Limited, Frimley, UK). All aspects of our study were compliant with the regulatory terms and conditions set out by the NRES committee and Keele University local ethics committee. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,252,826,268]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Human Serum Sample Collection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,269,922,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Whole human blood was collected into BD Vacutainer SST gel tubes without anticoagulant. Sample tubes were left for $30\\mathrm{min}$ to clot and centrifuged at $3,500\\mathrm{g}$ for $7\\mathrm{min}$ to separate the serum. Serum samples were stored at $4^{\\circ}\\mathrm{C}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,340,858,374]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Purification of CRP From the Human Serum Samples ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,374,922,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CRP was purified from human serum with markedly elevated CRP levels $(>100\\mathrm{mg / L})$ as determined by the routinely used clinical assay, via PCho affinity chromatography as described above. Serum sample volumes were $900~\\mu 1$ . Eluted samples were then purified via size exclusion chromatography as described for the in vitro analysis to separate out potential CRP isoforms. Briefly, samples were applied to the column via a $2\\mathrm{ml}$ sample injection loop. Sample elution using buffer A was monitored by UV absorbance at $280\\mathrm{nm}$ at a flow rate of $0.5\\mathrm{ml} / \\mathrm{min}$ . pCRP and mCRP elution times were calculated prior to purification based on the in vitro studies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,549,922,584]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ELISA Analysis of CRP From Human Serum Samples ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,585,922,759]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Following elution from the size exclusion chromatography column, the purified pCRP and mCRP from the human serum samples were also subject to ELISA analysis following the general procedures outlined above. The purified human serum pCRP and mCRP fractions were diluted in buffer A 1:100 and 1:10, respectively, prior to analysis. For the calibration, $50~\\mu \\mathrm{l}$ of calcium buffer (buffer A) was added to columns 1-8, rows A-B of the ELISA plate. $50~\\mu \\mathrm{l}$ of either native pCRP (Scripps) or mCRP (in vitro, purified following the $3\\mathrm{M}$ urea dissociation) was added to column 1, rows A-B $(0.165\\mu \\mathrm{g},0.0033\\mathrm{mg / ml})$ . Serial dilution through to column 7, rows A-B was carried out leaving only calcium buffer in column 8, rows A-B (negative control). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,774,902,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Experimental Procedures for the Human Serum Samples Applied to Commercially Sourced CRP ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,827,922,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The general methods for affinity and size exclusion chromatography, and for ELISA, are given elsewhere. Specifics for this experimental procedure were as follows: A total of $3.0\\mathrm{mg}$ $(1.2\\mathrm{ml}$ at $2.5\\mathrm{mg / ml})$ CRP (Binding Site) was applied to the PCho affinity column. EDTA eluted $3\\mathrm{ml}$ CRP fractions were collected and concentrated using a Vivaspin Turbo 15 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[73,77,485,370]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(10 kDa MWCO) at $4^{\\circ}\\mathrm{C}$ , 2,100 rpm for 10 min. Following recalibration of the size exclusion column (necessary due to a change of column) using molecular weight standards CRP (115 kDa), conalbumin (75 kDa), ovalbumin (43 kDa), carbonic anhydrase (29 kDa, ribonuclease (13.7 kDa), and aprotinin (6.5 kDa), size exclusion FPLC of this PCho purified CRP was carried out at a flow rate of 0.5 ml/min. Two size exclusion runs were carried out, the first loading 500 $\\mu$ g of the CRP, in excess of the CRP in the serum sample with the largest clinically assayed CRP level, the second loading 100 $\\mu$ g. The fractions spanning the mCRP elution volume indicated by the calibration were collected (six 5 ml fractions in each case), diluted 1:100 and 1:50 in calcium buffer and subjected to ELISA (primary antibody CRP-8) in triplicate for all fractions. Two ELISA plates were completed, one for the 500 $\\mu$ g size exclusion chromatography (SEC) fractions, the other for the fractions from the 100 $\\mu$ g SEC experiment. Both included a calibration in triplicate using serial dilution of 6 ng of mCRP (3 M urea dissociated) along with positive (4 ng mCRP) and negative (calcium buffer, buffer A) controls. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,400,164,415]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,424,431,456]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Production and Purification of in vitro Monomeric C-Reactive Protein ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,460,485,884]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Size exclusion chromatography was used to assess the level of dissociation of pentameric CRP into monomeric CRP in the presence of $1\\mathrm{mM}$ EDTA under a range of urea concentrations, each over a period of several weeks, and to purify out both pCRP and mCRP from the sample. This resulted in the selection of 2-4 M urea over a period of 10 weeks. For the calibration, the void volume was calculated to be $46.79\\mathrm{ml}$ and the column volume $120.6\\mathrm{ml}$ . Elution volumes for the molecular weight standards are given in Table S1 and the calibration graph in Figure S1. The elution traces are shown in Figure 1 and the elution volumes and calculated molecular weights in Table 1. There is no evidence in the elution traces of intermediate CRP aggregations comprising 2, 3, or 4 subunits. $5\\mathrm{ml}$ fractions were collected throughout the elutions, the two fractions associated with each peak, for example $75 - 80\\mathrm{ml}$ , $80 - 85\\mathrm{ml}$ for pCRP, $90 - 95\\mathrm{ml}$ , $95 - 100\\mathrm{ml}$ for mCRP for the $3\\mathrm{M}$ dissociation, being collected, pooled, and concentrated in the elution buffer for further characterization. Measurement of protein concentration (absorption at UV $280\\mathrm{nm}$ ) for the concentrated pCRP and mCRP samples suggested losses of up to $50\\%$ with respect to the starting pCRP. Losses do vary significantly, with a direct correlation between the amounts of CRP, and there appears to be a \"baseline\" loss, particularly during the concentration step, irrespective of the quantity. This clearly has a much greater effect for small quantities. For quantities of CRP in the mg range yields of up to $90\\%$ following size exclusion and concentration are achievable, while for small quantities, in the $\\mu\\mathrm{g}$ range, losses of up to $50\\%$ are common. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,885,485,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The 3 M urea dissociation (Figure 1C) clearly maximizes both mCRP yield and pCRP to mCRP conversion and was therefore ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,77,922,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"used in subsequent studies. No evidence of dissociation was observed in the presence of calcium $(5\\mathrm{mM})$ (results not shown). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,119,917,152]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Western Blots of the Purified in vitro pCRP Dissociation Products ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,154,922,211]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Western blots (Figure 2) of the size exclusion chromatography eluted monomeric and un-dissociated pentameric CRP fractions (Figure 1) confirmed the ability of the proteins to still be recognized by the anti-CRP antibody. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,225,922,260]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Binding of Purified in vitro Monomeric CRP to Phosphocholine ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,261,922,392]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The 3 M urea dissociated mCRP purified by size-exclusion was applied to a PCho affinity column followed by elution with EDTA chelating buffer (buffer D) (Figure 2). The pooled mCRP fractions were concentrated and subjected to western blot analysis (Figure 2) confirming the ability of the protein to still be recognized by the anti-CRP antibody. Measurement of protein concentration (absorption at UV $280\\mathrm{nm}$ ) for the concentrated mCRP sample suggested losses of up to $70\\%$ with respect to the starting mCRP. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,406,904,440]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Precipitation Studies With Streptococcus pneumoniae Cell Wall Polysaccharide ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,441,922,528]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Precipitation of mCRP and pCRP with CWPS was carried out. The ELISA calibration data and graphs for pCRP and mCRP are given in Tables S2, S3, Figures S2, S3. The levels of precipitation for both native pCRP and in vitro produced, size exclusion purified mCRP (3 M urea dissociated) when incubated with varying amounts of CWPS are shown in Figure 3. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,530,922,720]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pentameric CRP displays the classic precipitation curve (37) with little precipitation with CWPS at either end of the curve where protein or ligand is in significant excess. Approximately $2\\mu \\mathrm{g}$ of pCRP precipitates out of solution when incubated with $0.1\\mu \\mathrm{g}$ of CWPS, while $7\\mu \\mathrm{g}$ of pCRP precipitates out of solution when incubated with $300\\mu \\mathrm{g}$ of CWPS. Maximum precipitation $(17\\mu \\mathrm{g}$ out of a total of $20\\mu \\mathrm{g}$ of pCRP) occurs where protein and CWPS quantities are the same $(20\\mu \\mathrm{g})$ . Precipitation by mCRP maintains a general level of approximately $5 - 7\\mu \\mathrm{g}$ irrespective of the amount of CWPS, peaking at just over $7\\mu \\mathrm{g}$ , when mCRP is incubated with $50\\mu \\mathrm{g}$ of CWPS, although this peak level is still markedly lower than that for pCRP with $50\\mu \\mathrm{g}$ of CWPS (approximately $15\\mu \\mathrm{g}$ ). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,732,890,767]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Purification of CRP From Human Serum Samples ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,768,922,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Serum samples from 40 patients with elevated CRP levels ( $>100$ mg/L by clinical assay) were purified individually by PCho affinity chromatography (Figure S4). Further purification and characterization then followed the procedures employed for the in vitro mCRP. All affinity purified samples were subjected to size exclusion chromatography (Figure 4). The major peak eluted at $79.01\\mathrm{ml}$ (110 kDa; Figure S1; pCRP]. Although no mCRP peak, expected at $95\\mathrm{ml}$ , was observed in any of the purified samples (Figure 4), fractions 90-95 and $95 - 100\\mathrm{ml}$ (see Table 1, Figure 1) were pooled for further analysis. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[189,89,808,238]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0954/c6e884685727174a202aab9a6ccd92b2620a14e3ca8258b3722cff0690c64ac3.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,245,808,392]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0381/cff1a72920829c7b60f012a5428b0cdcd7aee970a29c2ed701a7168827331522.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,399,806,545]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0532/6a038c007aa497be8624218ae28ce896474b7adee51aec29ea545b4d312d3869.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[189,553,806,699]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 1 | Generation of monomeric CRP. Size exclusion chromatography traces for the urea dissociation experiments with $1\\\\mathrm{mM}$ EDTA. In each case Peak 1 represents eluted pentameric CRP and peak 2 represents eluted monomeric CRP. (A) $2\\\\mathrm{M}$ urea (B) $2.5\\\\mathrm{M}$ urea (C) $3\\\\mathrm{M}$ urea (D) $4\\\\mathrm{M}$ urea—peak 3 determined as not significant based on calculated molecular weight. \"]","image_footnote":"[]","img_path":"images/0768/f2d22036010a0245adc6df4fd3f42a2ce1e261a525f9a7650e9b2686dff063f5.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[70,799,924,894]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0393/ec0a43cce8adbf142338e5099a388821a10ed4258bfa2fc933aa83fc0f03e6c9.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\"></td><td colspan=\"2\">2 M urea</td><td colspan=\"2\">2.5 M urea</td><td colspan=\"2\">3 M urea</td><td colspan=\"2\">4 M urea</td></tr><tr><td>Elution vol (ml)</td><td>MW (kDa)</td><td>Elution vol (ml)</td><td>MW (kDa)</td><td>Elution vol (ml)</td><td>MW (kDa)</td><td>Elution vol (ml)</td><td>MW (kDa)</td></tr><tr><td>pCRP</td><td>79.02</td><td>108</td><td>79.09</td><td>109</td><td>79.60</td><td>103</td><td>79.27</td><td>107</td></tr><tr><td>mCRP</td><td>95.65</td><td>21.3</td><td>95.68</td><td>21.2</td><td>94.97</td><td>22.0</td><td>94.90</td><td>22.0</td></tr></table>","table_caption":"[\"TABLE 1 | Size exclusion column elution volumes and calculated molecular weights following pCRP dissociation via varying concentrations of urea. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[73,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[189,91,811,338]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0745/91336353c29eabfe1d9768dfe7d49dbf1a7eb7d7eb02eb6dcecd9810f5f03c19.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[189,345,754,559]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 2 | Characterization of in vitro monomeric CRP. (A) Western blots (non-reducing $12.5\\\\%$ SDS) of the (a) pentameric and (b) monomeric fractions of CRP from the size exclusion chromatography analysis following dissociation with urea. (a) Lane 1 $(0.1\\\\mu \\\\mathrm{g})$ and lane 2 $(1\\\\mu \\\\mathrm{g})$ contain the pentameric fraction separated from the 3 M urea dissociated sample with control pCRP in lane 3. (b) Lanes 1, 3, 5, 7 contain the monomeric fraction separated from the 2, 2.5, 3, and 4 M urea dissociated samples, respectively. Lanes 2, 4, 6, 8 contain buffer. Lane 9: 3 M urea dissociated mCRP (Lane 5) subsequently eluted from the PC affinity column by EDTA (b). This Lane was excised from the blot after $5\\\\mathrm{min}$ exposure, the remaining Lanes 1-8 being exposed for a further $40\\\\mathrm{min}$ . Lane 10 Molecular weight markers (Biorad precision plus unstained) excised before blotting and stained with Coomassie brilliant blue. The dashed line indicates $23\\\\mathrm{kDa}$ . (B) PCho affinity chromatography of the size-exclusion purified, in vitro produced mCRP (from 3M urea, Lane 5, Ab). The major peak represents elution of mCRP by the calcium chelator EDTA. Time represents elapsed time after the mCRP sample was loaded. The Western blot of the PCho affinity purified mCRP is shown in Lane 9 of the blot in (Ab). \"]","image_footnote":"[]","img_path":"images/0352/dd24bd72d03c30de4d1b5f75735405d80ffa4277ef5e5949251c01c9b444782b.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[73,704,448,758]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Analysis of Pentameric and Monomeric C-Reactive Protein Within the Human Serum Samples ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,759,487,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Affinity chromatography followed by size exclusion purified fractions of both pentameric and monomeric CRP were each subject to ELISA analysis and quantification. The calibration details are given in Table S4, Figure S5 (mCRP) and Table S5, Figure S6 (pCRP). All CRP concentrations were adjusted to represent the concentration in the initial serum samples. All 40 purified pCRP samples tested positive in the ELISA for the presence of CRP (Figure 5). The lowest recorded value of pentameric CRP for any of the samples was calculated at $2.5\\mathrm{mg / L}$ , with the highest being recorded at $71.3\\mathrm{mg / L}$ and a mean ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,708,922,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"value of $23.3\\mathrm{mg / L}$ $(\\mathrm{SE} = \\pm 2.3)$ . All 40 samples of the purified monomeric form of CRP from serum also tested positive for the presence of CRP (Figure 5) with a mean value of $1.03\\mathrm{mg / L}$ $(\\mathrm{SE} = \\pm 0.11)$ , the highest value being $3.14\\mathrm{mg / L}$ (sample 148). There is no significant correlation between the serum mCRP and pCRP (Figure 5) concentrations across all the samples with, for example, the higher mCRP values being associated in equal measure with both high and low pCRP levels (Figure S7). The purified pentameric and monomeric CRP fractions from the size exclusion column were also subject to western blot analysis. All 40 pCRP samples tested positive for CRP, a representative selection is shown in Figure 5. For mCRP, the western blots revealed CRP in 3 out of the 40 patient sample derived mCRP samples (Figure 5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[77,82,482,245]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 3 | Precipitation of pCRP $(20\\\\mu \\\\mathrm{g})$ and mCRP (3 M urea, $20~\\\\mu \\\\mathrm{g}$ ) with CWPS. Errors shown are $\\\\pm$ standard deviation $(n = 2)$ . \"]","image_footnote":"[]","img_path":"images/0002/8ccf86981abc88046ace280f20bade106abdc3eec191aa2eb5fade3933f065f1.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[512,82,919,219]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 4 | Typical size exclusion chromatography trace of one of the PCho affinity purified human serum samples. The pCRP peak is clear while no peak is visible for mCRP. \"]","image_footnote":"[]","img_path":"images/0361/a4791c8c35513eff6b2f130e803e9103f908b0c23f56c1d4e0484128ad8c3b82.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[73,322,463,374]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Experimental Procedures for the Human Serum Samples Applied to Commercially Sourced CRP ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,377,485,713]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Application to commercially sourced CRP of our experimental procedures (PCho-affinity chromatography followed by separation of pCRP and mCRP by SEC) for isolation of mCRP from patient serum samples, all showing markedly elevated CRP levels $>100\\mathrm{mg / L}$ by clinical assay, was carried out to confirm that these purification procedures do not produce the mCRP detected in patient samples. PCho affinity chromatography of the commercially sourced CRP gave a clean, sharp peak with EDTA elution (Figure S8A). EDTA eluted $3\\mathrm{ml}$ CRP fractions G9-G11 (Figure S8A) were collected and concentrated to $2\\mathrm{ml}$ at 1.44 $\\mathrm{mg / ml}$ (2.88 mg CRP). Application of the PCho purified CRP to the size exclusion column (two separate runs, loading $500~\\mu \\mathrm{g}$ and $100~\\mu \\mathrm{g}$ ) showed the pCRP peak at the expected position of 70-71 ml (Figures S8B,C) indicated by the calibration (Table S6, Figure S9) with no discernible peak at the mCRP position (90-91 ml). ELISA analysis of the PCho + size exclusion purified native CRP for both the $500~\\mu \\mathrm{g}$ (Tables S7, S8, Figure S10) and $100~\\mu \\mathrm{g}$ (Tables S9, S10, Figure S11) size exclusion runs revealed no detectable mCRP. Fraction E5 for the higher $(500~\\mu \\mathrm{g})$ size exclusion column loading shows a positive CRP reading of 1.25 $\\mathrm{mg / L}$ associated with the pCRP tail (Figure 6A), while CRP could not be identified in any fraction of either run in the region of the mCRP elution volume. (Figure 6B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,738,200,754]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,767,485,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C-reactive protein dissociation experiments using commercially sourced pCRP and a range of urea concentrations were carried out over a 10 week period to establish a suitable in vitro protocol for the production of monomeric C-reactive protein. The aim was to minimize the strength of urea whilst still inducing a high level of dissociation over a realistic time frame. Although the mechanism of dissociation in the presence of urea is not clear, we believe this is the most suitable method of those reported in the literature (20) since attempts to treat pentameric CRP with heat or acidic conditions resulted in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,327,922,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"complete denaturation of the protein (data not shown). The most appropriate urea concentration for the almost complete dissociation of pentameric to monomeric CRP $(>90\\%)$ was $3\\mathrm{M}$ (Figure 1). Lower concentrations of urea resulted in partial or no dissociation, while the removal of the CRP calcium ions was shown to be crucial regardless of the urea concentration. Dissociated samples were successfully separated into mCRP and residual pCRP by size exclusion chromatography, western blot analysis confirming the ability of both proteins to still be recognized by the anti-CRP antibody. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,474,922,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Further characterization of the in vitro mCRP was carried out using PCho affinity chromatography and precipitation with CWPS. The PCho affinity chromatography mCRP peak (Figure 2) confirms the calcium-dependent PCho-binding ability of the in vitro produced mCRP, further verified by western blot analysis of the eluted peak which, as expected, was positive for CRP. Based on this experimental evidence it was concluded that the urea dissociation experiments successfully dissociated pCRP into its constituent subunits yielding an in vitro form of mCRP that retained its PCho-binding ability. Precipitation studies with CWPS (Figure 3) revealed that the in vitro mCRP produced here also retains the ability to recognize its prototypical ligand CWPS. However, unlike the CWPS precipitation curve observed for pCRP, the in vitro produced mCRP does not follow the general bell-shaped curve typical of aggregation and precipitation of a cross-linked complex (37). The lower level of precipitation and its increased uniformity over a range of CWPS concentrations compared to pCRP, where each pentamer can achieve crosslinking through multi-site CWPS attachment to one or more CWPS, is consistent with the single PCho binding site per monomer reducing the opportunity for aggregation, although modification of the monomer which reduces, but does not abrogate, CWPS binding cannot be discounted. Previous reports using $8\\mathrm{M}$ urea for dissociation have described the production of a monomeric form of CRP which displayed a decrease in solubility [aggregating and forming precipitates at calcium concentrations as low as $0.05\\mathrm{mM}$ (9)] and isoelectric point, and loss of calcium-dependent binding to the prototypical CRP ligand CWPS (20). This suggests that the in vitro mCRP produced here at $3\\mathrm{M}$ urea differs from that previously described. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[141,86,537,336]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0802/50ec6f5b166273d5ae06bf10798d0c82e41d1b5cc97a87e127603c1d59c1db78.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[141,338,537,608]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0335/0f724972c3c931ae8691772bb76f5ff50a5ac7ca2f91549a2d0b22f0e1d77781.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[546,88,858,288]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0396/db2447185e3b161c3bff46e08b6f3ca58561107157a51fa54353bf432f9578c8.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[546,338,791,480]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 5 | ELISA and western blot analysis of pentameric and monomeric CRP in the human serum samples. (A,B) ELISA analysis. All 40 samples tested positive for both pCRP and mCRP. Scores are based on the average value minus the average control. Errors shown are $\\\\pm$ standard deviation $(n = 3)$ . (A) Samples were diluted 1:100 in triplicate. The average concentration of pCRP is $23.3\\\\mathrm{mg / L}$ $(SE = \\\\pm 2.3)$ . (B) Samples were diluted 1:10 in triplicate. The average concentration of mCRP is $1.03\\\\mathrm{mg / L}$ $(SE = \\\\pm 0.11)$ . (C,D) Western blot (non-reducing $12.5\\\\%$ SDS) analysis of the pentameric and monomeric human serum CRP fractions eluted from the size exclusion column. (C) Pentameric CRP was positive for all 40 samples tested (CRP 148, 146, 124, 120, 117, 115, 110, 109, 108 in lanes 1-9, respectively, are shown here). Control pCRP ( $\\\\sim 23\\\\mathrm{kDa}$ ) sample in lane 10. (D) Monomeric CRP: eight of the forty serum samples (018, 021, 023, 109, 115, 148, 153, 175) are shown with two samples (Lane 5, sample 115; Lane 6, sample 148; the two highest values in the mCRP ELISA) positive for mCRP at a molecular weight of approximately $23\\\\mathrm{kDa}$ . Lane 9 contains urea dissociated mCRP control at $23\\\\mathrm{kDa}$ , this lane being excised from the gel after $2.5\\\\mathrm{min}$ with the remainder exposed for a further $42.5\\\\mathrm{min}$ . One other sample (204, the fourth highest ELISA mCRP value) was positive for mCRP in western blots (data not shown). The mCRP from sample 012, which gave the highest pCRP ELISA reading and the third highest mCRP ELISA value, could not be visualized by western blotting. \"]","image_footnote":"[]","img_path":"images/0357/97e0e088e502dac0eec9df3b5445801e93ebc304475176ac8150820ff25be04b.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[73,777,485,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The experimental evidence provided by the in vitro dissociation studies, providing a monomeric CRP with MW approximately $23\\mathrm{kDa}$ which reversibly binds PCho in a calcium-dependent manner, precipitates with CWPS and is recognized by an anti-CRP monoclonal antibody, formed the basis for the methodology developed for the analysis of monomeric C-reactive protein in human serum from patients with markedly elevated CRP levels $>100~\\mathrm{mg / L}$ . Our aim was to carry out this analysis independent of antibodies specific for one or more forms ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,777,922,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of mCRP, or specific for particular mCRP epitopes, using samples from patients with clinically recorded raised pCRP levels, $>100$ $\\mathrm{mg / L}$ . Thus, PCho affinity chromatography followed by size exclusion, complemented by western blotting and ELISA were used for the isolation, purification, and detection of serum monomeric CRP. The average concentration of pentameric CRP in the patient serum samples was calculated from the ELISA data to be $23.3\\mathrm{mg / L}$ , with the minimum value calculated to be 2.5 $\\mathrm{mg / L}$ and the maximum $71.3\\mathrm{mg / L}$ (Figure 5). The difference ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[495,949,502,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[724,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[188,91,808,329]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0012/46d850289ab0983604dabf3ed46bd95a95553d7f1c0036419ba1e96b189a332b.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[188,335,808,568]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 6 | Size exclusion FPLC of PCho re-purified CRP. Elution traces are shown for both (A) $500\\\\mu \\\\mathrm{g}$ and (B) $100\\\\mu \\\\mathrm{g}$ CRP loaded onto the column. Fractions E5-E10 and J5-J10 (5 ml each) were diluted 1:100 and 1:50 in calcium buffer and subjected to ELISA (primary antibody CRP-8) in triplicate (see Tables S7-S10, Figures S10, S11). Total CRP in mg/L averaged over the two dilutions is shown for each fraction. Fraction E5 for the higher $(500\\\\mu \\\\mathrm{g})$ loading shows a positive reading associated with the pCRP tail, while CRP could not be identified in any other fraction or in any fraction of the $100\\\\mu \\\\mathrm{g}$ run. The two fractions within which mCRP would elute are indicated. \"]","image_footnote":"[]","img_path":"images/0298/d0cf68dcd2eb0bc31bac1e8a9ddf095341c78e1d8356828510447fb72fd06913.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[73,675,485,732]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"between the pCRP levels determined here and those provided by clinical assay, all of which were reported as $>100\\mathrm{mg / L}$ suggests significant losses during the purification procedure and the need for more efficient processes for the quantification of CRP forms. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,735,485,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP was successfully identified by ELISA in the purified CRP of all the 40 patient serum samples (Figure 5) with three of the four highest concentrations also being detected on western blots. Combined with the PCho affinity chromatography used for purification, our results demonstrate that the serum monomeric CRP not only displays the same ability as the dissociated in vitro mCRP to reversibly bind to PCho in a calcium dependent manner, but also is recognized by the same anti-CRP monoclonal as both pCRP and in vitro mCRP. From the ELISA, the mean recorded level of monomeric CRP within the serum samples was $1.03\\mathrm{mg / L}$ , with the minimum recorded value being $0.12\\mathrm{mg / L}$ and the maximum recorded value ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,675,922,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"being $3.14\\mathrm{mg / L}$ . Significantly, the two highest mCRP serum concentrations calculated from ELISA (samples 115 and samples 148; Figure 5) were detected by western blotting (Figure 5). There is no correlation between the abundance of the two molecular forms (Figure S7), for example of the ten highest serum pCRP values (Figure 5) only three corresponded to one of the ten highest mCRP values (Figure 5). These results suggest that serum monomeric CRP levels are significantly lower than those for pentameric CRP, with monomeric CRP levels varying across the cohort. Despite the loss of protein in the purification and concentration process, the PCho-binding monomeric CRP is detectable in the serum of patients with markedly elevated CRP levels at an order of magnitude higher levels when compared to previously published data based on serum ELISA (24, 36). While this may be due to the different procedures, to our inclusion of only patients with raised CRP levels $>100~\\mathrm{mg / L}$ , or to mCRP ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[734,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,949,300,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[492,949,505,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[722,949,924,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[73,77,485,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bound to microparticles evading the PCho affinity extraction (30, 35), it raises the possibility of two different forms of circulating mCRP. As the patient samples used here all have markedly elevated levels of CRP, no conclusions can be drawn from the data presented here as to whether mCRP is present in normal, healthy serum, or the nature of that mCRP if present. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,166,485,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to verify that the mCRP identified here in serum is not a product of our purification procedures, commercially sourced native CRP was subjected to those same procedures as the serum samples, involving PCho affinity chromatography (which would isolate any of the calcium dependent PCho binding soluble mCRP in addition to pCRP), concentration, size exclusion, and ELISA using the same antibody (CRP-8). The results (Figure 6) show that mCRP is not a product of our procedures, with no mCRP detectable by ELISA. Our conclusion therefore is that the calcium dependent PC binding, soluble mCRP identified and characterized here is present at detectable levels in serum with markedly elevated levels of CRP. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,342,485,693]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The mCRP isolated from human serum samples, in this case where pCRP levels were clinically assayed as $>100\\mathrm{mg / L}$ , and the 3 M urea for 10 weeks dissociated mCRP samples share key binding properties. Both display the ability to reversibly bind to PCho in a calcium-dependent manner and in common with pCRP both are recognized by the same anti-CRP monoclonal antibody. Precipitation of the urea dissociated mCRP with CWPS further suggests that both forms investigated here retain the overall structural and functional properties of CRP monomers within the pentameric CRP molecule. This suggests that the mCRP detected here in serum with markedly elevated CRP levels is similar to the membrane-bound dissociated subunit with near native structure proposed by Lv and Wang (22), Zhang et al. (36), and Ji et al. (25) rather than the variety of reduced, denatured and refolded mCRP reported elsewhere. It has been suggested that a near-native membrane-bound mCRP is an intermediate step between dissociation, following pCRP membrane attachment, and release following conformational change (25, 27). Whether the serum mCRP detected here is released from the cell surface following pCRP dissociation or whether it originates elsewhere is not clear. If it is of cell surface bound pCRP origin then this suggests that conversion to a conformationally distinct mCRP following dissociation is not a prerequisite for release from the membrane. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,695,485,767]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The overlapping characteristics of the in vitro and ex vivo mCRP reported here suggest that a physiologically relevant monomeric CRP, which retains near native pCRP subunit structure and function, has been produced through in vitro dissociation of pentameric CRP using $3\\mathrm{M}$ urea over an extended ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,808,210,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,838,485,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Pepys MB, Dash AC, Fletcher TC, Richardson N, Munn EA, Feinstein A. Analogues in other mammals and in fish of the human plasma proteins, C-reactive protein and amyloid P component. Nature. (1978) 273:168-70. doi: 10.1038/273168a0 ","text_format":null,"text_level":null,"type":"ref_text"},{"bbox":"[510,77,922,134]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"period. This has the potential to provide not only new routes to quantification of both pCRP and mCRP in the clinical setting, but also a firm basis for the in-depth study of the structure, function and diversity of physiological CRP. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,150,826,166]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DATA AVAILABILITY STATEMENT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,179,922,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All datasets generated for this study are included in the article/Supplementary Material. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,224,710,241]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ETHICS STATEMENT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,255,922,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The studies involving human participants were reviewed and approved by UK National Health Service Research Ethics Service (NRES) Committee South Central—Oxford B (REC reference: 15/SC/0179). The patients/participants provided their written informed consent to participate in this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,342,771,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHOR CONTRIBUTIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,373,922,519]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RW, JM, JL, and HW produced and characterized the in vitro mCRP. RW isolated and characterized the serum mCRP. AF managed and oversaw the collection of serum samples. AS conceived and managed the programme of work and led the interpretation of the results with input from TG, JL, and HW. TG carried out revisions of the manuscript drafted by RW and AS and completed production of the final version including the figures. All authors contributed to refinement of the manuscript and all approved the final version to be published. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,535,603,551]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"FUNDING ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,564,922,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was supported in part by an award from Keele University to AS, TG, and AF. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,609,729,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,639,922,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We thank the Pathology Directorate and research nurses at the University Hospital of North Midlands NHS Trust, Staffordshire, UK who collected patient samples throughout this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,695,794,711]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUPPLEMENTARY MATERIAL ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,725,922,768]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.00115/full#supplementary-material ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,813,924,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"2. Shrive AK, Cheetham GMT, Holden D, Myles DAA, Turnbull WG, Volanakis JE, et al. Three dimensional structure of human C-reactive protein. Nat Struct Biol. (1996) 3:346-54. doi: 10.1038/nsb0496-346 \",\"3. Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure. (1999) 7:169-77. doi: 10.1016/S0969-2126(99)80023-9 \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[72,35,142,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[732,35,924,44]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[73,951,300,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[492,951,505,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[722,951,924,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[73,79,487,867]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"4. Mortensen RF, Osmand AP, Gewurz H. Effects on C-reactive protein on the lymphoid system. I. Binding to thymus-dependant lymphocytes and alteration of their functions. J Exp Med. (1975) 141:821-39. doi: 10.1084/jem.141.4.821 \",\"5. Mortensen RF, Marcelletti JF, Johnson CS, Furmanski P. Human C-reactive protein (CRP): a selective regulator of bone-marrow monocyte progenitor cells. Ann N Y Acad Sci. (1982) 389:457-8. doi: 10.1111/j.1749-6632.1982.tb22171.x \",\"6. Tron K, Manolov DE, Rocker C, Kachele M, Torzewski J, Nienhaus GU. C-reactive protein specifically binds to Fcgamma receptor type 1 on a macrophage-like cell line. Eur J Immunol. (2008) 38:1414-22. doi: 10.1002/eji.200738002 \",\"7. Zhang Z, Ni H. C-reactive protein as a predictor of mortality in critically ill patients: a meta-analysis and systematic review. Anaesth Intensive Care. (2011) 39:854-61. doi: 10.1177/0310057X1103900509 \",\"8. Pepys MB, Hirschfield GM. (2003) C-reactive protein: a critical update. J Clin Invest. (2003) 111:1805-12. doi: 10.1172/JCI200318921 \",\"9. Koivunen ME, Krogsrud RL. Principles of immunochemical techniques used in clinical laboratories. Lab Med. (2006) 37:490-7. doi: 10.1309/MV9RM1FDLWAUWQ3F \",\"10. Rifai N, Ballantyne CM, Cushman M, Levy D, Myers GL. High-sensitivity C-reactive protein and cardiac C-reactive protein assays: is there a need to differentiate? Clin Chem. (2006) 52:1254-7. doi: 10.1373/clinchem.2006.070904 \",\"11. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. (2000) 102:2165-8. doi: 10.1161/01.CIR.102.18.2165 \",\"12. Pasceri V, Cheng JS, Willerson JT, Yeh ET. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. (2001) 103:2531-4. doi: 10.1161/01.CIR.103.21.2531 \",\"13. Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, Waltenberger J, et al. C-reactive protein frequently colocalises with the terminal complement complex in the intima of early atherosclerosis lesions of human coronary arteries. Atheroscler Thromb Vascu Biol. (1998) 18:1386-92. doi: 10.1161/01.ATV.18.9.1386 \",\"14. Zhang YX, Cliff WJ, Schoefl GI, Higgins G. Coronary C-reactive protein distribution: its relation to development of atherosclerosis. Atherosclerosis. (1999) 145:375-9. doi: 10.1016/S0021-9150(99)00105-7 \",\"15. Zhang Z, Yang Y, Hill MA, Wu J. Does C-reactive protein contribute to atherothrombosis via oxidant-mediated release of pro-thrombic factors and activation of platelets? Front Physiol. (2012) 3:1-6. doi: 10.3389/fphys.2012.00433 \",\"16. Cuiobotaru I, Potempa LA, Wander RC. Production of modified C-reactive protein in U937-derived macrophages. Exp Biol Med. (2005) 230:762-70. doi: 10.1177/153537020523001010 \",\"17. Ji S, Ma L, Bai C, Shi J, Li H, Potempa LA, et al. Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft microdomains. FASEB. J. (2009) 23:1806-16. doi: 10.1096/fj.08-116962 \",\"18. Li R, Ren, M, Luo M, Zhang Z, Luo B, Wy J. Monomeric C-reactive protein alters fibrin clot properties on endothelial cells. Thromb Res. (2012) 129:251-6. doi: 10.1016/j.thromres.2012.03.014 \",\"19. Zhao J, Shi X. A study of the interaction of the C-reactive protein monomer with the U937 monocyte. Cell Mol Biol Lett. (2010) 15:485-95. doi: 10.2478/s11658-010-0022-4 \",\"20. Potempa LA, Maldonado BA, Laurent P, Zemel ES, Gewurz H. Antigenic, electrophoretic and binding alterations of human C-reactive protein modified selectively in the absence of calcium. Mol. Immunol. (1983) 20:1165-75. doi: 10.1016/0161-5890(83)90140-2 \",\"21. Wang MY, Ji SR, Ba CJ, El Kebir D, Li HY, Shi JM, et al. A redox switch in C-reactive protein modulates activation of endothelial cells. FASEB J. (2011) 25:3186-96. doi: 10.1096/fj.11-182741 \",\"22. Lv JM, Wang MY. In vitro generation and bioactivity evaluation of C-reactive protein intermediate. PLoS ONE. (2018) 13:e0198375. doi: 10.1371/journal.pone.0198375 \"]","page_idx":"11","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[509,79,926,722]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"23. Ying SC, Gewurz H, Kinoshita CM, Potempa LA, Siegel JN. Identification and partial characterization of multiple native and neoantigenic epitopes of human C-reactive protein by using monoclonal antibodies. J Immunol. (1989) 143:221-8. \",\"24. Wang J, Tang B, Liu X, Wu X, Wang H, Xu D, et al. Increased monomeric CRP levels in acute myocardial infarction: a possible new and specific biomarker for diagnosis and severity assessment of disease. Atherosclerosis. (2015) 239:343-9. doi: 10.1016/j.atherosclerosis.2015.01.024 \",\"25. Ji S, Wu Y, Zhu L, Potempa LA, Sheng F, Lu W, et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: $\\\\mathrm{mCRP_m}$ . FASEB J. (2007) 21:284-94. doi: 10.1096/fj.06-6722com \",\"26. Kresl JJ, Potempa LA, Anderson BE. Conversion of native oligomeric to a modified monomeric form of human C-reactive protein. Int J Biochem Cell Biol. (1998) 30:1415-26. doi: 10.1016/S1357-2725(98)00078-8 \",\"27. Braig D, Nero TL, Koch HG, Kaiser B, Wang X, Thiele JR, et al. Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. Nat Commun. (2018) 8:14188. doi: 10.1038/ncomms14188 \",\"28. Yao Z, Zhang Y, Potempa LA, Rajab I, Ji L, Lv J, et al. A redox sensitivity-based method to quantify both pentameric and monomeric C-reactive protein in a single assay. J Immunol Methods. (2019) 470:40-5. doi: 10.1016/j.jim.2019.04.009 \",\"29. Eisenhardt SU, Thiele JR, Bannasch H, Stark B, Peter K. C - reactive protein, how conformational changes influence inflammatory properties. Cell Cycle. (2009) 8:3885-92. doi: 10.4161/cc.8.23.10068 \",\"30. Habersberger J, Frederik S, Scheichl A, Htun N, Bassler N, Merivirta R, et al. Circulating micro-particles generate and transport C-reactive protein in patients with myocardial infarction. Cardiovasc Res. (2012) 96:64-72. doi: 10.1093/cvr/cvs237 \",\"31. Slevin M, Krupinski J. A role for monomeric C-reactive protein in regulation of angiogenesis, endothelial cell inflammation and thrombus formation in cardiovascular/cerebrovascular disease? Histol Histopathol. (2009) 24:1473-8. doi: 10.14670/HH-24.1473 \",\"32. Li SL, Feng JR, Zhou HH, Zhang CM, Lv GB, Tan YB, et al. Acidic pH promotes oxidation-induced dissociation of C-reactive protein. Mol Immunol. (2018) 104:47-53. doi: 10.1016/j.molimm.2018.09.021 \",\"33. Thiele JR, Habersberger J, Braig D, Schmidt Y, Goerendt K, Maurer V, et al. Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation. (2014) 130:35-50. doi: 10.1161/CIRCULATIONAHA.113.007124 \",\"34. Molins B, Pena E, Vilahur G, Mendieta C, Slevin M, Badimon L. C-reactive protein isoforms differ in their effect on thrombus growth. Atheroscler Thromb Vascu Biol. (2008) 28:2239-46. doi: 10.1161/ATVBAHA.108.174359 \",\"35. Crawford JR, Trial J, Nambi V, Hoogeveen RC, Taffet GE, Entman ML. Plasma levels of endothelial microparticles bearing monomeric C-reactive protein are increased in peripheral artery disease. J Cardiovasc Transl Res. (2016) 9:184-93. doi: 10.1007/s12265-016-9678-0 \",\"36. Zhang L, Li HY, Li W, Shen ZY, Wang YD, Ji SR, et al. An ELISA assay for quantifying monomeric C-reactive protein in plasma. Front Immunol. (2018) 9:1-5. doi: 10.3389/fimmu.2018.00511 \",\"37. Volanakis JE. Complement activation by C-reactive protein complexes. Ann N Y Acad Sci. (1982) 389:235-250. doi: 10.1111/j.1749-6632.1982.tb22140.x \"]","page_idx":"11","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[507,735,926,772]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,783,926,869]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright © 2020 Williams, Moran, Fryer, Littlejohn, Williams, Greenhough and Shrive. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,34,144,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[731,34,926,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Monomeric CRP From Human Serum ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,948,302,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Immunology | www.frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,949,507,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[722,948,924,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"February 2020 | Volume 11 | Article 115 ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[295,181,897,385]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric C-Reactive Protein in Serum With Markedly Elevated CRP Levels Shares Common Calcium-Dependent Ligand Binding Properties With an in vitro Dissociated Form of C-Reactive Protein \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,369,268,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[208,397,268,409]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Edited by: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[189,410,267,421]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Janos G. 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\"text\"\n },\n {\n \"bbox\": \"[112,745,268,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published: 04 February 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[216,763,268,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Citation: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,777,268,788]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams RD, Moran JA, Fryer AA, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[132,790,268,801]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Littlejohn JR, Williams HM, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,803,268,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Greenhough TJ and Shrive AK (2020) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,815,268,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric C-Reactive Protein in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,827,268,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Serum With Markedly Elevated CRP \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[144,840,268,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Levels Shares Common \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,853,268,866]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Calcium-Dependent Ligand Binding \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,867,268,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Properties With an in vitro Dissociated \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[124,879,268,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Form of C-Reactive Protein. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,892,268,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Front. Immunol. 11:115. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,903,268,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi: 10.3389/fimmu.2020.00115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[292,403,862,433]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Robert D. Williams<sup>1†</sup>, Jennifer A. Moran<sup>1</sup>, Anthony A. Fryer<sup>2</sup>, Jamie R. Littlejohn<sup>1</sup>, Harry M. Williams<sup>1</sup>, Trevor J. Greenhough<sup>1</sup> and Annette K. Shrive<sup>1*</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[292,442,922,468]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"<sup>1</sup>School of Life Sciences, Keele University, Staffordshire, United Kingdom, <sup>2</sup>Department of Clinical Biochemistry, Institute for Applied Clinical Sciences, University Hospitals of North Midlands, Keele University, Staffordshire, United Kingdom \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[292,489,927,881]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A monomeric form of C-reactive protein (CRP) which precipitates with cell wall pneumococcal C polysaccharide (CWPS) and retains the ability to reversibly bind to its ligand phosphocholine has been produced through urea-induced dissociation at an optimized concentration of 3M urea over a 10 weeks period. Dissociated samples were purified via size exclusion chromatography and characterized by western blot, phosphocholine affinity chromatography and CWPS precipitation. Human serum samples from patients with raised CRP levels ( $>100\\\\mathrm{mg/L}$ as determined by the clinical laboratory assay) were purified by affinity and size exclusion chromatography and analyzed ( $n = 40$ ) to determine whether circulating monomeric CRP could be detected ex vivo. All 40 samples tested positive for pentameric CRP via western blot and enzyme linked immunosorbent assay (ELISA) analysis. Monomeric C-reactive protein was also identified in all 40 patient samples tested, with an average level recorded of $1.03\\\\mathrm{mg/L}$ ( $\\\\mathrm{SE} = \\\\pm 0.11$ ). Both the in vitro monomeric C-reactive protein and the human serum monomeric protein displayed a molecular weight of approximately $23\\\\mathrm{kDa}$ , both were recognized by the same anti-CRP monoclonal antibody and both reversibly bound to phosphocholine in a calcium-dependent manner. In common with native pentameric CRP, the in vitro mCRP precipitated with CWPS. These overlapping characteristics suggest that a physiologically relevant, near-native monomeric CRP, which retains the structure and binding properties of native CRP subunits, has been produced through in vitro dissociation of pentameric CRP and also isolated from serum with markedly elevated CRP levels. This provides a clear route toward the in-depth study of the structure and function of physiological monomeric CRP. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[292,890,924,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: monomeric C-reactive protein, serum C-reactive protein, dissociated C-reactive protein, calcium-dependent ligand binding, phosphocholine, C-polysaccharide, pentraxin, innate immunity \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,30,104,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[105,41,201,57]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiers \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[105,59,268,75]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in Immunology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[798,42,924,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORIGINAL RESEARCH \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[776,53,924,62]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"published: 04 February 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[757,64,924,74]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi: 10.3389/fimmu.2020.00115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[875,91,924,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,948,302,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[492,949,504,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[722,948,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[73,75,230,89]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,103,485,367]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C-reactive protein (CRP) belongs to the family of proteins known as the pentraxins, which have been highly conserved throughout evolution and can be identified in species ranging from mammals and fish to the primitive Atlantic horseshoe crab, Limulus polyphemus (1). The human form of CRP displays a ring structure of five non-covalently bound subunits around a central pore, with each subunit containing 206 amino acids folded into two antiparallel $\\\\beta$ -sheets with a flattened jellyroll topology (2). Two calcium ions are contained within each promoter, forming the site for the binding of ligands such as phosphocholine (PCho) expressed on the surface structures of pathogens and dead or damaged cell membranes (2, 3). The primary role of CRP within the human body is believed to be the initiation of the innate immune response via the classical complement pathway, cytokine induced inflammation and interactions with antibodies. However, more complex roles for CRP have been described, including immune exacerbation, regulation and suppression (4-7). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,369,485,661]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In normal, healthy individuals, baseline levels of CRP range from 1 to $5\\\\mathrm{mg / L}$ (8). During infection, inflammation or tissue damage, CRP levels will rise acutely to elicit a sufficient immune response over a $24 - 72\\\\mathrm{h}$ period. Due to this rapid increase in serum levels of CRP, it is routinely measured as a clinical biomarker for infection or inflammation in the healthcare setting. Over recent years, evidence has emerged linking CRP to the development and progression of chronic, auto-inflammatory diseases such as cardiovascular disease (9, 10). It has been hypothesized that CRP exerts an alternative, pro-inflammatory role in disease development, with in vitro studies demonstrating up-regulation of cell adhesion molecules, activation of endothelial cells, deposition within atherosclerotic lesions and the increased production of inflammatory cytokines; all common features found in the pathophysiology of cardiovascular disease (8, 11-15). This evidence has led to the development of a high sensitivity CRP assay which can accurately measure CRP levels $< 3\\\\mathrm{mg / L}$ and assess an individual's risk of developing cardiovascular disease (9, 10). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,663,485,793]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although human pentameric CRP (pCRP) is extremely stable under physiological conditions, there is increasing evidence which suggests a biological role for a monomeric form of CRP, commonly denoted mCRP (16-19). A wide variety of in vitro and ex vivo monomeric CRP (mCRP) conformers have been reported, ranging from the in vitro denatured mCRP produced by high concentrations of urea (up to $8\\\\mathrm{M}$ ) (20) through reduced membrane bound mCRP (21) to the hybrid mCRP with near native structure (22). Monoclonal antibodies for the various \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,77,922,311]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"conformers have been generated, including those targeting neoepitopes revealed by pCRP subunit dissociation, and used to identify monomeric forms as distinct from pCRP (23-25). The urea dissociated mCRP of Potempa et al. (20) remains very much the prototypical mCRP, being used in a wide variety of studies for over 30 years. This mCRP displays a decrease in solubility (being insoluble in calcium concentrations as low as $0.05\\\\mathrm{mM}$ ) and isoelectric point and a loss of calcium-dependent binding to the prototypical CRP ligand C-polysaccharide (20). This monomer could not be re-associated back into its pentameric form, the dissociation being accompanied by significant changes in both structure and function (26). On the basis of reduction of the intrachain disulphide in this mCRP, but not in pCRP, by reducing agents such as dithiothreitol, several reports have shown discrimination between pentameric and monomeric CRP (21, 27, 28). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,313,922,649]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Several models suggesting a physiological mechanism for the formation of mCRP have been postulated within the literature. The most widely accepted involves dissociation through calcium-dependent binding of pCRP to cell membranes (17, 18, 25, 27-32) although a clear picture is yet to emerge of the nature and fate of the resulting mCRP conformer. Binding to microvesicles has been proposed to lead to pCRP structural changes that allow binding of C1q and hence complement activation (27). In addition, increasing experimental evidence within the literature suggests a pro-inflammatory role for mCRP (33) and a link between mCRP and the progression of certain auto-inflammatory diseases within the body. Similarly to that described previously for pCRP, mCRP displays an ability to stimulate cytokine production and up-regulate the production of adhesion molecules as well as induce thrombus growth formation and alter fibrin properties and tissue factor expression (18, 34). It has been hypothesized that circulating micro-particles, generated from lipid membranes, can not only induce pCRP dissociation, but also act as a mode of transport around the body to sites of intensified inflammation (30). The failure of standard clinical CRP tests, employed in a large proportion of healthcare laboratories, to detect mCRP that is bound to circulating microparticles has also been highlighted (35). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,650,922,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"More recently, the development of ELISA methods which can quantify mCRP in clinical serum and tissue samples down to $1\\\\mathrm{ng / ml}$ have been reported (24, 36). Zhang et al. (36) demonstrated a sandwich ELISA that detected mCRP in patients with skin-related autoimmune disorders, with a statistical difference in mCRP levels when compared to the control group, even when native, pentameric samples showed no such difference (35). Levels of serum mCRP reported by Zhang et al. (36) were in the $\\\\mathrm{ng / ml}$ range, as were those reported by Wang et al. (24) who employed a monoclonal antibody based on the C-terminal octapeptide of CRP, proposed to be exposed on pCRP dissociation by treatment with $8\\\\mathrm{M}$ urea, in a study of mCRP levels in acute myocardial infarction (AMI). The antibody was shown to recognize mCRP from denatured pCRP, but not pCRP itself. This study of patients $(n = 101)$ who had recently suffered with an AMI reported an average recorded mCRP serum level of $0.021\\\\mathrm{mg / L}$ (24), with six patients out of 42 with raised levels of pCRP \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,817,485,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abbreviations: CRP, human C-reactive protein; pCRP, pentameric human C-reactive protein; mCRP, monomeric human C-reactive protein; BSA, bovine serum albumin; PBS, phosphate buffered saline; TMB, 3, $3^{\\\\prime}$ , 5, $5^{\\\\prime}$ , tetramethylbenzidine; APC, $p$ -aminophenyl phosphoryl choline; FPLC, Fast Protein Liquid Chromatography; CWPS, Streptococcus pneumoniae cell wall C-polysaccharide; NRES, National Health Service Research Ethics Service; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme linked immunosorbent assay; tris, tris(hydroxymethyl)aminomethane; PCho, phosphocholine. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[73,949,300,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[722,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[73,77,485,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(3-285 mg/L) displaying detectable mCRP levels of 0.0057 mg/L-0.1227 mg/L. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,107,485,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our aim was to generate, and find in serum with markedly elevated CRP levels, a near native mCRP that retains as far as possible the structure and binding of the monomer in the pentameric molecule. We describe the production, purification and characterization of in vitro mCRP, produced under milder dissociation conditions than those usually employed, alongside the analysis of human serum samples from patients exhibiting raised CRP levels $(>100\\\\mathrm{mg / L})$ by clinical assay. This analysis reveals an ex vivo form of mCRP in all patient samples analyzed. Both forms of mCRP were recognized by the same anti-CRP monoclonal antibody, both were soluble in tris buffered saline with $5 - 10\\\\mathrm{mM}$ $\\\\mathrm{CaCl}_2$ ,and both reversibly bound to PCho in a calcium-dependent manner. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,313,344,329]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MATERIALS AND METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,342,485,459]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Standard buffers used were as follows: buffer A: (storage buffer) $20\\\\mathrm{mM}$ tris(hydroxymethyl) aminomethane (tris), $280\\\\mathrm{mMNaCl}$ , $5\\\\mathrm{mM}\\\\mathrm{CaCl}_2$ , $0.01\\\\%$ sodium azide, $\\\\mathrm{pH}7.4$ ; buffer B: (elution buffer) $50\\\\mathrm{mM}$ tris, $150\\\\mathrm{mMNaCl}$ , $\\\\mathrm{pH}7.2$ ; buffer C: (equilibration buffer) $10\\\\mathrm{mM}\\\\mathrm{CaCl}_2$ , $50\\\\mathrm{mM}$ tris $\\\\mathrm{pH}7.4$ , $150\\\\mathrm{mMNaCl}$ , $0.01\\\\%$ sodium azide; buffer D: (chelating buffer) $10\\\\mathrm{mM}$ ethylenediaminetetraacetic acid (EDTA), $50\\\\mathrm{mM}$ tris $\\\\mathrm{pH}7.4$ , $150\\\\mathrm{mMNaCl}$ , $0.01\\\\%$ sodium azide. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,469,220,486]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ELISA Protocol \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,487,485,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The general procedures for ELISA were as follows: All ELISA analysis was carried out on a sterile, 96-well plate (Costar). $50~\\\\mu \\\\mathrm{l}$ of each sample was added to each well. Plates were blocked with $3\\\\%$ bovine serum albumin (BSA) and washed with phosphate buffered saline (PBS)-Tween (Sigma). The primary antibody used was a monoclonal anti-C-reactive protein antibody (CRP-8, Sigma) produced in a mouse; the secondary antibody was an antimouse IgG (whole molecule)-peroxidase antibody produced in rabbit (Sigma). Both were used at 1:40,000 dilution. Positive and negative controls were included in analysis and all samples were tested in triplicate. The developing substrate used was $3, 3^{\\\\prime}, 5, 5^{\\\\prime}$ , tetramethylbenzidine (TMB) liquid substrate (Sigma). ELISA plates were left to develop for $10\\\\mathrm{min}$ prior to addition of $2\\\\mathrm{M}$ sulfuric acid. Plates were read at $450\\\\mathrm{nm}$ on a BioTek EL800 plate reader using Gen5 software. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,718,389,750]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Production of in vitro Monomeric C-Reactive Protein \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,753,485,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Native pentameric human CRP (pCRP) was purchased from Scripps in storage buffer (buffer A). Dissociation was achieved through the addition of pCRP to a range of dissociation buffers $(20\\\\mathrm{mM}$ tris, $280\\\\mathrm{mMNaCl},$ 1 mM EDTA, and 2, 2.5, 3, and 4 M urea), followed by storage at $4^{\\\\circ}\\\\mathrm{C}$ for periods of up to 12 weeks. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,835,369,871]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Phosphocholine (PCho) Affinity Chromatography \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,872,485,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Immobilized $p$ -aminophenyl phosphoryl choline (APC) was purchased from Fisher Scientific in the form of a gel, crosslinked with $6\\\\%$ beaded agarose. The binding capacity of the APC \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,77,922,252]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"was $>3\\\\mathrm{mg}$ of CRP per $1\\\\mathrm{ml}$ of gel. All affinity chromatography experiments for both in vitro and ex vivo CRP were run using the Biologic LP Chromatography System (BioRad) with a flow rate of $0.5\\\\mathrm{ml / min}$ throughout. The absorbance was measured at $280~\\\\mathrm{nm}$ . Prior to samples being run through the column, the column was equilibrated with 20 column volumes of equilibration buffer (buffer C) and the UV absorbance baseline reading was then blanked to a value of 0 absorbance units (Au) prior to application of the sample. Once the entire sample had been applied, the column was re-equilibrated with 5 column volumes of buffer C followed by elution with the chelating buffer (buffer D) until the UV absorbance reading had returned to its baseline value of 0 Au. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,270,831,304]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Purification of in vitro Monomeric C-Reactive Protein (mCRP) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,305,922,480]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"mCRP and pCRP in the urea dissociated samples were separated and purified using the AKTA explorer 100 Fast Protein Liquid Chromatography (FPLC) system (GE Healthcare) with a HiLoad 16/60 Superdex $200~\\\\mathrm{pg}$ column. Calibration was performed using a Gel Filtration Calibration Kit (GE Healthcare), with the included molecular weight markers ferritin, aldolase, conalbumin, ovalbumin, and ribonuclease (elution buffer: buffer B). The void volume was determined using Blue Dextran (Sigma). Samples were injected onto the column via a $2\\\\mathrm{ml}$ sample injection loop and elution was monitored by UV absorbance at $280~\\\\mathrm{nm}$ at a flow rate of $0.5\\\\mathrm{ml / min}$ . Samples were eluted off and collected in $5\\\\mathrm{ml}$ fractions in the storage buffer A. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,496,897,532]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SDS PAGE and Western Blots of Purified pCRP and in vitro mCRP Samples \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,532,922,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Both purified dissociated CRP samples and CRP purified from human serum were confirmed to contain CRP through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and western blot analysis. Samples were run under non-reducing conditions on a $12.5\\\\%$ resolving and $4\\\\%$ stacking gel. All reagents were purchased from Sigma. SDS PAGE was run in a BioRad mini-Protein II cell at $200\\\\mathrm{V}$ for approximately $45 - 50\\\\mathrm{min}$ . All samples were run with positive and negative controls and molecular weight markers. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,664,922,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Western blot analysis was performed using the Mini TransBlot Electrophoretic Transfer Cell (BioRad), using nitrocellulose blotting paper or Polyvinylidene difluoride (PVDF) membrane. The transfer was run at $350\\\\mathrm{mA}$ for $1\\\\mathrm{h}$ at $4^{\\\\circ}\\\\mathrm{C}$ . Membranes were blocked with Marvel dried milk powder and washed with BLOTTO (Marvel dried milk, Triton-X 100 or Tween-20, and tris-buffered saline). The primary antibody, a monoclonal anti-C-reactive protein antibody (CRP-8, Sigma) produced in a mouse, was used at a 1:1,000 dilution except for the mCRP purified from human serum (1:400) and for the non-dissociated pCRP following treatment with urea (1:200). The secondary antibody, an anti-mouse IgG (whole molecule)-peroxidase antibody produced in rabbit (Sigma), was used at a 1:40,000 dilution except for the non-dissociated pCRP following treatment with urea (1:2,000). Clarity Western Enzyme Chemiluminescence substrate (BioRad) or Thermo Scientific™ SuperSignal™ West Pico Chemiluminescent Substrate diluted x4 was used to detect \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[73,77,485,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"protein bands which were visualized using a CCD digital image detector. Exposure time was approximately 30-60 min. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,116,334,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Binding of in vitro mCRP to Phosphocholine \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,152,485,240]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The calcium-dependent binding to PCho of the size exclusion purified mCRP from the 3M urea dissociation was assessed using PCho affinity chromatography as described above. Protein samples were prepared by diluting $500\\\\mu \\\\mathrm{l}$ $(250~\\\\mu \\\\mathrm{g})$ of the mCRP in $5\\\\mathrm{ml}$ of buffer C. Larger volumes of samples were used to prevent air bubbles entering the column whilst applying a sample. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,250,467,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Precipitation Studies With Streptococcus pneumoniae Cell Wall Polysaccharide \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,286,211,300]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ELISA Calibration \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,301,485,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$50~\\\\mu \\\\mathrm{l}$ of calcium buffer (buffer A) was added to columns 1-12, rows A-F of the ELISA plate. $50~\\\\mu \\\\mathrm{l}$ $(3.0~\\\\mu \\\\mathrm{g}$ in $50~\\\\mu \\\\mathrm{l}, 60~\\\\mathrm{mg / L})$ of pCRP (Scripps) was added to column 1, rows A-C, and mCRP (in vitro, purified following the $3\\\\mathrm{M}$ dissociation) to rows D-F. Serial dilution through to column 11, rows A-F was carried out leaving buffer A in column 12 rows A-F (negative control). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,400,268,415]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CRP/CWPS Precipitation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,415,485,650]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Native pCRP (Scripps) alongside mCRP (dissociated with $3\\\\mathrm{M}$ urea and purified by size exclusion), were incubated with varying amounts of Streptococcus pneumoniae cell wall C-polysaccharide (CWPS; Oxford Biosystems). CWPS quantities used were 0.1, 0.5, 1, 10, 20, 50, 100, 200, $300~\\\\mu \\\\mathrm{g}$ . Both CRP samples contained 20 $\\\\mu \\\\mathrm{g}$ in $400~\\\\mu \\\\mathrm{l}$ buffer A. All samples were incubated at $37^{\\\\circ}\\\\mathrm{C}$ for $1\\\\mathrm{h}$ whilst being gently agitated. The samples were then centrifuged at $6,500\\\\times \\\\mathrm{g}$ for $15\\\\mathrm{min}$ to pellet the precipitate and the supernatant from each sample was transferred to separate tubes. Precipitation levels were calculated based on the remaining concentration of protein within the supernatant via ELISA following the general procedures outlined above. CRP concentrations were determined using the calibration line equations and the total level of precipitation was calculated by subtracting the total amount of CRP remaining in solution post CWPS incubation from the initial amount $(20~\\\\mu \\\\mathrm{g})$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,661,467,677]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein Concentration and Quantification \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,679,485,840]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Eluted protein samples were stored for use at $4^{\\\\circ}\\\\mathrm{C}$ in the various elution buffers following concentration using a Vivaspin Centrifugal Concentrator (Fisher Scientific), $10\\\\mathrm{kDa}$ molecular weight cut off. The concentrator was initially primed with deionised water and spun at $1,000\\\\times \\\\mathrm{g}, 4^{\\\\circ}\\\\mathrm{C}$ for $10\\\\mathrm{min}$ . The protein sample was then spun at $1,000\\\\times \\\\mathrm{g}, 4^{\\\\circ}\\\\mathrm{C}$ for $15\\\\mathrm{min}$ or until the desired concentration had been achieved. The protein content of the CRP samples was determined from absorbance at UV $280\\\\mathrm{nm}$ . The extinction coefficient was calculated from the CRP sequence as 1.7 (Expasy, http://web.expasy.org/protparam/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,849,450,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ethical Application and Research Study Design \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,885,485,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ethical approval for the human serum samples pilot study was granted by UK National Health Service Research Ethics Service \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,77,922,237]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(NRES) Committee South Central—Oxford B (REC reference: 15/SC/0179). A total of 40 inpatients at the University Hospitals of North Midlands (UHNM), identified only by sample numbers, were recruited who were over the age of 18, were able to give informed consent, were due to undergo a routine blood test and who had a serum CRP level $>100\\\\mathrm{mg/L}$ as measured by immunoturbidimetry on the Siemens Advia 2400 assay (Siemens Healthcare Diagnostics Limited, Frimley, UK). All aspects of our study were compliant with the regulatory terms and conditions set out by the NRES committee and Keele University local ethics committee. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,252,826,268]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Human Serum Sample Collection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,269,922,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Whole human blood was collected into BD Vacutainer SST gel tubes without anticoagulant. Sample tubes were left for $30\\\\mathrm{min}$ to clot and centrifuged at $3,500\\\\mathrm{g}$ for $7\\\\mathrm{min}$ to separate the serum. Serum samples were stored at $4^{\\\\circ}\\\\mathrm{C}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,340,858,374]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Purification of CRP From the Human Serum Samples \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,374,922,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CRP was purified from human serum with markedly elevated CRP levels $(>100\\\\mathrm{mg / L})$ as determined by the routinely used clinical assay, via PCho affinity chromatography as described above. Serum sample volumes were $900~\\\\mu 1$ . Eluted samples were then purified via size exclusion chromatography as described for the in vitro analysis to separate out potential CRP isoforms. Briefly, samples were applied to the column via a $2\\\\mathrm{ml}$ sample injection loop. Sample elution using buffer A was monitored by UV absorbance at $280\\\\mathrm{nm}$ at a flow rate of $0.5\\\\mathrm{ml} / \\\\mathrm{min}$ . pCRP and mCRP elution times were calculated prior to purification based on the in vitro studies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,549,922,584]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ELISA Analysis of CRP From Human Serum Samples \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,585,922,759]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Following elution from the size exclusion chromatography column, the purified pCRP and mCRP from the human serum samples were also subject to ELISA analysis following the general procedures outlined above. The purified human serum pCRP and mCRP fractions were diluted in buffer A 1:100 and 1:10, respectively, prior to analysis. For the calibration, $50~\\\\mu \\\\mathrm{l}$ of calcium buffer (buffer A) was added to columns 1-8, rows A-B of the ELISA plate. $50~\\\\mu \\\\mathrm{l}$ of either native pCRP (Scripps) or mCRP (in vitro, purified following the $3\\\\mathrm{M}$ urea dissociation) was added to column 1, rows A-B $(0.165\\\\mu \\\\mathrm{g},0.0033\\\\mathrm{mg / ml})$ . Serial dilution through to column 7, rows A-B was carried out leaving only calcium buffer in column 8, rows A-B (negative control). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,774,902,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Experimental Procedures for the Human Serum Samples Applied to Commercially Sourced CRP \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,827,922,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The general methods for affinity and size exclusion chromatography, and for ELISA, are given elsewhere. Specifics for this experimental procedure were as follows: A total of $3.0\\\\mathrm{mg}$ $(1.2\\\\mathrm{ml}$ at $2.5\\\\mathrm{mg / ml})$ CRP (Binding Site) was applied to the PCho affinity column. EDTA eluted $3\\\\mathrm{ml}$ CRP fractions were collected and concentrated using a Vivaspin Turbo 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[73,77,485,370]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(10 kDa MWCO) at $4^{\\\\circ}\\\\mathrm{C}$ , 2,100 rpm for 10 min. Following recalibration of the size exclusion column (necessary due to a change of column) using molecular weight standards CRP (115 kDa), conalbumin (75 kDa), ovalbumin (43 kDa), carbonic anhydrase (29 kDa, ribonuclease (13.7 kDa), and aprotinin (6.5 kDa), size exclusion FPLC of this PCho purified CRP was carried out at a flow rate of 0.5 ml/min. Two size exclusion runs were carried out, the first loading 500 $\\\\mu$ g of the CRP, in excess of the CRP in the serum sample with the largest clinically assayed CRP level, the second loading 100 $\\\\mu$ g. The fractions spanning the mCRP elution volume indicated by the calibration were collected (six 5 ml fractions in each case), diluted 1:100 and 1:50 in calcium buffer and subjected to ELISA (primary antibody CRP-8) in triplicate for all fractions. Two ELISA plates were completed, one for the 500 $\\\\mu$ g size exclusion chromatography (SEC) fractions, the other for the fractions from the 100 $\\\\mu$ g SEC experiment. Both included a calibration in triplicate using serial dilution of 6 ng of mCRP (3 M urea dissociated) along with positive (4 ng mCRP) and negative (calcium buffer, buffer A) controls. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,400,164,415]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,424,431,456]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Production and Purification of in vitro Monomeric C-Reactive Protein \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,460,485,884]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Size exclusion chromatography was used to assess the level of dissociation of pentameric CRP into monomeric CRP in the presence of $1\\\\mathrm{mM}$ EDTA under a range of urea concentrations, each over a period of several weeks, and to purify out both pCRP and mCRP from the sample. This resulted in the selection of 2-4 M urea over a period of 10 weeks. For the calibration, the void volume was calculated to be $46.79\\\\mathrm{ml}$ and the column volume $120.6\\\\mathrm{ml}$ . Elution volumes for the molecular weight standards are given in Table S1 and the calibration graph in Figure S1. The elution traces are shown in Figure 1 and the elution volumes and calculated molecular weights in Table 1. There is no evidence in the elution traces of intermediate CRP aggregations comprising 2, 3, or 4 subunits. $5\\\\mathrm{ml}$ fractions were collected throughout the elutions, the two fractions associated with each peak, for example $75 - 80\\\\mathrm{ml}$ , $80 - 85\\\\mathrm{ml}$ for pCRP, $90 - 95\\\\mathrm{ml}$ , $95 - 100\\\\mathrm{ml}$ for mCRP for the $3\\\\mathrm{M}$ dissociation, being collected, pooled, and concentrated in the elution buffer for further characterization. Measurement of protein concentration (absorption at UV $280\\\\mathrm{nm}$ ) for the concentrated pCRP and mCRP samples suggested losses of up to $50\\\\%$ with respect to the starting pCRP. Losses do vary significantly, with a direct correlation between the amounts of CRP, and there appears to be a \\\"baseline\\\" loss, particularly during the concentration step, irrespective of the quantity. This clearly has a much greater effect for small quantities. For quantities of CRP in the mg range yields of up to $90\\\\%$ following size exclusion and concentration are achievable, while for small quantities, in the $\\\\mu\\\\mathrm{g}$ range, losses of up to $50\\\\%$ are common. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,885,485,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The 3 M urea dissociation (Figure 1C) clearly maximizes both mCRP yield and pCRP to mCRP conversion and was therefore \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,77,922,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"used in subsequent studies. No evidence of dissociation was observed in the presence of calcium $(5\\\\mathrm{mM})$ (results not shown). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,119,917,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Western Blots of the Purified in vitro pCRP Dissociation Products \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,154,922,211]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Western blots (Figure 2) of the size exclusion chromatography eluted monomeric and un-dissociated pentameric CRP fractions (Figure 1) confirmed the ability of the proteins to still be recognized by the anti-CRP antibody. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,225,922,260]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Binding of Purified in vitro Monomeric CRP to Phosphocholine \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,261,922,392]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The 3 M urea dissociated mCRP purified by size-exclusion was applied to a PCho affinity column followed by elution with EDTA chelating buffer (buffer D) (Figure 2). The pooled mCRP fractions were concentrated and subjected to western blot analysis (Figure 2) confirming the ability of the protein to still be recognized by the anti-CRP antibody. Measurement of protein concentration (absorption at UV $280\\\\mathrm{nm}$ ) for the concentrated mCRP sample suggested losses of up to $70\\\\%$ with respect to the starting mCRP. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,406,904,440]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Precipitation Studies With Streptococcus pneumoniae Cell Wall Polysaccharide \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,441,922,528]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Precipitation of mCRP and pCRP with CWPS was carried out. The ELISA calibration data and graphs for pCRP and mCRP are given in Tables S2, S3, Figures S2, S3. The levels of precipitation for both native pCRP and in vitro produced, size exclusion purified mCRP (3 M urea dissociated) when incubated with varying amounts of CWPS are shown in Figure 3. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,530,922,720]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pentameric CRP displays the classic precipitation curve (37) with little precipitation with CWPS at either end of the curve where protein or ligand is in significant excess. Approximately $2\\\\mu \\\\mathrm{g}$ of pCRP precipitates out of solution when incubated with $0.1\\\\mu \\\\mathrm{g}$ of CWPS, while $7\\\\mu \\\\mathrm{g}$ of pCRP precipitates out of solution when incubated with $300\\\\mu \\\\mathrm{g}$ of CWPS. Maximum precipitation $(17\\\\mu \\\\mathrm{g}$ out of a total of $20\\\\mu \\\\mathrm{g}$ of pCRP) occurs where protein and CWPS quantities are the same $(20\\\\mu \\\\mathrm{g})$ . Precipitation by mCRP maintains a general level of approximately $5 - 7\\\\mu \\\\mathrm{g}$ irrespective of the amount of CWPS, peaking at just over $7\\\\mu \\\\mathrm{g}$ , when mCRP is incubated with $50\\\\mu \\\\mathrm{g}$ of CWPS, although this peak level is still markedly lower than that for pCRP with $50\\\\mu \\\\mathrm{g}$ of CWPS (approximately $15\\\\mu \\\\mathrm{g}$ ). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,732,890,767]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Purification of CRP From Human Serum Samples \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,768,922,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Serum samples from 40 patients with elevated CRP levels ( $>100$ mg/L by clinical assay) were purified individually by PCho affinity chromatography (Figure S4). Further purification and characterization then followed the procedures employed for the in vitro mCRP. All affinity purified samples were subjected to size exclusion chromatography (Figure 4). The major peak eluted at $79.01\\\\mathrm{ml}$ (110 kDa; Figure S1; pCRP]. Although no mCRP peak, expected at $95\\\\mathrm{ml}$ , was observed in any of the purified samples (Figure 4), fractions 90-95 and $95 - 100\\\\mathrm{ml}$ (see Table 1, Figure 1) were pooled for further analysis. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[189,89,808,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0954/c6e884685727174a202aab9a6ccd92b2620a14e3ca8258b3722cff0690c64ac3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,245,808,392]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0381/cff1a72920829c7b60f012a5428b0cdcd7aee970a29c2ed701a7168827331522.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,399,806,545]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0532/6a038c007aa497be8624218ae28ce896474b7adee51aec29ea545b4d312d3869.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[189,553,806,699]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 1 | Generation of monomeric CRP. Size exclusion chromatography traces for the urea dissociation experiments with $1\\\\\\\\mathrm{mM}$ EDTA. In each case Peak 1 represents eluted pentameric CRP and peak 2 represents eluted monomeric CRP. (A) $2\\\\\\\\mathrm{M}$ urea (B) $2.5\\\\\\\\mathrm{M}$ urea (C) $3\\\\\\\\mathrm{M}$ urea (D) $4\\\\\\\\mathrm{M}$ urea—peak 3 determined as not significant based on calculated molecular weight. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0768/f2d22036010a0245adc6df4fd3f42a2ce1e261a525f9a7650e9b2686dff063f5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[70,799,924,894]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0393/ec0a43cce8adbf142338e5099a388821a10ed4258bfa2fc933aa83fc0f03e6c9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\"></td><td colspan=\\\"2\\\">2 M urea</td><td colspan=\\\"2\\\">2.5 M urea</td><td colspan=\\\"2\\\">3 M urea</td><td colspan=\\\"2\\\">4 M urea</td></tr><tr><td>Elution vol (ml)</td><td>MW (kDa)</td><td>Elution vol (ml)</td><td>MW (kDa)</td><td>Elution vol (ml)</td><td>MW (kDa)</td><td>Elution vol (ml)</td><td>MW (kDa)</td></tr><tr><td>pCRP</td><td>79.02</td><td>108</td><td>79.09</td><td>109</td><td>79.60</td><td>103</td><td>79.27</td><td>107</td></tr><tr><td>mCRP</td><td>95.65</td><td>21.3</td><td>95.68</td><td>21.2</td><td>94.97</td><td>22.0</td><td>94.90</td><td>22.0</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 1 | Size exclusion column elution volumes and calculated molecular weights following pCRP dissociation via varying concentrations of urea. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[73,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[189,91,811,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0745/91336353c29eabfe1d9768dfe7d49dbf1a7eb7d7eb02eb6dcecd9810f5f03c19.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[189,345,754,559]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 2 | Characterization of in vitro monomeric CRP. (A) Western blots (non-reducing $12.5\\\\\\\\%$ SDS) of the (a) pentameric and (b) monomeric fractions of CRP from the size exclusion chromatography analysis following dissociation with urea. (a) Lane 1 $(0.1\\\\\\\\mu \\\\\\\\mathrm{g})$ and lane 2 $(1\\\\\\\\mu \\\\\\\\mathrm{g})$ contain the pentameric fraction separated from the 3 M urea dissociated sample with control pCRP in lane 3. (b) Lanes 1, 3, 5, 7 contain the monomeric fraction separated from the 2, 2.5, 3, and 4 M urea dissociated samples, respectively. Lanes 2, 4, 6, 8 contain buffer. Lane 9: 3 M urea dissociated mCRP (Lane 5) subsequently eluted from the PC affinity column by EDTA (b). This Lane was excised from the blot after $5\\\\\\\\mathrm{min}$ exposure, the remaining Lanes 1-8 being exposed for a further $40\\\\\\\\mathrm{min}$ . Lane 10 Molecular weight markers (Biorad precision plus unstained) excised before blotting and stained with Coomassie brilliant blue. The dashed line indicates $23\\\\\\\\mathrm{kDa}$ . (B) PCho affinity chromatography of the size-exclusion purified, in vitro produced mCRP (from 3M urea, Lane 5, Ab). The major peak represents elution of mCRP by the calcium chelator EDTA. Time represents elapsed time after the mCRP sample was loaded. The Western blot of the PCho affinity purified mCRP is shown in Lane 9 of the blot in (Ab). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0352/dd24bd72d03c30de4d1b5f75735405d80ffa4277ef5e5949251c01c9b444782b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[73,704,448,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Analysis of Pentameric and Monomeric C-Reactive Protein Within the Human Serum Samples \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,759,487,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Affinity chromatography followed by size exclusion purified fractions of both pentameric and monomeric CRP were each subject to ELISA analysis and quantification. The calibration details are given in Table S4, Figure S5 (mCRP) and Table S5, Figure S6 (pCRP). All CRP concentrations were adjusted to represent the concentration in the initial serum samples. All 40 purified pCRP samples tested positive in the ELISA for the presence of CRP (Figure 5). The lowest recorded value of pentameric CRP for any of the samples was calculated at $2.5\\\\mathrm{mg / L}$ , with the highest being recorded at $71.3\\\\mathrm{mg / L}$ and a mean \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,708,922,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"value of $23.3\\\\mathrm{mg / L}$ $(\\\\mathrm{SE} = \\\\pm 2.3)$ . All 40 samples of the purified monomeric form of CRP from serum also tested positive for the presence of CRP (Figure 5) with a mean value of $1.03\\\\mathrm{mg / L}$ $(\\\\mathrm{SE} = \\\\pm 0.11)$ , the highest value being $3.14\\\\mathrm{mg / L}$ (sample 148). There is no significant correlation between the serum mCRP and pCRP (Figure 5) concentrations across all the samples with, for example, the higher mCRP values being associated in equal measure with both high and low pCRP levels (Figure S7). The purified pentameric and monomeric CRP fractions from the size exclusion column were also subject to western blot analysis. All 40 pCRP samples tested positive for CRP, a representative selection is shown in Figure 5. For mCRP, the western blots revealed CRP in 3 out of the 40 patient sample derived mCRP samples (Figure 5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[77,82,482,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 3 | Precipitation of pCRP $(20\\\\\\\\mu \\\\\\\\mathrm{g})$ and mCRP (3 M urea, $20~\\\\\\\\mu \\\\\\\\mathrm{g}$ ) with CWPS. Errors shown are $\\\\\\\\pm$ standard deviation $(n = 2)$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0002/8ccf86981abc88046ace280f20bade106abdc3eec191aa2eb5fade3933f065f1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,82,919,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 4 | Typical size exclusion chromatography trace of one of the PCho affinity purified human serum samples. The pCRP peak is clear while no peak is visible for mCRP. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0361/a4791c8c35513eff6b2f130e803e9103f908b0c23f56c1d4e0484128ad8c3b82.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[73,322,463,374]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Experimental Procedures for the Human Serum Samples Applied to Commercially Sourced CRP \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,377,485,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Application to commercially sourced CRP of our experimental procedures (PCho-affinity chromatography followed by separation of pCRP and mCRP by SEC) for isolation of mCRP from patient serum samples, all showing markedly elevated CRP levels $>100\\\\mathrm{mg / L}$ by clinical assay, was carried out to confirm that these purification procedures do not produce the mCRP detected in patient samples. PCho affinity chromatography of the commercially sourced CRP gave a clean, sharp peak with EDTA elution (Figure S8A). EDTA eluted $3\\\\mathrm{ml}$ CRP fractions G9-G11 (Figure S8A) were collected and concentrated to $2\\\\mathrm{ml}$ at 1.44 $\\\\mathrm{mg / ml}$ (2.88 mg CRP). Application of the PCho purified CRP to the size exclusion column (two separate runs, loading $500~\\\\mu \\\\mathrm{g}$ and $100~\\\\mu \\\\mathrm{g}$ ) showed the pCRP peak at the expected position of 70-71 ml (Figures S8B,C) indicated by the calibration (Table S6, Figure S9) with no discernible peak at the mCRP position (90-91 ml). ELISA analysis of the PCho + size exclusion purified native CRP for both the $500~\\\\mu \\\\mathrm{g}$ (Tables S7, S8, Figure S10) and $100~\\\\mu \\\\mathrm{g}$ (Tables S9, S10, Figure S11) size exclusion runs revealed no detectable mCRP. Fraction E5 for the higher $(500~\\\\mu \\\\mathrm{g})$ size exclusion column loading shows a positive CRP reading of 1.25 $\\\\mathrm{mg / L}$ associated with the pCRP tail (Figure 6A), while CRP could not be identified in any fraction of either run in the region of the mCRP elution volume. (Figure 6B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,738,200,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,767,485,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C-reactive protein dissociation experiments using commercially sourced pCRP and a range of urea concentrations were carried out over a 10 week period to establish a suitable in vitro protocol for the production of monomeric C-reactive protein. The aim was to minimize the strength of urea whilst still inducing a high level of dissociation over a realistic time frame. Although the mechanism of dissociation in the presence of urea is not clear, we believe this is the most suitable method of those reported in the literature (20) since attempts to treat pentameric CRP with heat or acidic conditions resulted in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,327,922,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"complete denaturation of the protein (data not shown). The most appropriate urea concentration for the almost complete dissociation of pentameric to monomeric CRP $(>90\\\\%)$ was $3\\\\mathrm{M}$ (Figure 1). Lower concentrations of urea resulted in partial or no dissociation, while the removal of the CRP calcium ions was shown to be crucial regardless of the urea concentration. Dissociated samples were successfully separated into mCRP and residual pCRP by size exclusion chromatography, western blot analysis confirming the ability of both proteins to still be recognized by the anti-CRP antibody. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,474,922,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Further characterization of the in vitro mCRP was carried out using PCho affinity chromatography and precipitation with CWPS. The PCho affinity chromatography mCRP peak (Figure 2) confirms the calcium-dependent PCho-binding ability of the in vitro produced mCRP, further verified by western blot analysis of the eluted peak which, as expected, was positive for CRP. Based on this experimental evidence it was concluded that the urea dissociation experiments successfully dissociated pCRP into its constituent subunits yielding an in vitro form of mCRP that retained its PCho-binding ability. Precipitation studies with CWPS (Figure 3) revealed that the in vitro mCRP produced here also retains the ability to recognize its prototypical ligand CWPS. However, unlike the CWPS precipitation curve observed for pCRP, the in vitro produced mCRP does not follow the general bell-shaped curve typical of aggregation and precipitation of a cross-linked complex (37). The lower level of precipitation and its increased uniformity over a range of CWPS concentrations compared to pCRP, where each pentamer can achieve crosslinking through multi-site CWPS attachment to one or more CWPS, is consistent with the single PCho binding site per monomer reducing the opportunity for aggregation, although modification of the monomer which reduces, but does not abrogate, CWPS binding cannot be discounted. Previous reports using $8\\\\mathrm{M}$ urea for dissociation have described the production of a monomeric form of CRP which displayed a decrease in solubility [aggregating and forming precipitates at calcium concentrations as low as $0.05\\\\mathrm{mM}$ (9)] and isoelectric point, and loss of calcium-dependent binding to the prototypical CRP ligand CWPS (20). This suggests that the in vitro mCRP produced here at $3\\\\mathrm{M}$ urea differs from that previously described. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[141,86,537,336]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0802/50ec6f5b166273d5ae06bf10798d0c82e41d1b5cc97a87e127603c1d59c1db78.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[141,338,537,608]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0335/0f724972c3c931ae8691772bb76f5ff50a5ac7ca2f91549a2d0b22f0e1d77781.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[546,88,858,288]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0396/db2447185e3b161c3bff46e08b6f3ca58561107157a51fa54353bf432f9578c8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[546,338,791,480]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 5 | ELISA and western blot analysis of pentameric and monomeric CRP in the human serum samples. (A,B) ELISA analysis. All 40 samples tested positive for both pCRP and mCRP. Scores are based on the average value minus the average control. Errors shown are $\\\\\\\\pm$ standard deviation $(n = 3)$ . (A) Samples were diluted 1:100 in triplicate. The average concentration of pCRP is $23.3\\\\\\\\mathrm{mg / L}$ $(SE = \\\\\\\\pm 2.3)$ . (B) Samples were diluted 1:10 in triplicate. The average concentration of mCRP is $1.03\\\\\\\\mathrm{mg / L}$ $(SE = \\\\\\\\pm 0.11)$ . (C,D) Western blot (non-reducing $12.5\\\\\\\\%$ SDS) analysis of the pentameric and monomeric human serum CRP fractions eluted from the size exclusion column. (C) Pentameric CRP was positive for all 40 samples tested (CRP 148, 146, 124, 120, 117, 115, 110, 109, 108 in lanes 1-9, respectively, are shown here). Control pCRP ( $\\\\\\\\sim 23\\\\\\\\mathrm{kDa}$ ) sample in lane 10. (D) Monomeric CRP: eight of the forty serum samples (018, 021, 023, 109, 115, 148, 153, 175) are shown with two samples (Lane 5, sample 115; Lane 6, sample 148; the two highest values in the mCRP ELISA) positive for mCRP at a molecular weight of approximately $23\\\\\\\\mathrm{kDa}$ . Lane 9 contains urea dissociated mCRP control at $23\\\\\\\\mathrm{kDa}$ , this lane being excised from the gel after $2.5\\\\\\\\mathrm{min}$ with the remainder exposed for a further $42.5\\\\\\\\mathrm{min}$ . One other sample (204, the fourth highest ELISA mCRP value) was positive for mCRP in western blots (data not shown). The mCRP from sample 012, which gave the highest pCRP ELISA reading and the third highest mCRP ELISA value, could not be visualized by western blotting. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0357/97e0e088e502dac0eec9df3b5445801e93ebc304475176ac8150820ff25be04b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[73,777,485,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The experimental evidence provided by the in vitro dissociation studies, providing a monomeric CRP with MW approximately $23\\\\mathrm{kDa}$ which reversibly binds PCho in a calcium-dependent manner, precipitates with CWPS and is recognized by an anti-CRP monoclonal antibody, formed the basis for the methodology developed for the analysis of monomeric C-reactive protein in human serum from patients with markedly elevated CRP levels $>100~\\\\mathrm{mg / L}$ . Our aim was to carry out this analysis independent of antibodies specific for one or more forms \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,777,922,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of mCRP, or specific for particular mCRP epitopes, using samples from patients with clinically recorded raised pCRP levels, $>100$ $\\\\mathrm{mg / L}$ . Thus, PCho affinity chromatography followed by size exclusion, complemented by western blotting and ELISA were used for the isolation, purification, and detection of serum monomeric CRP. The average concentration of pentameric CRP in the patient serum samples was calculated from the ELISA data to be $23.3\\\\mathrm{mg / L}$ , with the minimum value calculated to be 2.5 $\\\\mathrm{mg / L}$ and the maximum $71.3\\\\mathrm{mg / L}$ (Figure 5). The difference \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[495,949,502,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[724,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[188,91,808,329]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0012/46d850289ab0983604dabf3ed46bd95a95553d7f1c0036419ba1e96b189a332b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[188,335,808,568]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 6 | Size exclusion FPLC of PCho re-purified CRP. Elution traces are shown for both (A) $500\\\\\\\\mu \\\\\\\\mathrm{g}$ and (B) $100\\\\\\\\mu \\\\\\\\mathrm{g}$ CRP loaded onto the column. Fractions E5-E10 and J5-J10 (5 ml each) were diluted 1:100 and 1:50 in calcium buffer and subjected to ELISA (primary antibody CRP-8) in triplicate (see Tables S7-S10, Figures S10, S11). Total CRP in mg/L averaged over the two dilutions is shown for each fraction. Fraction E5 for the higher $(500\\\\\\\\mu \\\\\\\\mathrm{g})$ loading shows a positive reading associated with the pCRP tail, while CRP could not be identified in any other fraction or in any fraction of the $100\\\\\\\\mu \\\\\\\\mathrm{g}$ run. The two fractions within which mCRP would elute are indicated. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0298/d0cf68dcd2eb0bc31bac1e8a9ddf095341c78e1d8356828510447fb72fd06913.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[73,675,485,732]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"between the pCRP levels determined here and those provided by clinical assay, all of which were reported as $>100\\\\mathrm{mg / L}$ suggests significant losses during the purification procedure and the need for more efficient processes for the quantification of CRP forms. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,735,485,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP was successfully identified by ELISA in the purified CRP of all the 40 patient serum samples (Figure 5) with three of the four highest concentrations also being detected on western blots. Combined with the PCho affinity chromatography used for purification, our results demonstrate that the serum monomeric CRP not only displays the same ability as the dissociated in vitro mCRP to reversibly bind to PCho in a calcium dependent manner, but also is recognized by the same anti-CRP monoclonal as both pCRP and in vitro mCRP. From the ELISA, the mean recorded level of monomeric CRP within the serum samples was $1.03\\\\mathrm{mg / L}$ , with the minimum recorded value being $0.12\\\\mathrm{mg / L}$ and the maximum recorded value \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,675,922,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"being $3.14\\\\mathrm{mg / L}$ . Significantly, the two highest mCRP serum concentrations calculated from ELISA (samples 115 and samples 148; Figure 5) were detected by western blotting (Figure 5). There is no correlation between the abundance of the two molecular forms (Figure S7), for example of the ten highest serum pCRP values (Figure 5) only three corresponded to one of the ten highest mCRP values (Figure 5). These results suggest that serum monomeric CRP levels are significantly lower than those for pentameric CRP, with monomeric CRP levels varying across the cohort. Despite the loss of protein in the purification and concentration process, the PCho-binding monomeric CRP is detectable in the serum of patients with markedly elevated CRP levels at an order of magnitude higher levels when compared to previously published data based on serum ELISA (24, 36). While this may be due to the different procedures, to our inclusion of only patients with raised CRP levels $>100~\\\\mathrm{mg / L}$ , or to mCRP \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[734,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,949,300,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[492,949,505,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[722,949,924,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[73,77,485,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bound to microparticles evading the PCho affinity extraction (30, 35), it raises the possibility of two different forms of circulating mCRP. As the patient samples used here all have markedly elevated levels of CRP, no conclusions can be drawn from the data presented here as to whether mCRP is present in normal, healthy serum, or the nature of that mCRP if present. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,166,485,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to verify that the mCRP identified here in serum is not a product of our purification procedures, commercially sourced native CRP was subjected to those same procedures as the serum samples, involving PCho affinity chromatography (which would isolate any of the calcium dependent PCho binding soluble mCRP in addition to pCRP), concentration, size exclusion, and ELISA using the same antibody (CRP-8). The results (Figure 6) show that mCRP is not a product of our procedures, with no mCRP detectable by ELISA. Our conclusion therefore is that the calcium dependent PC binding, soluble mCRP identified and characterized here is present at detectable levels in serum with markedly elevated levels of CRP. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,342,485,693]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The mCRP isolated from human serum samples, in this case where pCRP levels were clinically assayed as $>100\\\\mathrm{mg / L}$ , and the 3 M urea for 10 weeks dissociated mCRP samples share key binding properties. Both display the ability to reversibly bind to PCho in a calcium-dependent manner and in common with pCRP both are recognized by the same anti-CRP monoclonal antibody. Precipitation of the urea dissociated mCRP with CWPS further suggests that both forms investigated here retain the overall structural and functional properties of CRP monomers within the pentameric CRP molecule. This suggests that the mCRP detected here in serum with markedly elevated CRP levels is similar to the membrane-bound dissociated subunit with near native structure proposed by Lv and Wang (22), Zhang et al. (36), and Ji et al. (25) rather than the variety of reduced, denatured and refolded mCRP reported elsewhere. It has been suggested that a near-native membrane-bound mCRP is an intermediate step between dissociation, following pCRP membrane attachment, and release following conformational change (25, 27). Whether the serum mCRP detected here is released from the cell surface following pCRP dissociation or whether it originates elsewhere is not clear. If it is of cell surface bound pCRP origin then this suggests that conversion to a conformationally distinct mCRP following dissociation is not a prerequisite for release from the membrane. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,695,485,767]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The overlapping characteristics of the in vitro and ex vivo mCRP reported here suggest that a physiologically relevant monomeric CRP, which retains near native pCRP subunit structure and function, has been produced through in vitro dissociation of pentameric CRP using $3\\\\mathrm{M}$ urea over an extended \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,808,210,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,838,485,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Pepys MB, Dash AC, Fletcher TC, Richardson N, Munn EA, Feinstein A. Analogues in other mammals and in fish of the human plasma proteins, C-reactive protein and amyloid P component. Nature. (1978) 273:168-70. doi: 10.1038/273168a0 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"ref_text\"\n },\n {\n \"bbox\": \"[510,77,922,134]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"period. This has the potential to provide not only new routes to quantification of both pCRP and mCRP in the clinical setting, but also a firm basis for the in-depth study of the structure, function and diversity of physiological CRP. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,150,826,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DATA AVAILABILITY STATEMENT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,179,922,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All datasets generated for this study are included in the article/Supplementary Material. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,224,710,241]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ETHICS STATEMENT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,255,922,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The studies involving human participants were reviewed and approved by UK National Health Service Research Ethics Service (NRES) Committee South Central—Oxford B (REC reference: 15/SC/0179). The patients/participants provided their written informed consent to participate in this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,342,771,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHOR CONTRIBUTIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,373,922,519]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RW, JM, JL, and HW produced and characterized the in vitro mCRP. RW isolated and characterized the serum mCRP. AF managed and oversaw the collection of serum samples. AS conceived and managed the programme of work and led the interpretation of the results with input from TG, JL, and HW. TG carried out revisions of the manuscript drafted by RW and AS and completed production of the final version including the figures. All authors contributed to refinement of the manuscript and all approved the final version to be published. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,535,603,551]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"FUNDING \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,564,922,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was supported in part by an award from Keele University to AS, TG, and AF. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,609,729,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,639,922,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We thank the Pathology Directorate and research nurses at the University Hospital of North Midlands NHS Trust, Staffordshire, UK who collected patient samples throughout this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,695,794,711]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUPPLEMENTARY MATERIAL \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,725,922,768]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.00115/full#supplementary-material \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,813,924,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"2. Shrive AK, Cheetham GMT, Holden D, Myles DAA, Turnbull WG, Volanakis JE, et al. Three dimensional structure of human C-reactive protein. Nat Struct Biol. (1996) 3:346-54. doi: 10.1038/nsb0496-346 \\\",\\\"3. Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure. (1999) 7:169-77. doi: 10.1016/S0969-2126(99)80023-9 \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[72,35,142,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[732,35,924,44]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[73,951,300,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[492,951,505,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[722,951,924,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[73,79,487,867]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"4. 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Plasma levels of endothelial microparticles bearing monomeric C-reactive protein are increased in peripheral artery disease. J Cardiovasc Transl Res. (2016) 9:184-93. doi: 10.1007/s12265-016-9678-0 \\\",\\\"36. Zhang L, Li HY, Li W, Shen ZY, Wang YD, Ji SR, et al. An ELISA assay for quantifying monomeric C-reactive protein in plasma. Front Immunol. (2018) 9:1-5. doi: 10.3389/fimmu.2018.00511 \\\",\\\"37. Volanakis JE. Complement activation by C-reactive protein complexes. Ann N Y Acad Sci. (1982) 389:235-250. doi: 10.1111/j.1749-6632.1982.tb22140.x \\\"]\",\n \"page_idx\": \"11\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[507,735,926,772]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,783,926,869]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright © 2020 Williams, Moran, Fryer, Littlejohn, Williams, Greenhough and Shrive. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,34,144,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[731,34,926,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Monomeric CRP From Human Serum \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,948,302,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Immunology | www.frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[490,949,507,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[722,948,924,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"February 2020 | Volume 11 | Article 115 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.3389/fimmu.2020.00115"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"8c6d4f07ec1ce8098e746463ca7b587dfe72125af955af8dbcbfdf168c4d3dff"},"title":{"kind":"string","value":"Monomeric C-Reactive Protein in Serum With Markedly Elevated CRP Levels Shares Common Calcium-Dependent Ligand Binding Properties With an in vitro Dissociated Form of C-Reactive Protein"}}},{"rowIdx":152,"cells":{"abstract":{"kind":"string","value":"To evaluate the value of single-photon emission computed tomography / computed tomography (SPECT/CT) compared with planar bone scintigraphy (BS) in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures. Retrospective evaluation of patients with traumatic fractures and suspected delayed healing or non-union and/or persistent pain or suspected infection who had undergone planar late phase BS and SPECT/CT between 2011 and 2018. On the BS and SPECT/CT images, a necrotic fragment was considered if there was an area of absent radiotracer uptake (photopenia) related to bone at the fracture site. Histology served as a reference standard (presence or absence of necrotic bone fragments). If histology was not available, intraoperative findings and combined clinical and imaging follow-up served as reference standards. In 37 consecutive patients with traumatic fractures (femur (n = 18), tibia (11), humerus (6), radius (1), jaw (1)), necrotic bone fragments were suspected in 11 fractures (29.7%) on BS and in 16 fractures (43.2%) on SPECT/CT. 35 fractures (94.6%) had metallic implants. Histology showed necrotic fragments in 10/11 (90.9%) patients. For the detection of necrotic bone fragments, SPECT/CT showed sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 95%, 94%, 100%, and 97%, respectively, and BS 67%, 95%, 91%, 81%, and 83%, respectively. SPECT/CT significantly outperformed BS with better area under curve (AUC) for SPECT/CT (0.9773) compared to planar imaging (0.8106) (p-value < 0.01). SPECT/CT is an accurate tool in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic bone fractures and is superior to conventional planar BS. SPECT/CT is accurate and superior to planar BS in identification of necrotic bone fragments, responsible for delayed bone healing/non-union after fractures."},"author":{"kind":"string","value":"Strobel, Klaus|Bhure, Ujwal|Lehnick, Dirk|Beeres, Frank|Perez-Lago, Maria del Sol|Link, Björn-Christian|Agten, Christoph"},"content_list":{"kind":"list like","value":[{"bbox":"[102,129,215,140]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cite this article as: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,140,902,149]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bhure U, Agten C, Lehnick D, Perez-Lago MdS, Beeres F, Link B-C, et al. Value of SPECT/CT in the assessment of necrotic bone fragments ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,149,742,159]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in patients with delayed bone healing or non-union after traumatic fractures. Br J Radiol 2020; 93: 20200300. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,205,257,222]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"FULL PAPER ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[100,235,870,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Value of SPECT/CT in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[100,324,800,350]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ UJWAL BHURE, MD, $^{1}$ CHRISTOPH AGTEN, MD, $^{2}$ DIRK LEHNICK, MD, $^{1}$ MARIA DEL SOL PEREZ-LAGO, MD, $^{3}$ FRANK BEERES, MD, PhD, $^{3}$ BJÖRN-CHRISTIAN LINK, MD and $^{1}$ KLAUS STROBEL, MD ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,355,667,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Department of Radiology and Nuclear Medicine, Cantonal Hospital Lucerne, Lucerne, Switzerland ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,366,539,376]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{2}$ Biostatistics and Methodology, University of Lucerne, Lucerne, Switzerland ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,376,667,388]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{3}$ Department of Orthopedic and Trauma Surgery, Cantonal Hospital Lucerne, Lucerne, Switzerland ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,401,376,412]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Address correspondence to: Prof Klaus Strobel ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,412,272,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E-mail: klaus.strobel@luks.ch ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,449,482,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objective: To evaluate the value of single-photon emission computed tomography / computed tomography (SPECT/CT) compared with planar bone scintigraphy (BS) in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,527,482,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: Retrospective evaluation of patients with traumatic fractures and suspected delayed healing or non-union and/or persistent pain or suspected infection who had undergone planar late phase BS and SPECT/CT between 2011 and 2018. On the BS and SPECT/CT images, a necrotic fragment was considered if there was an area of absent radiotracer uptake (photopenia) related to bone at the fracture site. Histology served as a reference standard (presence or absence of necrotic bone fragments). If histology was not available, intraoperative findings and combined clinical and imaging follow-up served as reference standards. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,684,482,709]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: In 37 consecutive patients with traumatic fractures (femur $(n = 18)$ ,tibia (11), humerus (6), radius (1), ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,449,894,606]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"jaw (1)), necrotic bone fragments were suspected in 11 fractures $(29.7\\%)$ on BS and in 16 fractures $(43.2\\%)$ on SPECT/CT. 35 fractures $(94.6\\%)$ had metallic implants. Histology showed necrotic fragments in 10/11 $(90.9\\%)$ patients. For the detection of necrotic bone fragments, SPECT/CT showed sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of $100\\%$ , $95\\%$ , $94\\%$ , $100\\%$ , and $97\\%$ , respectively, and BS $67\\%$ , $95\\%$ , $91\\%$ , $81\\%$ , and $83\\%$ , respectively. SPECT/ CT significantly outperformed BS with better area under curve (AUC) for SPECT/CT (0.9773) compared to planar imaging (0.8106) $(p$ -value $< 0.01)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,607,892,658]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions: SPECT/CT is an accurate tool in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic bone fractures and is superior to conventional planar BS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,659,892,709]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Advances in knowledge: SPECT/CT is accurate and superior to planar BS in identification of necrotic bone fragments, responsible for delayed bone healing/nonunion after fractures. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,736,236,749]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[100,752,482,932]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Approximately 5.6 million fractures occur annually in the USA and up to $10\\%$ of these fractures result in delayed healing or non-union. Risk factors for delayed healing or non-union are either patient-dependent or patient-independent. The patient-dependent risk factors include sex, old age, history of smoking, various medical comorbidities like diabetes, hypertension, genetic disorders, prolonged use of NSAIDs, nutritional deficiencies, and metabolic disorders. Patient-independent risk factors responsible for delayed healing or non-union include pattern of fracture (such as transverse, linear, oblique, spiral, comminuted, etc), its location and extent of displacement, degree of bone loss, severity of soft tissue injury (minor or severe), ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,737,895,932]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"presence or absence of infection, and quality of surgical treatment (clean and skilled surgery versus post operative complications). Correct assessment of fracture healing is essential for patients because it determines whether they will tolerate weight-bearing, whether they can return to work and routine activities with restored quality of life, or whether any additional surgery is required for further improvement. Non-unions are not only challenging from the treatment side but also have socio-economic implications with loss of job, wages, coupled with mounting treatment cost leading to debt trap and subsequent social fall outs. Diagnostic tests for assessment of fracture healing include plain radiography, CT, MRI, bone scintigraphy (BS), and several laboratory tests, which are important for ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,64,137,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[505,65,904,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. Published by the British Institute of Radiology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[102,89,161,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[102,99,189,109]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"31 March 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[213,89,265,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Revised: ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[213,99,290,109]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22 May 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[314,89,376,98]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted: ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[314,98,396,108]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"29 June 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[685,82,902,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1259/bjr.20200300 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,98,480,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the evaluation and detection of infection as well as metabolic and endocrine abnormalities. The imaging hallmarks which point to delayed healing or non-union include absence of bony bridging between the fracture ends, persistent fracture lines with visualized gap, absence of improvement or evidence of healing on serial radiographs, problems with the surgical metal implants (loosened or broken), and persistent or progressive deformity. $^{4}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,208,480,318]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The diagnosis of sequestrum or necrotic bone fragment in patients with non-union after traumatic fractures has important impact on the surgical approach. Necrotic bone fragments prevent bone healing, thus have to be removed and augmentation with bone grafts might be necessary.[5] CT is a very accurate modality for the assessment of fracture healing but limited regarding the detection of necrotic fragments.[6] MRI may be limited by artifacts caused by metal hardware used for fracture fixation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,331,480,537]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BS with Tc-99m $(^{99}\\mathrm{mTc})$ -labeled diphosphonates has been used for decades for the assessment of bone disorders. The two important factors responsible for the degree and intensity of radiotracer accumulation at a particular site in bone are its blood supply and the rate of new bone formation.[7] BS can detect most of the fractures within $24\\mathrm{h}$ of the occurrence. On an average, the minimum time for normalization of radiotracer activity is around 6 months post-development of fracture, and by around 2 years of the event, most of the fractures would have shown normalization of the radiotracer activity.[8] However, in non-aligned fractures, the process of bone remodeling is going on continuously, and hence, these fractures may not exhibit regression of the radiotracer activity with normal scintigraphic appearance. One of the causes for delayed healing or non-union of the fracture is presence of a necrotic fragment at the fracture site. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,551,480,634]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this study, we assessed the value of single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection of necrotic fragments in patients with delayed bone healing or non-union and/or persistent pain or suspected infection after traumatic fractures and compared the performance of SPECT/CT with planar BS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,653,299,665]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"METHODS AND MATERIALS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,668,480,764]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Retrospective analysis of consecutive patients with traumatic fracture and suspected delayed healing or non-union and/or persistent pain between 2011 and 2018 who had undergone both BS and SPECT/CT was performed. 10 out of 54 patients without available follow-up were excluded. This study was approved by the ethics committee, and the need for written informed consent was waived (EKNZ 2019-00594). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,778,480,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study includes consecutive patients from a single institution. The inclusion criteria were: (a) patients who underwent BS with SPECT/CT from 2011 to 2018; (b) clinical indication being delayed bone healing/non-union of traumatic fracture with suspicion of necrotic bone fragment; (c) in house surgery and further clinical management; and (d) histology or follow-up (clinical/radiological) available. Most of these patients had only X-ray as a prior imaging due to the presence of metal implant MRI was not feasible and not performed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,99,699,111]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SPECT/CT PROTOCOL ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,114,927,441]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All patients underwent BS with Tc-99m-DPD (Tc-99m-3,3-diphosphono-1,2-propanedicarboxylic acid; Teceos, Behringwerke AG, Marburg, Germany). The radiotracer was injected intravenously (average tracer activity 657.92 MBq (17.78 mCi); range: 580 to 704 MBq (15.7 to 19 mCi)) and early-phase planar scintigraphy images were obtained 5 min post-injection (matrix size: $256 \\times 256 \\mathrm{~mm}$ , field of view: $40 \\mathrm{~cm}$ ) under the hybrid SPECT/CT scanner with a built-in flat-panel CT component (BrightView XCT; Philips Healthcare, Best, The Netherlands). Planar late-phase scintigraphy images were acquired $3 \\mathrm{~h}$ post-radiotracer injection (matrix size: $256 \\times 256$ , field of view: $40 \\mathrm{~cm}$ ), followed by the acquisition of SPECT/CT images of the region of interest (fracture site). SPECT was performed in step-and-shoot mode with 64 projections, at the speed of 20 s per projection (SPECT frame matrix size: $128 \\times 128$ ). SPECT images were reconstructed with an iterative 3D ordered subsets expectation maximization (OSEM) algorithm (Astonish, Philips, Netherlands). CT images were acquired in high-resolution mode with an isotropic CT voxel size of $0.33 \\times 0.33 \\times 0.33 \\mathrm{~mm}^3$ (CT slice thickness $0.33 \\mathrm{~mm}$ , matrix size of $512 \\times 512 \\mathrm{~mm}$ ) and reconstructed with iterative filters. SPECT and CT images were automatically fused with dedicated software (Extended Brilliance Workspace; Philips Healthcare, Netherlands), reformatted in coronal and sagittal planes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,456,722,468]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IMAGE INTERPRETATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,470,927,552]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Planar (early and late phase) and SPECT/CT images were reviewed by an experienced nuclear medicine physician and a double board-certified radiologist and nuclear medicine physician with specialized training in musculoskeletal (MSK) imaging. The final image interpretation was done with consensus of these two reviewing physicians. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,558,929,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"(1) The state of fracture healing was assessed using the CT images from the SPECT/CT [non-union (no bony bridging), partial union (partial bridging), complete union (complete bridging)]. \",\"(2) The early and late planar phases of every BS were assessed for the presence or absence of abnormal radiotracer accumulations. \",\"(3) The radiotracer uptake at the fracture site on the planar image of the BS was visually graded as absent (grade 0), mild (Grade 1), moderate (Grade 2), and high (Grade 3) in relationship to normal bone uptake on the contralateral side. \",\"(4) On the planar late-phase images and SPECT/CT images, necrotic fragment was considered present if there was an area of absent radiotracer uptake (photopenia) related to bone at the fracture site. The two physicians reviewing the images were blinded to the detailed clinical information except for the main purpose of the study: assessment of delayed bone healing/non-union with suspicion of necrotic bone fragment. \",\"(5) The size of the necrotic bone fragment was measured (largest diameter in any plane). \",\"(6) Statistics: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were assessed and the performance of SPECT/CT and BS was compared with ROC analysis. \"]","page_idx":"1","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[78,65,314,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"\"SPECT/CT in necrotic bone fragments\" ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,64,919,74]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,948,270,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 7 birpublications.org/bjr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[757,948,927,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Br J Radiol;93:20200300 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[67,99,480,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(7) Reference standard: In operated patients, intraoperative finding and histology served as reference standard. In histology, osteocytes with missing nucleoli and fat necrosis were signs of necrotic bone. In those patients in which no histology was obtained, imaging and clinical follow-up served as reference standards. If complete fracture healing was visible on follow-up imaging (X-ray and/or CT) without demarcation of a bony fragment, this case was diagnosed as \"no necrotic fragment\". Clinically absence of pain, overall improvement in general condition with improved quality of life, as well as improved mobility of the bone/joint in question, and no more suspicion of infection were taken as improvement and negative for necrotic fragment. The average follow-up period was 25 months [range: 3 to 91 months]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,323,144,336]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,338,480,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"44 patients were identified. Seven patients who were not available for follow-up were excluded. Therefore, 37 patients [23 male, 14 female; average age 51.6 years (range: 22 to 84 years)] were assessed with following fractures: femur $(n = 18)$ , tibia (11), humerus (6), radius (1) and jaw (1). The average time from fracture to BS was 30 months (range: 2 to 312 months). 35 fractures $(94.6\\%)$ had metal implants in the form of metal plates, screws, rods, intramedullary nails, external fixators, or wires. 19 fractures showed non-union, 11 partial union and seven complete union in SPECT/CT based on the bridging of fracture line as seen on the CT part of the SPET/CT. Out of 37 patients, 13 had SPECT/CT within 6 months of the fracture, whereas 24 patients had it more than 6 months after the fracture. (Table 1) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,529,480,571]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 patients had suspicion of infection and the early phase of bone scan showed hyperemia in 10 patients, of which six had necrotic bone fragments. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,583,480,612]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The late phase of BS and SPECT/CT showed increased activity at the fracture site in all patients. There was suspicion of necrotic ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,656,480,898]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0059/13d0b528689d7abd2f6967b12fe1b39a894d63370c72ad3a3375041117dda994.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>N (Total Number)</td><td>37 patients</td></tr><tr><td>Male : Female</td><td>23 : 14</td></tr><tr><td>Age</td><td>Average 52 years (range: 22-84)</td></tr><tr><td>Bones involved</td><td>18 (Femur), 11 (Tibia), 6 (Humerus), 1 (Radius), 1 (Jaw)</td></tr><tr><td>Metal Implant</td><td>Present: 35; Absent: 2</td></tr><tr><td>Average time from fracture to BS</td><td>30 months (range: 2-312)</td></tr><tr><td>BS within 6 months of fracture</td><td>13</td></tr><tr><td>BS more than 6 months after fracture</td><td>24</td></tr><tr><td>Histology available</td><td>11</td></tr><tr><td>Average follow-up period</td><td>25 months (range: 3-91)</td></tr><tr><td>Surgery</td><td>25</td></tr><tr><td>Conservative management</td><td>12</td></tr></table>","table_caption":"[\"Table 1. Patient characteristics \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[512,99,929,168]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bone fragment (presence of focal photopenia) on late phase of planar BS in 11 fractures out of 37 $(29.7\\%)$ and in 16 fractures out of 37 $(43.2\\%)$ on SPECT/CT. Out of 16 fracture sites with necrotic fragments, three fracture sites had two necrotic fragments, while the rest had one necrotic fragment only. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,180,927,319]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Out of the 37 fracture sites, seven had mild degree of uptake (of which two showed no bridging on CT, four showed partial bridging, and one showed complete bridging), 22 had moderate uptake (of which 11 showed no bridging, six partial bridging, and five complete bridging) and remaining eight had high uptake (of which six showed no bridging, one partial bridging, and one complete bridging). This translates as 17 patients with moderate-to-high radiotracer uptake had no bridging on the CT images, and 16 patients with mild-to-moderate uptake had partial-to-complete bridging on the CT images (Table 2, Figure 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,332,927,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The sizes of the necrotic fragments ranged from 1 to $10\\mathrm{cm}$ (average size: $3.7\\mathrm{cm}$ ). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,372,929,579]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Out of these 37 patients, 25 underwent surgery. Necrotic fragments were resected in 11 patients of which 10 had positive histology for necrotic fragment and one was negative (Figures 2-4). The remaining patients had conservative management and routine follow-up. According to the defined reference standards, SPECT/CT showed sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of $100\\%$ , $95\\%$ , $94\\%$ , $100\\%$ , and $97\\%$ , respectively, for detection of necrotic bone fragments and delayed healing/non-union. Corresponding values for planar imaging for prediction of necrotic fragment and non-union were $67\\%$ , $95\\%$ , $91\\%$ , $81\\%$ , and $83\\%$ respectively (Tables 3-5). The ROC analysis showed improved performance with SPECT/CT with better area under the curve (AUC) for SPECT/CT (0.9773) compared to planar imaging (0.8106) ( $p$ -value $< 0.01$ ) (Figure 5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,599,623,611]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,613,929,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the present study, SPECT/CT was an accurate tool for the assessment of necrotic bone fragments in non-unions after traumatic fractures. SPECT/CT was superior to planar BS. Detection of a necrotic bone fragment with SPECT/CT helps in deciding subsequent revision surgery. Critical factors for the viability of bone in a traumatic fracture are sufficient blood and oxygen supply and adequate balance between different local osteoblastic and osteoclastic factors. Functional imaging with BS and SPECT/ CT has been successfully used for the detection of avascular necrosis and osteonecrosis. The main biochemical mechanism underlying the uptake of radiotracer in BS during the process of bone remodeling and new bone formation is the high affinity of Tc-99m-labelled bisphosphonates to newly formed hydroxyapatite crystals by the process of chemisorption. This process of chemisorption, in turn, depends upon maintained regional vascular supply of the bone and preserved osteoblastic activity. According to the pathological definition, a bony sequestrum or necrotic fragment is defined as a piece of devitalized bone which has separated from the surrounding bone during the process of necrosis. The imaging appearance of a sequestrum on radiographic and CT images is in the form of a piece of calcified bone, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,65,105,74]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[850,66,919,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bhure et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,947,270,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 of 7 birpublications.org/bjr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[757,947,927,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Br J Radiol;93:20200300 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,114,929,231]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0369/580423a979453070b61ad27550b72464a9f23b6ba010c14a47d0521378e47a9b.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Grade of osseous bridging in CT images</td><td colspan=\"4\">Grade of radiotracer uptake at the fracture site</td></tr><tr><td>No uptake</td><td>Mild</td><td>Moderate</td><td>High</td></tr><tr><td>No bridging</td><td>0</td><td>2</td><td>11</td><td>6</td></tr><tr><td>Partial bridging</td><td>0</td><td>4</td><td>6</td><td>1</td></tr><tr><td>Complete bridging</td><td>0</td><td>1</td><td>5</td><td>1</td></tr><tr><td>Total (n = 37):</td><td>0</td><td>7</td><td>22</td><td>8</td></tr></table>","table_caption":"[\"Table 2. Grade of radiotracer uptake at the fracture site versus grade of osseous bridging in CT images \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[65,249,480,400]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"sometimes within a lucent lesion. $^{11}$ CT with multiplanar reformations is a better modality compared to conventional X-rays for the evaluation and detection of a sequestrum. However, differentiating between necrotic bone, residual viable bone, or foci of matrix calcification or ossification on the imaging is not always possible with radiography or CT. MRI has the potential to differentiate sequestrum from vascularized normal bone but in traumatic fractures presence of metal hardware restricts the use of MRI because of artifacts. SPECT/CT is less vulnerable for metal artifacts. In our study, 35 $(94.6\\%)$ patients had metal implants at the fracture site. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,414,480,524]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fracture healing is an ongoing dynamic and complex process, which includes biological as well as mechanical components. Unfortunately, assessment of fracture healing is still limited. In current practice, fractures not healing for more than 6 months without cortical bridging and persistent fracture lines on conventional radiographs might be labeled as delayed union and more than 9 months as non-union. [12] CT scans add important additional cross-sectional morphological information. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,537,482,675]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pseudarthrosis, literally translated means a false joint, refers to a failure of fusion of fractured ends of a bone, leading to an abnormal union with fibrous tissue between the fragments, and is a long-term outcome of non-union.[12,13] It may take months to years to develop and not all patients with pseudarthrosis are symptomatic. There are two main types of non-unions according to the viability of the ends of fractured bone fragments, hypervascular or hypertrophic and avascular or atrophic non-unions.[12] The hypervascular non-unions have presence of blood supply in the ends of the fractured bone fragments and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[72,724,478,898]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Osseous bridging on CT versus grade of radiotracer activity at the fracture sites. \"]","image_footnote":"[]","img_path":"images/0383/afa4ca9f7e7ed593cf03c252dcb8b6344362fa5da34770843622c235ad1790b2.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[510,250,929,464]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"are capable of biological reaction and there is variable amount of callus formation. In avascular non-unions, the bony fragments have a poor blood supply and are incapable of biological reaction, and there is lack of callus formation, eventually leading to formation of necrotic bone fragments or dead bone within. In such situation, debridement of dead bone with bridging of viable bone ends with bone grafts is needed for good recovery. The typical scintigraphic appearance of the lesions reveals increased radiotracer uptake during the chronic reparative process, which is usually peripheral with central photopenia (area of reduced activity). Published literature regarding the performance of SPECT/CT for the evaluation of necrotic bone or pseudarthrosis is very sparse. SPECT has proven to be valuable for the diagnosis of femoral head osteonecrosis and was more sensitive than MRI $(100\\% \\text{ vs } 66\\%)$ in a study by Ryu et al. $^{14}$ In our study, SPECT/ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,491,929,714]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 2. 26-year-old male with osteosynthesis of left distal femur fracture 6 months ago. He was being evaluated in view on delayed union. Early-phase [images A (anterior), B (posterior)] and late-phase [images C (anterior), D (posterior)] images of planar bone scintigraphy show moderate radiotracer accumulation in the area of left distal femur fracture site. Plain radiography (E) shows incomplete consolidation of the fracture. SPECT/CT (Coronal SPECT/CT: F and Coronal CT: G) images show increased uptake at some parts of the former fracture as signs of bone remodeling. Additionally, there is a loose unconsolidated bone fragment of $6.0 \\times 1.3 \\mathrm{~cm}$ size, dorsolaterally at the fracture site with complete absence of radiotracer uptake (photopenia), suggestive of necrotic bone fragment. The patient underwent revision surgery with removal of necrotic bone fragment. Follow-up CT (post 15 months) images (CT coronal: H, 3D VRT: I, J) and X-ray (post 21 months) images (K, L) show union at the fracture site. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,719,606,808]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0374/dac7ed73f331d889c65a4a6123458e3412aacb2cf1ce901fba240ededf409edb.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[605,720,727,804]","code_body":null,"code_caption":null,"image_caption":"[\"F-up CT post 15 months \"]","image_footnote":"[]","img_path":"images/0648/954117eab4a2b452642ad744a01074c4e15a8305e79a269bf4c9af708b8f6eb4.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,810,603,898]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0127/6c40d75b8ec529daf6150eef842a06b061f907eb6faf35201c7359c669ce0d47.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[603,814,727,898]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0485/6f75bf419ce14258e8b3583aecced687efd6e741ca18606a24b0c00ee3f19770.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[726,720,818,801]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0978/3a75c97fa803e7d8a92bdde6eb7b17041db39ebe3e76098afbb0f058995cae42.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[818,720,927,802]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0227/104de5043c0483dca1ba3077ad506d88969411ce649b763eab156fc08c61937e.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[818,802,927,898]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0772/679ec5700ffe30d13ae5c6d9d3dbb440f7f6966e7b43041d49f89a748df71265.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[78,65,314,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"\"SPECT/CT in necrotic bone fragments\" ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,65,917,74]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,948,272,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 7 birpublications.org/bjr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[757,948,927,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Br J Radiol;93:20200300 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,170,273,279]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Hematoxylin and Eosin staining of the resected bone fragment of the same patient as in figure 2. Images show missing osteocyte nuclei and fat necrosis indicating necrotic bone fragments (images courtesy Dr. Zenklusen, Institute of pathology, Cantonal Hospital Lucerne, Switzerland). \"]","image_footnote":"[]","img_path":"images/0107/b865b62e214eeafc06ee7ed50cfd22dc367c7e1d9382e2d77bcb017caf27d1a3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[275,170,480,279]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0884/3b7a73b2c0cb45a1314a225a6ccf497385aaae293737b4076098d4e45c7b1e2d.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[68,280,273,390]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0086/51e8e8808b0a94d213457c29534d663737725206bb5dfcb1fff2c67c959803fb.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[70,719,176,808]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. 54-year-old female with osteosynthesis of left distal femur fracture after car accident 6 months ago. Osteosynthesis was removed because of infection and external fixator was installed. Early phase of bone scintigraphy (BS) [images A (anterior), B (posterior)] shows mild-to-moderate amount of radiotracer accumulation in the left distal femur, knee joint, as well as in the region of left ankle. The late phase images [C (anterior), D (posterior)] of planar BS show persistent increasing accumulation of radiotracer in above areas along with a photopenic area in the left distal femur. SPECT/CT images (E: coronal CT, F: coronal SPECT, G: coronal SPECT/CT fusion, H: sagittal CT, I: sagittal SPECT, J: sagittal SPECT/CT fusion) show absence of radiotracer accumulation in the two bone fragments in the left distal femur in and around the fracture site. The patient underwent revision surgery with removal of necrotic bone fragments. A vitality was proven histologically. Follow-up X-ray (image K) post 6 months shows improvement with good healing and union of the fracture site. \"]","image_footnote":"[]","img_path":"images/0652/4b420da4bccb3f90da03791eada37d5f75b4d23cdcb0b97dd7a56144ce1dc908.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[70,808,176,898]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0869/1bd0126ee2bd5ac5be3584d6418b39422908db109f3f6b79cc310b9603cb5919.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[176,720,295,797]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0754/b00f45ed0c6afcd2cfb974e8655b5225205c0379a07f9f24f731f1e0ef7a30dd.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[295,720,386,797]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0826/bd4cdd587da337a8e713ac67f4a22b8b2c2689448607b1a1127c0811a467ecaa.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[389,720,480,797]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0726/bea0dd1ef3077908c0a4aa3af40b3b7b34462aded590692071670b227efd99a5.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[176,799,265,888]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0566/883f6fdcaaeb3b0e576b6183d38379437d77cb38be89aa1dcb6fa221576278d3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[265,799,329,888]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0348/5be90ff4f1d7d1c44d21249eb1e879eb0158ce724b195ce25ec67785fbcc3394.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[329,799,389,888]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0968/01e4d1298bb0a9832ccb1093b47be9226db96bc41e6f97ce8f5c8a0d0f1f13e4.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[389,799,480,897]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0301/56badcb6883e9e518bffb97f762f66fc067f8ba88350869082c617440dedd6cf.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,114,927,211]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0665/3f1760c951498eaca30fd7c800e972be1ddd40e1ef46d03220bd8f002f92095c.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>Bone Scintigraphy</td><td></td></tr><tr><td>Reference Standard</td><td>Positive</td><td>Negative</td><td>Total</td></tr><tr><td>Positive</td><td>10</td><td>5</td><td>15</td></tr><tr><td>Negative</td><td>1</td><td>21</td><td>22</td></tr><tr><td>Total</td><td>11</td><td>26</td><td>37</td></tr></table>","table_caption":"[\"Table 3. Frequency table for bone scintigraphy \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[512,233,927,261]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CT could detect necrotic bone fragments in 16 out of 37 fracture sites $(43.2\\%)$ compared to only 11 $(29.7\\%)$ detected on planar BS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,274,929,697]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The absence of activity on bone SPECT/CT in persistent fractures is a highly specific marker for non-union.[15] Liodakis et al retrospectively evaluated the role of SPECT/CT in 10 patients, involving fractures of upper and lower extremity, in diagnosing and planning the treatment of avascular/atrophic non-unions with surgical exploration as the reference standard.[15] SPECT/CT identified all the four vital pseudarthroses and three of the six non-vital pseudarthroses. The sensitivity of SPECT/CT in diagnosing non-vital atrophic non-unions was $50\\%$ , and the specificity was $100\\%$ . We obtained improved sensitivity for SPECT/CT detection of necrotic bone fragments leading to delayed healing/non-union with sensitivity of $100\\%$ and specificity of $95\\%$ . Diederichs and colleagues compared the diagnostic performance of bone SPECT/CT and MRI for the evaluation of bone viability in patients after girdlestone arthroplasty (two-stage revision technique).[16] In their study, the prostheses were removed after the diagnosis of periprosthetic joint infection, and it was followed by 6 to 8 weeks of antibiotic therapy. Revision total hip arthroplasty was performed after successful treatment of infection; and $24\\mathrm{h}$ prior to this revision surgery, SPECT/CT and MRI were performed. So, their patients did not have metal hardware in situ, and hence they could perform MRI. They found high sensitivity and specificity for SPECT/CT as well as for MRI for differentiation between viable and non-viable bone tissue, although SPECT/CT had slightly better sensitivity $(90\\%)$ and specificity $(94\\%)$ compared to MRI. They found statistically significantly higher uptake values for vital bone compared to non-vital bone. Although the metal prosthesis was removed before imaging, some metal particles remaining behind in tissues close to the bone gave rise to imaging artifacts on MRI contributing to some false-positive results. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,711,927,766]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Niikura et al[17] evaluated 48 patients with uninfected fracture non-unions, in a retrospective study, and compared radiographs with Tc-99m BS and tried to study the detailed pattern and features of radiotracer uptake. They observed positive radiotracer uptake ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,804,927,898]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0129/2f9365128e8209f9cb90a3e8065175cdc8c2120d2e1b66aafd6a32e61f8e9ed6.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>SPECT/CT</td><td></td></tr><tr><td>Reference Standard</td><td>Positive</td><td>Negative</td><td>Total</td></tr><tr><td>Positive</td><td>15</td><td>0</td><td>15</td></tr><tr><td>Negative</td><td>1</td><td>21</td><td>22</td></tr><tr><td>Total</td><td>16</td><td>21</td><td>37</td></tr></table>","table_caption":"[\"Table 4. Frequency table for SPECT/CT \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[78,65,105,74]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[850,66,919,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bhure et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,948,270,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 of 7 birpublications.org/bjr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[757,948,927,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Br J Radiol;93:20200300 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,149,480,263]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0879/5ffc74a03d3d796503d1b4bbc6f7bff2a8bbce53ad4a28bc884f3251d1800b64.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td></td><td>SPECT/CT</td><td>BS</td></tr><tr><td>Sensitivity (%)</td><td>100</td><td>67</td></tr><tr><td>Specificity (%)</td><td>95</td><td>95</td></tr><tr><td>Positive Predictive Value (PPV) (%)</td><td>94</td><td>91</td></tr><tr><td>Negative Predictive Value (NPV) (%)</td><td>100</td><td>81</td></tr><tr><td>Accuracy (%)</td><td>97</td><td>83</td></tr></table>","table_caption":"[\"Table 5. Comparative values of sensitivity, specificity, PPV, NPV, and accuracy in SPECT/CT and bone scintigraphy for the detection of necrotic bone fragments in traumatic fractures with suspected delayed healing or non-union \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[65,281,480,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in all cases and classified the uptake patterns into four types. They proposed a treatment algorithm of uninfected non-unions which incorporated BS. They recommended BS in the evaluation of non-hypertrophic non-unions, whereas hypertrophic non-unions can do without BS and secured fixation will lead to bony union. If BS reveals a photon-deficient area, then an autologous bone graft can be implanted for better and faster healing. On the other hand, if BS does not reveal any photopenic area, then secured fixation is good enough to achieve bony union and appropriate healing. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,438,480,468]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Song Q et al[18] evaluated 144 patients with known/suspected chronic-infected fracture non-union osteomyelitis in lower ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,518,485,728]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. Receiver operative curve (ROC) analysis of SPECT/CT versus planar scintigraphy (BS). \"]","image_footnote":"[]","img_path":"images/0751/36c1aaece5eea9419d10f512db09b88f2e97985f3ee8fd4e1b0522d49f7e2042.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[512,99,929,223]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"limb using SPECT/CT and found it better than standalone BS and CT imaging with improved diagnosis of non-union with precise localization of osteomyelitis which is critical for surgical management. Their group looked at osteomyelitis and soft tissue infection and their focus was on increased radiotracer activity suggesting infection. Our group, on the other hand, assessed the presence of necrotic bone fragments which might be responsible for delayed bone healing and non-union and is characterized by absence of radiotracer activity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,235,929,331]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We did not intend to compare SPECT with SPECT/CT as in our opinion SPECT/CT has completely replaced SPECT alone in bone and joint imaging as demonstrated in many studies. The CT part of the study is so important for anatomic correlation and bone healing assessment in this situation of fractures that referring surgeons would not want to waive this important information. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,344,929,441]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Limitations of our study include: a) possible selection bias, as we targeted traumatic bone fractures with delayed bone healing specifically; b) retrospective design of the study; c) the reference standard histology was available in only 11 patients (out of 37); d) quantitation of the radiotracer uptake using SUV max could not be performed due to technical issues and should be evaluated in subsequent studies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,453,633,464]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,468,929,521]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SPECT/CT is an accurate tool in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures and is superior to conventional planar BS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,536,752,549]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHORS' CONTRIBUTIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,551,927,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All authors contributed in a significant way to the content and revision of the manuscript. All authors read and approved the final manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,606,867,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMPLIANCE WITH ETHICAL STANDARDS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,621,929,731]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics committee approval was obtained for the study (Ethikkommission Nordwest- und Zentralschweiz EKNZ 2019-00594). Informed consent was waived by the ethics committee due to the retrospective design. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,778,184,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,800,341,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Einhorn TA. Enhancement of fracture-healing. J Bone Joint Surg Am 1995; 77: 940-56. doi: https://doi.org/10.2106/00004623-199506000-00016 \",\"2. Rajasekaran S, Giannoudis PV. Open injuries of the lower extremity: issues and unknown \"]","page_idx":"5","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[386,800,625,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiers. Injury 2012; 43: 1783-4. doi: https://doi.org/10.1016/j.injury.2012.08.039 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[368,826,633,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Bishop JA, Palanca AA, Bellino MJ, Lowenberg DW. Assessment of compromised fracture healing. J Am Acad Orthop Surg 2012; 20: 273-82. doi: https://doi.org/10.5435/JAAOS-20-05-273 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[658,800,927,879]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Hak DJ, Fitzpatrick D, Bishop JA, Marsh JL, Tilp S, Schnettler R, et al. Delayed Union and nonunions: epidemiology, clinical issues, and financial aspects. Injury 2014; 45 Suppl 2(Suppl 2): S3-7. doi: https://doi.org/10.1016/j.injury.2014.04.002 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,65,314,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"\"SPECT/CT in necrotic bone fragments\" ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,64,919,74]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,948,272,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 7 birpublications.org/bjr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[757,948,927,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Br J Radiol;93:20200300 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[70,98,341,437]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"5. Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury 2007; 38 Suppl 4(Suppl 4): S3-6. doi: https://doi.org/10.1016/S0020-1383(08) 70003-2 \",\"6. Bhattacharyya T, Bouchard KA, Phadke A, Meigs JB, Kassarjian A, Salamipour H. The accuracy of computed tomography for the diagnosis of tibial nonunion. J Bone Joint Surg Am 2006; 88: 692-7. doi: https://doi.org/10.2106/JBJS.E.00232 \",\"7. Galasko CS. The pathological basis for skeletal scintigraphy. J Bone Joint Surg Br 1975; 57: 353-9. doi: https://doi.org/10.1302/0301-620X.57B3.353 \",\"8. Matin P. The appearance of bone scans following fractures, including immediate and long-term studies. J Nucl Med 1979; 20: 1227-31. \",\"9. Sarikaya I, Sarikaya A, Holder LE. The role of single photon emission computed tomography in bone imaging. Semin Nucl Med 2001; 31: 3-16. doi: https://doi.org/10.1053/snuc.2001.18736 \",\"10. Lisbona R, Rennie WR, Daniel RK. Radionuclide evaluation of free vascularized \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[363,99,635,438]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"bone graft viability. AJR Am J Roentgenol 1980; 134: 387-8. doi: https://doi.org/10. 2214/ajr.134.2.387 \",\"11. Jennin F, Bousson V, Parlier C, Jomaah N, Khanine V, Laredo J-D. Bony Sequestrum: a radiologic review. *Skeletal Radiol* 2011; 40: 963-75. doi: https://doi.org/10.1007/s00256-010-0975-4 \",\"12. Frolke JPM, Patka P. Definition and classification of fracture non-unions. Injury 2007; 38 Suppl 2(Suppl 2): S19-22. doi: https://doi.org/10.1016/S0020-1383(07)80005-2 \",\"13. Leven D, Cho SK. Pseudarthrosis of the cervical spine: risk factors, diagnosis and management. Asian Spine J 2016; 10: 776-86. doi: https://doi.org/10.4184/ajj.2016.10.4.776 \",\"14. Ryu J-S, Kim JS, Moon DH, Kim SM, Shin MJ, Chang JS, et al. Bone SPECT is more sensitive than MRI in the detection of early osteonecrosis of the femoral head after renal transplantation. J Nucl Med 2002; 43: 1006-11. \",\"15. Liodakis E, Liodaki E, Krettek C, Citak M, Gaulke R, Konstantinidis L, et al. Can the viability of a nonunion be evaluated using \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[657,99,927,437]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"SPECT/CT? A preliminary retrospective study. Technol Health Care 2011; 19: 103-8. doi: https://doi.org/10.3233/THC-2011-0617 \",\"16. Diederichs G, Hoppe P, Collettini F, Wassilew G, Hamm B, Brenner W, et al. Evaluation of bone viability in patients after girdlestone arthroplasty: comparison of bone SPECT/CT and MRI. Skeletal Radiol 2017;46:1249-58. doi: https://doi.org/10.1007/s00256-017-2692-8 \",\"17. Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Comparison of radiographic appearance and bone scintigraphy in fracture nonunions. Orthopedics 2014; 37: e44-50. doi: https://doi.org/10.3928/01477447-20131219-16 \",\"18. Song Q, Long L, Cui S, Shu H, Wan C, Wu B, et al. Utility of technetium-99m-methylene diphosphonate single-photon emission computed tomography/computed tomography fusion in detecting posttraumatic chronic-infected nonunion in the lower limb. Nucl Med Commun 2019; 40: 778-85. doi: https://doi.org/10.1097/MNM.0000000000001027 \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[78,65,105,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BJR ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[850,66,919,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bhure et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,948,270,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 of 7 birpublications.org/bjr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[759,948,927,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Br J Radiol;93:20200300 ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[102,129,215,140]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cite this article as: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,140,902,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bhure U, Agten C, Lehnick D, Perez-Lago MdS, Beeres F, Link B-C, et al. Value of SPECT/CT in the assessment of necrotic bone fragments \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,149,742,159]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in patients with delayed bone healing or non-union after traumatic fractures. Br J Radiol 2020; 93: 20200300. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,205,257,222]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"FULL PAPER \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,235,870,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Value of SPECT/CT in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,324,800,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ UJWAL BHURE, MD, $^{1}$ CHRISTOPH AGTEN, MD, $^{2}$ DIRK LEHNICK, MD, $^{1}$ MARIA DEL SOL PEREZ-LAGO, MD, $^{3}$ FRANK BEERES, MD, PhD, $^{3}$ BJÖRN-CHRISTIAN LINK, MD and $^{1}$ KLAUS STROBEL, MD \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,355,667,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Department of Radiology and Nuclear Medicine, Cantonal Hospital Lucerne, Lucerne, Switzerland \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,366,539,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{2}$ Biostatistics and Methodology, University of Lucerne, Lucerne, Switzerland \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,376,667,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{3}$ Department of Orthopedic and Trauma Surgery, Cantonal Hospital Lucerne, Lucerne, Switzerland \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,401,376,412]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Address correspondence to: Prof Klaus Strobel \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,412,272,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E-mail: klaus.strobel@luks.ch \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,449,482,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objective: To evaluate the value of single-photon emission computed tomography / computed tomography (SPECT/CT) compared with planar bone scintigraphy (BS) in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,527,482,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: Retrospective evaluation of patients with traumatic fractures and suspected delayed healing or non-union and/or persistent pain or suspected infection who had undergone planar late phase BS and SPECT/CT between 2011 and 2018. On the BS and SPECT/CT images, a necrotic fragment was considered if there was an area of absent radiotracer uptake (photopenia) related to bone at the fracture site. Histology served as a reference standard (presence or absence of necrotic bone fragments). If histology was not available, intraoperative findings and combined clinical and imaging follow-up served as reference standards. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,684,482,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: In 37 consecutive patients with traumatic fractures (femur $(n = 18)$ ,tibia (11), humerus (6), radius (1), \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,449,894,606]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"jaw (1)), necrotic bone fragments were suspected in 11 fractures $(29.7\\\\%)$ on BS and in 16 fractures $(43.2\\\\%)$ on SPECT/CT. 35 fractures $(94.6\\\\%)$ had metallic implants. Histology showed necrotic fragments in 10/11 $(90.9\\\\%)$ patients. For the detection of necrotic bone fragments, SPECT/CT showed sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of $100\\\\%$ , $95\\\\%$ , $94\\\\%$ , $100\\\\%$ , and $97\\\\%$ , respectively, and BS $67\\\\%$ , $95\\\\%$ , $91\\\\%$ , $81\\\\%$ , and $83\\\\%$ , respectively. SPECT/ CT significantly outperformed BS with better area under curve (AUC) for SPECT/CT (0.9773) compared to planar imaging (0.8106) $(p$ -value $< 0.01)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,607,892,658]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions: SPECT/CT is an accurate tool in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic bone fractures and is superior to conventional planar BS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,659,892,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Advances in knowledge: SPECT/CT is accurate and superior to planar BS in identification of necrotic bone fragments, responsible for delayed bone healing/nonunion after fractures. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,736,236,749]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,752,482,932]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Approximately 5.6 million fractures occur annually in the USA and up to $10\\\\%$ of these fractures result in delayed healing or non-union. Risk factors for delayed healing or non-union are either patient-dependent or patient-independent. The patient-dependent risk factors include sex, old age, history of smoking, various medical comorbidities like diabetes, hypertension, genetic disorders, prolonged use of NSAIDs, nutritional deficiencies, and metabolic disorders. Patient-independent risk factors responsible for delayed healing or non-union include pattern of fracture (such as transverse, linear, oblique, spiral, comminuted, etc), its location and extent of displacement, degree of bone loss, severity of soft tissue injury (minor or severe), \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,737,895,932]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"presence or absence of infection, and quality of surgical treatment (clean and skilled surgery versus post operative complications). Correct assessment of fracture healing is essential for patients because it determines whether they will tolerate weight-bearing, whether they can return to work and routine activities with restored quality of life, or whether any additional surgery is required for further improvement. Non-unions are not only challenging from the treatment side but also have socio-economic implications with loss of job, wages, coupled with mounting treatment cost leading to debt trap and subsequent social fall outs. Diagnostic tests for assessment of fracture healing include plain radiography, CT, MRI, bone scintigraphy (BS), and several laboratory tests, which are important for \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,64,137,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[505,65,904,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. Published by the British Institute of Radiology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[102,89,161,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[102,99,189,109]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"31 March 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[213,89,265,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Revised: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[213,99,290,109]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22 May 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[314,89,376,98]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[314,98,396,108]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"29 June 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[685,82,902,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1259/bjr.20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,98,480,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the evaluation and detection of infection as well as metabolic and endocrine abnormalities. The imaging hallmarks which point to delayed healing or non-union include absence of bony bridging between the fracture ends, persistent fracture lines with visualized gap, absence of improvement or evidence of healing on serial radiographs, problems with the surgical metal implants (loosened or broken), and persistent or progressive deformity. $^{4}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,208,480,318]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The diagnosis of sequestrum or necrotic bone fragment in patients with non-union after traumatic fractures has important impact on the surgical approach. Necrotic bone fragments prevent bone healing, thus have to be removed and augmentation with bone grafts might be necessary.[5] CT is a very accurate modality for the assessment of fracture healing but limited regarding the detection of necrotic fragments.[6] MRI may be limited by artifacts caused by metal hardware used for fracture fixation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,331,480,537]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BS with Tc-99m $(^{99}\\\\mathrm{mTc})$ -labeled diphosphonates has been used for decades for the assessment of bone disorders. The two important factors responsible for the degree and intensity of radiotracer accumulation at a particular site in bone are its blood supply and the rate of new bone formation.[7] BS can detect most of the fractures within $24\\\\mathrm{h}$ of the occurrence. On an average, the minimum time for normalization of radiotracer activity is around 6 months post-development of fracture, and by around 2 years of the event, most of the fractures would have shown normalization of the radiotracer activity.[8] However, in non-aligned fractures, the process of bone remodeling is going on continuously, and hence, these fractures may not exhibit regression of the radiotracer activity with normal scintigraphic appearance. One of the causes for delayed healing or non-union of the fracture is presence of a necrotic fragment at the fracture site. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,551,480,634]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this study, we assessed the value of single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection of necrotic fragments in patients with delayed bone healing or non-union and/or persistent pain or suspected infection after traumatic fractures and compared the performance of SPECT/CT with planar BS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,653,299,665]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"METHODS AND MATERIALS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,668,480,764]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Retrospective analysis of consecutive patients with traumatic fracture and suspected delayed healing or non-union and/or persistent pain between 2011 and 2018 who had undergone both BS and SPECT/CT was performed. 10 out of 54 patients without available follow-up were excluded. This study was approved by the ethics committee, and the need for written informed consent was waived (EKNZ 2019-00594). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,778,480,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study includes consecutive patients from a single institution. The inclusion criteria were: (a) patients who underwent BS with SPECT/CT from 2011 to 2018; (b) clinical indication being delayed bone healing/non-union of traumatic fracture with suspicion of necrotic bone fragment; (c) in house surgery and further clinical management; and (d) histology or follow-up (clinical/radiological) available. Most of these patients had only X-ray as a prior imaging due to the presence of metal implant MRI was not feasible and not performed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,99,699,111]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SPECT/CT PROTOCOL \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,114,927,441]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All patients underwent BS with Tc-99m-DPD (Tc-99m-3,3-diphosphono-1,2-propanedicarboxylic acid; Teceos, Behringwerke AG, Marburg, Germany). The radiotracer was injected intravenously (average tracer activity 657.92 MBq (17.78 mCi); range: 580 to 704 MBq (15.7 to 19 mCi)) and early-phase planar scintigraphy images were obtained 5 min post-injection (matrix size: $256 \\\\times 256 \\\\mathrm{~mm}$ , field of view: $40 \\\\mathrm{~cm}$ ) under the hybrid SPECT/CT scanner with a built-in flat-panel CT component (BrightView XCT; Philips Healthcare, Best, The Netherlands). Planar late-phase scintigraphy images were acquired $3 \\\\mathrm{~h}$ post-radiotracer injection (matrix size: $256 \\\\times 256$ , field of view: $40 \\\\mathrm{~cm}$ ), followed by the acquisition of SPECT/CT images of the region of interest (fracture site). SPECT was performed in step-and-shoot mode with 64 projections, at the speed of 20 s per projection (SPECT frame matrix size: $128 \\\\times 128$ ). SPECT images were reconstructed with an iterative 3D ordered subsets expectation maximization (OSEM) algorithm (Astonish, Philips, Netherlands). CT images were acquired in high-resolution mode with an isotropic CT voxel size of $0.33 \\\\times 0.33 \\\\times 0.33 \\\\mathrm{~mm}^3$ (CT slice thickness $0.33 \\\\mathrm{~mm}$ , matrix size of $512 \\\\times 512 \\\\mathrm{~mm}$ ) and reconstructed with iterative filters. SPECT and CT images were automatically fused with dedicated software (Extended Brilliance Workspace; Philips Healthcare, Netherlands), reformatted in coronal and sagittal planes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,456,722,468]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IMAGE INTERPRETATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,470,927,552]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Planar (early and late phase) and SPECT/CT images were reviewed by an experienced nuclear medicine physician and a double board-certified radiologist and nuclear medicine physician with specialized training in musculoskeletal (MSK) imaging. The final image interpretation was done with consensus of these two reviewing physicians. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,558,929,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"(1) The state of fracture healing was assessed using the CT images from the SPECT/CT [non-union (no bony bridging), partial union (partial bridging), complete union (complete bridging)]. \\\",\\\"(2) The early and late planar phases of every BS were assessed for the presence or absence of abnormal radiotracer accumulations. \\\",\\\"(3) The radiotracer uptake at the fracture site on the planar image of the BS was visually graded as absent (grade 0), mild (Grade 1), moderate (Grade 2), and high (Grade 3) in relationship to normal bone uptake on the contralateral side. \\\",\\\"(4) On the planar late-phase images and SPECT/CT images, necrotic fragment was considered present if there was an area of absent radiotracer uptake (photopenia) related to bone at the fracture site. The two physicians reviewing the images were blinded to the detailed clinical information except for the main purpose of the study: assessment of delayed bone healing/non-union with suspicion of necrotic bone fragment. \\\",\\\"(5) The size of the necrotic bone fragment was measured (largest diameter in any plane). \\\",\\\"(6) Statistics: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were assessed and the performance of SPECT/CT and BS was compared with ROC analysis. \\\"]\",\n \"page_idx\": \"1\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[78,65,314,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\\\"SPECT/CT in necrotic bone fragments\\\" \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,64,919,74]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,948,270,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 7 birpublications.org/bjr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[757,948,927,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Br J Radiol;93:20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[67,99,480,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(7) Reference standard: In operated patients, intraoperative finding and histology served as reference standard. In histology, osteocytes with missing nucleoli and fat necrosis were signs of necrotic bone. In those patients in which no histology was obtained, imaging and clinical follow-up served as reference standards. If complete fracture healing was visible on follow-up imaging (X-ray and/or CT) without demarcation of a bony fragment, this case was diagnosed as \\\"no necrotic fragment\\\". Clinically absence of pain, overall improvement in general condition with improved quality of life, as well as improved mobility of the bone/joint in question, and no more suspicion of infection were taken as improvement and negative for necrotic fragment. The average follow-up period was 25 months [range: 3 to 91 months]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,323,144,336]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,338,480,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"44 patients were identified. Seven patients who were not available for follow-up were excluded. Therefore, 37 patients [23 male, 14 female; average age 51.6 years (range: 22 to 84 years)] were assessed with following fractures: femur $(n = 18)$ , tibia (11), humerus (6), radius (1) and jaw (1). The average time from fracture to BS was 30 months (range: 2 to 312 months). 35 fractures $(94.6\\\\%)$ had metal implants in the form of metal plates, screws, rods, intramedullary nails, external fixators, or wires. 19 fractures showed non-union, 11 partial union and seven complete union in SPECT/CT based on the bridging of fracture line as seen on the CT part of the SPET/CT. Out of 37 patients, 13 had SPECT/CT within 6 months of the fracture, whereas 24 patients had it more than 6 months after the fracture. (Table 1) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,529,480,571]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 patients had suspicion of infection and the early phase of bone scan showed hyperemia in 10 patients, of which six had necrotic bone fragments. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,583,480,612]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The late phase of BS and SPECT/CT showed increased activity at the fracture site in all patients. There was suspicion of necrotic \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,656,480,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0059/13d0b528689d7abd2f6967b12fe1b39a894d63370c72ad3a3375041117dda994.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>N (Total Number)</td><td>37 patients</td></tr><tr><td>Male : Female</td><td>23 : 14</td></tr><tr><td>Age</td><td>Average 52 years (range: 22-84)</td></tr><tr><td>Bones involved</td><td>18 (Femur), 11 (Tibia), 6 (Humerus), 1 (Radius), 1 (Jaw)</td></tr><tr><td>Metal Implant</td><td>Present: 35; Absent: 2</td></tr><tr><td>Average time from fracture to BS</td><td>30 months (range: 2-312)</td></tr><tr><td>BS within 6 months of fracture</td><td>13</td></tr><tr><td>BS more than 6 months after fracture</td><td>24</td></tr><tr><td>Histology available</td><td>11</td></tr><tr><td>Average follow-up period</td><td>25 months (range: 3-91)</td></tr><tr><td>Surgery</td><td>25</td></tr><tr><td>Conservative management</td><td>12</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Patient characteristics \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[512,99,929,168]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bone fragment (presence of focal photopenia) on late phase of planar BS in 11 fractures out of 37 $(29.7\\\\%)$ and in 16 fractures out of 37 $(43.2\\\\%)$ on SPECT/CT. Out of 16 fracture sites with necrotic fragments, three fracture sites had two necrotic fragments, while the rest had one necrotic fragment only. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,180,927,319]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Out of the 37 fracture sites, seven had mild degree of uptake (of which two showed no bridging on CT, four showed partial bridging, and one showed complete bridging), 22 had moderate uptake (of which 11 showed no bridging, six partial bridging, and five complete bridging) and remaining eight had high uptake (of which six showed no bridging, one partial bridging, and one complete bridging). This translates as 17 patients with moderate-to-high radiotracer uptake had no bridging on the CT images, and 16 patients with mild-to-moderate uptake had partial-to-complete bridging on the CT images (Table 2, Figure 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,332,927,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The sizes of the necrotic fragments ranged from 1 to $10\\\\mathrm{cm}$ (average size: $3.7\\\\mathrm{cm}$ ). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,372,929,579]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Out of these 37 patients, 25 underwent surgery. Necrotic fragments were resected in 11 patients of which 10 had positive histology for necrotic fragment and one was negative (Figures 2-4). The remaining patients had conservative management and routine follow-up. According to the defined reference standards, SPECT/CT showed sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of $100\\\\%$ , $95\\\\%$ , $94\\\\%$ , $100\\\\%$ , and $97\\\\%$ , respectively, for detection of necrotic bone fragments and delayed healing/non-union. Corresponding values for planar imaging for prediction of necrotic fragment and non-union were $67\\\\%$ , $95\\\\%$ , $91\\\\%$ , $81\\\\%$ , and $83\\\\%$ respectively (Tables 3-5). The ROC analysis showed improved performance with SPECT/CT with better area under the curve (AUC) for SPECT/CT (0.9773) compared to planar imaging (0.8106) ( $p$ -value $< 0.01$ ) (Figure 5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,599,623,611]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,613,929,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the present study, SPECT/CT was an accurate tool for the assessment of necrotic bone fragments in non-unions after traumatic fractures. SPECT/CT was superior to planar BS. Detection of a necrotic bone fragment with SPECT/CT helps in deciding subsequent revision surgery. Critical factors for the viability of bone in a traumatic fracture are sufficient blood and oxygen supply and adequate balance between different local osteoblastic and osteoclastic factors. Functional imaging with BS and SPECT/ CT has been successfully used for the detection of avascular necrosis and osteonecrosis. The main biochemical mechanism underlying the uptake of radiotracer in BS during the process of bone remodeling and new bone formation is the high affinity of Tc-99m-labelled bisphosphonates to newly formed hydroxyapatite crystals by the process of chemisorption. This process of chemisorption, in turn, depends upon maintained regional vascular supply of the bone and preserved osteoblastic activity. According to the pathological definition, a bony sequestrum or necrotic fragment is defined as a piece of devitalized bone which has separated from the surrounding bone during the process of necrosis. The imaging appearance of a sequestrum on radiographic and CT images is in the form of a piece of calcified bone, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,65,105,74]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[850,66,919,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bhure et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,947,270,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 of 7 birpublications.org/bjr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[757,947,927,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Br J Radiol;93:20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,114,929,231]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0369/580423a979453070b61ad27550b72464a9f23b6ba010c14a47d0521378e47a9b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Grade of osseous bridging in CT images</td><td colspan=\\\"4\\\">Grade of radiotracer uptake at the fracture site</td></tr><tr><td>No uptake</td><td>Mild</td><td>Moderate</td><td>High</td></tr><tr><td>No bridging</td><td>0</td><td>2</td><td>11</td><td>6</td></tr><tr><td>Partial bridging</td><td>0</td><td>4</td><td>6</td><td>1</td></tr><tr><td>Complete bridging</td><td>0</td><td>1</td><td>5</td><td>1</td></tr><tr><td>Total (n = 37):</td><td>0</td><td>7</td><td>22</td><td>8</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Grade of radiotracer uptake at the fracture site versus grade of osseous bridging in CT images \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[65,249,480,400]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"sometimes within a lucent lesion. $^{11}$ CT with multiplanar reformations is a better modality compared to conventional X-rays for the evaluation and detection of a sequestrum. However, differentiating between necrotic bone, residual viable bone, or foci of matrix calcification or ossification on the imaging is not always possible with radiography or CT. MRI has the potential to differentiate sequestrum from vascularized normal bone but in traumatic fractures presence of metal hardware restricts the use of MRI because of artifacts. SPECT/CT is less vulnerable for metal artifacts. In our study, 35 $(94.6\\\\%)$ patients had metal implants at the fracture site. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,414,480,524]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fracture healing is an ongoing dynamic and complex process, which includes biological as well as mechanical components. Unfortunately, assessment of fracture healing is still limited. In current practice, fractures not healing for more than 6 months without cortical bridging and persistent fracture lines on conventional radiographs might be labeled as delayed union and more than 9 months as non-union. [12] CT scans add important additional cross-sectional morphological information. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,537,482,675]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pseudarthrosis, literally translated means a false joint, refers to a failure of fusion of fractured ends of a bone, leading to an abnormal union with fibrous tissue between the fragments, and is a long-term outcome of non-union.[12,13] It may take months to years to develop and not all patients with pseudarthrosis are symptomatic. There are two main types of non-unions according to the viability of the ends of fractured bone fragments, hypervascular or hypertrophic and avascular or atrophic non-unions.[12] The hypervascular non-unions have presence of blood supply in the ends of the fractured bone fragments and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[72,724,478,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Osseous bridging on CT versus grade of radiotracer activity at the fracture sites. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0383/afa4ca9f7e7ed593cf03c252dcb8b6344362fa5da34770843622c235ad1790b2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[510,250,929,464]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"are capable of biological reaction and there is variable amount of callus formation. In avascular non-unions, the bony fragments have a poor blood supply and are incapable of biological reaction, and there is lack of callus formation, eventually leading to formation of necrotic bone fragments or dead bone within. In such situation, debridement of dead bone with bridging of viable bone ends with bone grafts is needed for good recovery. The typical scintigraphic appearance of the lesions reveals increased radiotracer uptake during the chronic reparative process, which is usually peripheral with central photopenia (area of reduced activity). Published literature regarding the performance of SPECT/CT for the evaluation of necrotic bone or pseudarthrosis is very sparse. SPECT has proven to be valuable for the diagnosis of femoral head osteonecrosis and was more sensitive than MRI $(100\\\\% \\\\text{ vs } 66\\\\%)$ in a study by Ryu et al. $^{14}$ In our study, SPECT/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,491,929,714]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 2. 26-year-old male with osteosynthesis of left distal femur fracture 6 months ago. He was being evaluated in view on delayed union. Early-phase [images A (anterior), B (posterior)] and late-phase [images C (anterior), D (posterior)] images of planar bone scintigraphy show moderate radiotracer accumulation in the area of left distal femur fracture site. Plain radiography (E) shows incomplete consolidation of the fracture. SPECT/CT (Coronal SPECT/CT: F and Coronal CT: G) images show increased uptake at some parts of the former fracture as signs of bone remodeling. Additionally, there is a loose unconsolidated bone fragment of $6.0 \\\\times 1.3 \\\\mathrm{~cm}$ size, dorsolaterally at the fracture site with complete absence of radiotracer uptake (photopenia), suggestive of necrotic bone fragment. The patient underwent revision surgery with removal of necrotic bone fragment. Follow-up CT (post 15 months) images (CT coronal: H, 3D VRT: I, J) and X-ray (post 21 months) images (K, L) show union at the fracture site. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,719,606,808]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0374/dac7ed73f331d889c65a4a6123458e3412aacb2cf1ce901fba240ededf409edb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[605,720,727,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"F-up CT post 15 months \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0648/954117eab4a2b452642ad744a01074c4e15a8305e79a269bf4c9af708b8f6eb4.jpg\",\n 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\"table_footnote\": null,\n \"text\": \"\\\"SPECT/CT in necrotic bone fragments\\\" \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,65,917,74]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,948,272,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 7 birpublications.org/bjr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[757,948,927,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Br J Radiol;93:20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,170,273,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Hematoxylin and Eosin staining of the resected bone fragment of the same patient as in figure 2. Images show missing osteocyte nuclei and fat necrosis indicating necrotic bone fragments (images courtesy Dr. Zenklusen, Institute of pathology, Cantonal Hospital Lucerne, Switzerland). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0107/b865b62e214eeafc06ee7ed50cfd22dc367c7e1d9382e2d77bcb017caf27d1a3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[275,170,480,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0884/3b7a73b2c0cb45a1314a225a6ccf497385aaae293737b4076098d4e45c7b1e2d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[68,280,273,390]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0086/51e8e8808b0a94d213457c29534d663737725206bb5dfcb1fff2c67c959803fb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[70,719,176,808]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. 54-year-old female with osteosynthesis of left distal femur fracture after car accident 6 months ago. Osteosynthesis was removed because of infection and external fixator was installed. Early phase of bone scintigraphy (BS) [images A (anterior), B (posterior)] shows mild-to-moderate amount of radiotracer accumulation in the left distal femur, knee joint, as well as in the region of left ankle. The late phase images [C (anterior), D (posterior)] of planar BS show persistent increasing accumulation of radiotracer in above areas along with a photopenic area in the left distal femur. SPECT/CT images (E: coronal CT, F: coronal SPECT, G: coronal SPECT/CT fusion, H: sagittal CT, I: sagittal SPECT, J: sagittal SPECT/CT fusion) show absence of radiotracer accumulation in the two bone fragments in the left distal femur in and around the fracture site. The patient underwent revision surgery with removal of necrotic bone fragments. A vitality was proven histologically. Follow-up X-ray (image K) post 6 months shows improvement with good healing and union of the fracture site. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0652/4b420da4bccb3f90da03791eada37d5f75b4d23cdcb0b97dd7a56144ce1dc908.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[70,808,176,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0869/1bd0126ee2bd5ac5be3584d6418b39422908db109f3f6b79cc310b9603cb5919.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": 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\"[265,799,329,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0348/5be90ff4f1d7d1c44d21249eb1e879eb0158ce724b195ce25ec67785fbcc3394.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[329,799,389,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0968/01e4d1298bb0a9832ccb1093b47be9226db96bc41e6f97ce8f5c8a0d0f1f13e4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[389,799,480,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0301/56badcb6883e9e518bffb97f762f66fc067f8ba88350869082c617440dedd6cf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[515,114,927,211]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0665/3f1760c951498eaca30fd7c800e972be1ddd40e1ef46d03220bd8f002f92095c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>Bone Scintigraphy</td><td></td></tr><tr><td>Reference Standard</td><td>Positive</td><td>Negative</td><td>Total</td></tr><tr><td>Positive</td><td>10</td><td>5</td><td>15</td></tr><tr><td>Negative</td><td>1</td><td>21</td><td>22</td></tr><tr><td>Total</td><td>11</td><td>26</td><td>37</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3. Frequency table for bone scintigraphy \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[512,233,927,261]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CT could detect necrotic bone fragments in 16 out of 37 fracture sites $(43.2\\\\%)$ compared to only 11 $(29.7\\\\%)$ detected on planar BS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,274,929,697]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The absence of activity on bone SPECT/CT in persistent fractures is a highly specific marker for non-union.[15] Liodakis et al retrospectively evaluated the role of SPECT/CT in 10 patients, involving fractures of upper and lower extremity, in diagnosing and planning the treatment of avascular/atrophic non-unions with surgical exploration as the reference standard.[15] SPECT/CT identified all the four vital pseudarthroses and three of the six non-vital pseudarthroses. The sensitivity of SPECT/CT in diagnosing non-vital atrophic non-unions was $50\\\\%$ , and the specificity was $100\\\\%$ . We obtained improved sensitivity for SPECT/CT detection of necrotic bone fragments leading to delayed healing/non-union with sensitivity of $100\\\\%$ and specificity of $95\\\\%$ . Diederichs and colleagues compared the diagnostic performance of bone SPECT/CT and MRI for the evaluation of bone viability in patients after girdlestone arthroplasty (two-stage revision technique).[16] In their study, the prostheses were removed after the diagnosis of periprosthetic joint infection, and it was followed by 6 to 8 weeks of antibiotic therapy. Revision total hip arthroplasty was performed after successful treatment of infection; and $24\\\\mathrm{h}$ prior to this revision surgery, SPECT/CT and MRI were performed. So, their patients did not have metal hardware in situ, and hence they could perform MRI. They found high sensitivity and specificity for SPECT/CT as well as for MRI for differentiation between viable and non-viable bone tissue, although SPECT/CT had slightly better sensitivity $(90\\\\%)$ and specificity $(94\\\\%)$ compared to MRI. They found statistically significantly higher uptake values for vital bone compared to non-vital bone. Although the metal prosthesis was removed before imaging, some metal particles remaining behind in tissues close to the bone gave rise to imaging artifacts on MRI contributing to some false-positive results. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,711,927,766]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Niikura et al[17] evaluated 48 patients with uninfected fracture non-unions, in a retrospective study, and compared radiographs with Tc-99m BS and tried to study the detailed pattern and features of radiotracer uptake. They observed positive radiotracer uptake \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,804,927,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0129/2f9365128e8209f9cb90a3e8065175cdc8c2120d2e1b66aafd6a32e61f8e9ed6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>SPECT/CT</td><td></td></tr><tr><td>Reference Standard</td><td>Positive</td><td>Negative</td><td>Total</td></tr><tr><td>Positive</td><td>15</td><td>0</td><td>15</td></tr><tr><td>Negative</td><td>1</td><td>21</td><td>22</td></tr><tr><td>Total</td><td>16</td><td>21</td><td>37</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 4. Frequency table for SPECT/CT \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[78,65,105,74]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[850,66,919,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bhure et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,948,270,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 of 7 birpublications.org/bjr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[757,948,927,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Br J Radiol;93:20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,149,480,263]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0879/5ffc74a03d3d796503d1b4bbc6f7bff2a8bbce53ad4a28bc884f3251d1800b64.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td>SPECT/CT</td><td>BS</td></tr><tr><td>Sensitivity (%)</td><td>100</td><td>67</td></tr><tr><td>Specificity (%)</td><td>95</td><td>95</td></tr><tr><td>Positive Predictive Value (PPV) (%)</td><td>94</td><td>91</td></tr><tr><td>Negative Predictive Value (NPV) (%)</td><td>100</td><td>81</td></tr><tr><td>Accuracy (%)</td><td>97</td><td>83</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 5. Comparative values of sensitivity, specificity, PPV, NPV, and accuracy in SPECT/CT and bone scintigraphy for the detection of necrotic bone fragments in traumatic fractures with suspected delayed healing or non-union \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[65,281,480,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in all cases and classified the uptake patterns into four types. They proposed a treatment algorithm of uninfected non-unions which incorporated BS. They recommended BS in the evaluation of non-hypertrophic non-unions, whereas hypertrophic non-unions can do without BS and secured fixation will lead to bony union. If BS reveals a photon-deficient area, then an autologous bone graft can be implanted for better and faster healing. On the other hand, if BS does not reveal any photopenic area, then secured fixation is good enough to achieve bony union and appropriate healing. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,438,480,468]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Song Q et al[18] evaluated 144 patients with known/suspected chronic-infected fracture non-union osteomyelitis in lower \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,518,485,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. Receiver operative curve (ROC) analysis of SPECT/CT versus planar scintigraphy (BS). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0751/36c1aaece5eea9419d10f512db09b88f2e97985f3ee8fd4e1b0522d49f7e2042.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,99,929,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"limb using SPECT/CT and found it better than standalone BS and CT imaging with improved diagnosis of non-union with precise localization of osteomyelitis which is critical for surgical management. Their group looked at osteomyelitis and soft tissue infection and their focus was on increased radiotracer activity suggesting infection. Our group, on the other hand, assessed the presence of necrotic bone fragments which might be responsible for delayed bone healing and non-union and is characterized by absence of radiotracer activity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,235,929,331]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We did not intend to compare SPECT with SPECT/CT as in our opinion SPECT/CT has completely replaced SPECT alone in bone and joint imaging as demonstrated in many studies. The CT part of the study is so important for anatomic correlation and bone healing assessment in this situation of fractures that referring surgeons would not want to waive this important information. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,344,929,441]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Limitations of our study include: a) possible selection bias, as we targeted traumatic bone fractures with delayed bone healing specifically; b) retrospective design of the study; c) the reference standard histology was available in only 11 patients (out of 37); d) quantitation of the radiotracer uptake using SUV max could not be performed due to technical issues and should be evaluated in subsequent studies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,453,633,464]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,468,929,521]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SPECT/CT is an accurate tool in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures and is superior to conventional planar BS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,536,752,549]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHORS' CONTRIBUTIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,551,927,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All authors contributed in a significant way to the content and revision of the manuscript. All authors read and approved the final manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,606,867,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMPLIANCE WITH ETHICAL STANDARDS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,621,929,731]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics committee approval was obtained for the study (Ethikkommission Nordwest- und Zentralschweiz EKNZ 2019-00594). Informed consent was waived by the ethics committee due to the retrospective design. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,778,184,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,800,341,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Einhorn TA. Enhancement of fracture-healing. J Bone Joint Surg Am 1995; 77: 940-56. doi: https://doi.org/10.2106/00004623-199506000-00016 \\\",\\\"2. Rajasekaran S, Giannoudis PV. Open injuries of the lower extremity: issues and unknown \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[386,800,625,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiers. Injury 2012; 43: 1783-4. doi: https://doi.org/10.1016/j.injury.2012.08.039 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[368,826,633,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Bishop JA, Palanca AA, Bellino MJ, Lowenberg DW. Assessment of compromised fracture healing. J Am Acad Orthop Surg 2012; 20: 273-82. doi: https://doi.org/10.5435/JAAOS-20-05-273 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[658,800,927,879]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Hak DJ, Fitzpatrick D, Bishop JA, Marsh JL, Tilp S, Schnettler R, et al. Delayed Union and nonunions: epidemiology, clinical issues, and financial aspects. Injury 2014; 45 Suppl 2(Suppl 2): S3-7. doi: https://doi.org/10.1016/j.injury.2014.04.002 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,65,314,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\\\"SPECT/CT in necrotic bone fragments\\\" \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,64,919,74]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,948,272,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 7 birpublications.org/bjr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[757,948,927,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Br J Radiol;93:20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[70,98,341,437]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"5. Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury 2007; 38 Suppl 4(Suppl 4): S3-6. doi: https://doi.org/10.1016/S0020-1383(08) 70003-2 \\\",\\\"6. Bhattacharyya T, Bouchard KA, Phadke A, Meigs JB, Kassarjian A, Salamipour H. The accuracy of computed tomography for the diagnosis of tibial nonunion. J Bone Joint Surg Am 2006; 88: 692-7. doi: https://doi.org/10.2106/JBJS.E.00232 \\\",\\\"7. Galasko CS. The pathological basis for skeletal scintigraphy. J Bone Joint Surg Br 1975; 57: 353-9. doi: https://doi.org/10.1302/0301-620X.57B3.353 \\\",\\\"8. Matin P. The appearance of bone scans following fractures, including immediate and long-term studies. J Nucl Med 1979; 20: 1227-31. \\\",\\\"9. Sarikaya I, Sarikaya A, Holder LE. The role of single photon emission computed tomography in bone imaging. Semin Nucl Med 2001; 31: 3-16. doi: https://doi.org/10.1053/snuc.2001.18736 \\\",\\\"10. Lisbona R, Rennie WR, Daniel RK. Radionuclide evaluation of free vascularized \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[363,99,635,438]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"bone graft viability. AJR Am J Roentgenol 1980; 134: 387-8. doi: https://doi.org/10. 2214/ajr.134.2.387 \\\",\\\"11. Jennin F, Bousson V, Parlier C, Jomaah N, Khanine V, Laredo J-D. Bony Sequestrum: a radiologic review. *Skeletal Radiol* 2011; 40: 963-75. doi: https://doi.org/10.1007/s00256-010-0975-4 \\\",\\\"12. Frolke JPM, Patka P. Definition and classification of fracture non-unions. Injury 2007; 38 Suppl 2(Suppl 2): S19-22. doi: https://doi.org/10.1016/S0020-1383(07)80005-2 \\\",\\\"13. Leven D, Cho SK. Pseudarthrosis of the cervical spine: risk factors, diagnosis and management. Asian Spine J 2016; 10: 776-86. doi: https://doi.org/10.4184/ajj.2016.10.4.776 \\\",\\\"14. Ryu J-S, Kim JS, Moon DH, Kim SM, Shin MJ, Chang JS, et al. Bone SPECT is more sensitive than MRI in the detection of early osteonecrosis of the femoral head after renal transplantation. J Nucl Med 2002; 43: 1006-11. \\\",\\\"15. Liodakis E, Liodaki E, Krettek C, Citak M, Gaulke R, Konstantinidis L, et al. Can the viability of a nonunion be evaluated using \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[657,99,927,437]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"SPECT/CT? A preliminary retrospective study. Technol Health Care 2011; 19: 103-8. doi: https://doi.org/10.3233/THC-2011-0617 \\\",\\\"16. Diederichs G, Hoppe P, Collettini F, Wassilew G, Hamm B, Brenner W, et al. Evaluation of bone viability in patients after girdlestone arthroplasty: comparison of bone SPECT/CT and MRI. Skeletal Radiol 2017;46:1249-58. doi: https://doi.org/10.1007/s00256-017-2692-8 \\\",\\\"17. Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Comparison of radiographic appearance and bone scintigraphy in fracture nonunions. Orthopedics 2014; 37: e44-50. doi: https://doi.org/10.3928/01477447-20131219-16 \\\",\\\"18. Song Q, Long L, Cui S, Shu H, Wan C, Wu B, et al. Utility of technetium-99m-methylene diphosphonate single-photon emission computed tomography/computed tomography fusion in detecting posttraumatic chronic-infected nonunion in the lower limb. Nucl Med Commun 2019; 40: 778-85. doi: https://doi.org/10.1097/MNM.0000000000001027 \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[78,65,105,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BJR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[850,66,919,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bhure et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,948,270,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 of 7 birpublications.org/bjr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[759,948,927,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Br J Radiol;93:20200300 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1259/bjr.20200300"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"25e0a4de09487d5ff53bdc9122603aa2a8a3ef4e0dd1eafe83bf32035f4fe8c4"},"title":{"kind":"string","value":"Value of SPECT/CT in the assessment of necrotic bone fragments in patients with delayed bone healing or non-union after traumatic fractures"}}},{"rowIdx":153,"cells":{"abstract":{"kind":"string","value":"\n \nWe propose a physics-aware generative adversarial network model, FluxGAN, capable of simultaneously generating high-quality images of large microstructures and description of their thermal properties. During the training phase, the model learns about the relationship between the local structural features and the physical processes, such as the heat flux in the microstructures, due to external temperature gradients. Once trained, the model generates new structural and associated heat flux environments, bypassing the computationally expensive modeling. Our model provides a cost effective and efficient approach over conventional modeling techniques, such as the finite element method (FEM), for describing the thermal properties of microstructures. The conventional approach requires computational modeling that scales with the size of the microstructure model, therefore limiting the simulation to a given size, resolution, and complexity of the model. In contrast, the FluxGAN model uses synthesis-by-part approach and generates arbitrary large size images at low computational cost. We demonstrate that the model can be utilized to generate designs of thermal sprayed coatings that satisfies target thermal properties. Furthermore, the model is capable of generating coating microstructures and physical processes in three-dimensional (3D) domain after being trained on two-dimensional (2D) examples. Our approach has the potential to transform the design and optimization of thermal sprayed coatings for various applications, including high-temperature and long-duration operation of gas turbines for aircraft or ground-based power generators.\n "},"author":{"kind":"string","value":"Manoj Settipalli|Sanghamitra Neogi|Artem K. Pimachev"},"content_list":{"kind":"list like","value":[{"bbox":"[94,61,908,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"FluxGAN: A Physics-Aware Generative Adversarial Network Model for Generating Microstructures That Maintain Target Heat Flux ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[250,112,750,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Artem K. Pimachev, $^{1}$ Manoj Settipalli, $^{1}$ and Sanghamitra Neogi $^{1}$ ,* ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[303,131,702,172]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Ann and H.J. Smead Aerospace Engineering Sciences, University of Colorado Boulder, Boulder, CO 80303, USA (Dated: October 10, 2023) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[169,179,831,405]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We propose a physics-aware generative adversarial network model, FluxGAN, capable of simultaneously generating high-quality images of large microstructures and description of their thermal properties. During the training phase, the model learns about the relationship between the local structural features and the physical processes, such as the heat flux in the microstructures, due to external temperature gradients. Once trained, the model generates new structural and associated heat flux environments, bypassing the computationally expensive modeling. Our model provides a cost effective and efficient approach over conventional modeling techniques, such as the finite element method (FEM), for describing the thermal properties of microstructures. The conventional approach requires computational modeling that scales with the size of the microstructure model, therefore limiting the simulation to a given size, resolution, and complexity of the model. In contrast, the FluxGAN model uses synthesis-by-part approach and generates arbitrary large size images at low computational cost. We demonstrate that the model can be utilized to generate designs of thermal sprayed coatings that satisfies target thermal properties. Furthermore, the model is capable of generating coating microstructures and physical processes in three-dimensional (3D) domain after being trained on two-dimensional (2D) examples. Our approach has the potential to transform the design and optimization of thermal sprayed coatings for various applications, including high-temperature and long-duration operation of gas turbines for aircraft or ground-based power generators. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[212,430,361,444]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,462,488,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In recent years, machine learning techniques, such as generative adversarial networks (GANs), are increasingly being used to explain deterministic multiphysics phenomena where the underlying physical model is complex or unknown. Physics-informed generative adversarial networks have been proposed for solving forward, inverse, and mixed stochastic problems using data from a limited number of scattered measurements [1]. Instead of relying solely on data for training, this approach encoded the governing physical laws in the GAN architecture in the form of stochastic differential equations. FluidGAN has been proposed for learning and predicting time-dependent convective flow coupled with energy transport [2]. StressGAN model was developed to generate mechanical stress distributions for various complex cases of geometry, load, and boundary conditions [3]. The model was shown to predict more accurate high-resolution stress distributions than a convolutional neural network model. In parallel, GANs have shown remarkable progress for creating high-resolution synthetic images, visually similar to their real counterparts, supported by revolutionary adverts in the graphical data domain. Until recently, training such model required enormous amount of training images and was highly unstable. GANs have been shown to be highly effective in generating realistic microstructural data that can be used to augment limited experimental data or simulate microstructures that are challenging to obtain experimentally [4, 5]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,429,919,503]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The style-based GAN (StyleGAN2) architecture [6], implemented the style transfer approach [7] with the adaptive discriminator augmentation (ADA) [8] mechanism, and demonstrated that high-quality images can be generated with limited training data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,510,921,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this study, we propose a new FluxGAN model that simultaneously generates high-quality microstructural images and high-resolution description of thermal properties of these microstructures. We adopt the StyleGAN2 architecture to develop the model and train the model using images that include both microstructural information and the associated physical (i.e., thermal) phenomena. We demonstrate the capabilities of our approach for the analysis and design of microstructure-controlled thermal properties of thermal sprayed coatings. The thermal sprayed coatings exhibit highly diverse structural environments, including pores with different shapes and sizes, and varied size grains aligned at different crystallographic orientations. The microstructural features strongly affect interface-sensitive material properties, such as thermal diffusivity. Additionally, the structural features could change and evolve due to sintering in high temperature environments. The presence of microstructural features is often quantified by the porosity parameter: (pore volume)/(total volume)×100 %. The variation of thermal properties of coatings has commonly been described in relation with porosity, using phenomenological models [9]. However, global parameter (e.g. porosity) based models may not accurately capture the physics of heat transfer across various microstructural features and feature interfaces. The complexity of structural features and their evolution makes it highly challenging to characterize the physical properties ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[22,232,57,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"arXiv:2310.04622v1 [cond-mat.dis-nn] 6 Oct 2023 ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[84,898,300,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"* sanghamitra.neogi@colorado.edu ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[83,65,491,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of these coatings, especially after aging, using existing experimental and numerical approaches. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,95,491,633]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our proposed FluxGAN model provides highly accurate prediction of thermal phenomena in coatings with different microstructures that include different porosities, grain sizes, and crystallographic orientations. We use a small number of two-dimensional (2D) images of niobium thermal sprayed coatings, obtained with backscatter electron (BSE) imaging technique, as the 'true' image of the coating microstructures. We compute the thermal properties of the microstructures using the image-based finite element method (FEM). We train the FluxGAN model using superimposed images that include both microstructural and thermal property data. The FluxGAN model combines the physical properties predicted by FEM and the GAN architecture, for generating diverse microstructures with desired thermal properties. We use separate FEM simulations to validate the generated thermal data. The model uses synthesis-by-part approach and generates images of arbitrary size patch by patch, which requires constant memory usage. In contrast, the FEM memory usage and computational time scales with the image size. The combination of image-based FEM and GAN models offers a promising solution to overcome the limitations of traditional experimental and numerical methods. Our model provides a cost effective and efficient approach for describing the microstructure-controlled thermal properties of thermal sprayed coatings. The model establishes a direct relationship between structural features and thermal properties of coatings, which could be utilized to better control and optimize their thermal properties. We demonstrate that our model can be used to design thermal sprayed coatings that can maintain tailored heat flux that meets application-specific requirements. Our approach has the potential to transform the design and optimization of thermal sprayed coatings for various industrial applications, including high-temperature and long-duration operation of gas turbines for aircraft or ground-based power generators. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[240,662,333,674]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[222,691,351,705]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Model Overview ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,724,491,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 1(i) shows the overview of our physics-informed FluxGAN model. The model includes a training and a generation phase. We train the model with images that include information about structural as well as thermal properties of the microstructure. We obtain the 2D structural images, as shown in Fig. 1(a), using backscatter electron (BSE) imaging and simulate the thermal properties using FEM techniques. Figure 1(e) shows the spatial distribution of heat flux, $Q(x,y)$ , generated in the microstructure, due to the application of temperature gradient along the top-to-bottom direction. Figure 1(c) and (d) show the graphical domain representation of the heat flux components, $Q_{x}$ and $Q_{y}$ , respectively. We ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,65,921,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"create RGB images by superimposing the experimental structural images and the heat flux maps, as shown in Fig. 1(b). We provide the RGB images as input to the FluxGAN model. The model identifies the different features of the RGB training images, referred to as styles, in an unsupervised manner. The styles not only classify structural features but are strongly associated with heat flux patterns of the RGB images. In the unguided generation phase, the FluxGAN model requires minimal input from the user and generates a new image corresponding to the input. An example input is shown in Fig. 1(f). The input specifies the overall height and width of the image and the spatial map of styles to be included. The spatial map includes the number of styles that can be identified in the image (styles 1 and 2), the locations for regions with styles 1 and 2 (anchors), and the merging function that can be applied to obtain smooth interfaces between the regions. Figure 1(g) shows a representative microstructure, generated by the FluxGAN model. The generated image includes structural features that correspond to styles 1 and 2 as specified by the user input. The image also includes information about the heat flux that will be observed if the microstructure is subjected to temperature gradients along the top-to-bottom image direction. Thus, the FluxGAN model directly generates designs of representative microstructures and corresponding physical properties from a minimal user input. The model can even generate designs of new classes of structures that are not present in original experimental images. For example, different designs can be created by combining different styles, varying the positions of the styles in two-dimensional (2D) or three-dimensional (3D) spatial domains. Additionally, the model offers guided assignment of styles in the generated microstructures, based on the specifications of the input image. For example, given a known heat flux distribution in the heat source or sink region as input, the model allows for inverse design of microstructures that satisfies the target heat flux condition. We describe the different components of the FluxGAN model in the following sections. We demonstrate the effectiveness of the FluxGAN model by using single phase niobium (Nb) thermal spray coatings as an example. However, our model can be broadly applied to different materials and structures to assess how well they satisfy target physical properties. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,724,921,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The conventional approach for designing new coatings, as outlined in Fig. 1(ii), typically iterates through the following steps: (1) fabrication of coatings, (2) experimental characterization, (3) developing computational models based on experimental images, (4) physical property calculation, and repeat (1-4) till the fabricated structures satisfy target physical properties. Our FluxGAN model provides an expedited approach to inform the design of new microstructures that satisfy target physical properties, bypassing the expensive iterative process. In this study, we have chosen the styles in an arbitrary manner. However, the styles can be associated with specific physical conditions. For example, the different spray in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,919,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[267,61,746,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(i) Generative ML Framework (FluxGAN) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[127,83,225,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Training ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[127,107,880,619]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 1. Overview of FluxGAN model and its advantage over conventional approach: (i) The model includes a training and a generation phase. We train the model with (b) superimposed RGB images that include (a) experimental structural images and (c,d) heat flux data, simulated with FEM techniques. The model classifies the distinct features of the RGB images and assigns them as different styles. Once trained, the model generates images based on user input. (f) Spatial map of different styles as input. (g) The model generates new structural image superimposed with associated heat flux, that satisfies target thermal properties. (ii) In contrast, conventional design approach follows an expensive and iterative cycle until microstructures with target physical properties are obtained. \"]","image_footnote":"[]","img_path":"images/0693/fd25d1ecdaad443ecc7ac44c6c0b077001822f090c6e44ae27f04d79c0bde73f.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,763,490,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"tervals in a thermal spray process could result in different structural features. The different features can also be associated with diverse environmental conditions, such as high temperatures or corrosion. As styles are strongly associated with the heat flux, physical meaning of styles can be regions of high or low thermal conductance and temperature hot spots, etc. A FluxGAN model aware of the relationship between the styles and synthesis or environmental conditions can offer great practical advantage. For example, the styles in generated images can ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,763,919,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"inform strategies to synthesize microstructures with target functionalities and also, provide information about the reliability of microstructure in diverse environmental conditions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,918,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[106,78,468,273]","code_body":null,"code_caption":null,"image_caption":"[\"(i) Width: $160\\\\mu \\\\mathrm{m}587\\\\mathrm{px}$ , Height: $112\\\\mu \\\\mathrm{m}410\\\\mathrm{px}$ \"]","image_footnote":"[]","img_path":"images/0389/1125340f1ba0b30fd5e93a7ca4e0dd5324e3e807f366614a95d818a78bc83778.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[106,292,467,488]","code_body":null,"code_caption":null,"image_caption":"[\"(ii) Width: $50\\\\mu \\\\mathrm{m}$ \",\"FIG. 2. Experimental images of coating microstructures: (i) Raw BSE images of niobium thermal spray coatings. (ii) Magnified image of microstructure shows a wide variety of structural features, such as flat splats and porosities due to conditions during the synthesis process. \"]","image_footnote":"[]","img_path":"images/0353/cfedf6fc20e2b225fe4a9c6de4267b5f55a81faff3f30c3ead11c29e0c437b4a.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[205,614,366,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"TRAINING PHASE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[150,647,421,662]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Processing of Experimental Images ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,681,490,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 2 shows the 2D experimental BSE images of the Nb thermal spray coatings that we use to demonstrate the performance of the FluxGAN model. The dimension of each image is $112\\mu \\mathrm{m} \\times 160\\mu \\mathrm{m}$ ( $410\\mathrm{px} \\times 587\\mathrm{px}$ ). Three distinct regions can be visually identified from the images: the gray middle region that shows the presence of the coating microstructure, the top and bottom dark regions where no coating material is present and the two interface regions between the gray coating and the dark regions. We assume that the dark regions of the images represent presence of air. We show a magnified version of a representative coating microstructure in Fig. 2(ii). As can be noted, the microstructure includes distinct features, such as flat splats and globular and interfacial porosities. In addition to these features, a wide variety of small features can also be noted that are repre ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,66,919,429]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"sentative of materials properties or processing conditions. However, some features may appear due to difference in lighting conditions during imaging. Note that the FluxGAN model identifies the different styles of the training images in an unsupervised manner. To ensure that the microstructure images only include 'true' features, we preprocess the grayscale BSE images and remove features that appear due to irregular image brightness. The preprocessing is an essential step since our goal is to develop a model that can relate 'true' structural features with the corresponding physical properties. First, we obtain the pixel intensity distribution of the BSE images, by counting the number of pixels that has a given intensity in the range between 0 and 255. Figure 2(a) shows that the coating region of the images have intensities $\\geq$ 50 in this scale. The appearance of the distinct peaks can be attributed to different lighting conditions during imaging. We scale the intensities to values in the range between 0 and 1. We then shift the mean of the distribution to 0.5 using a power transformation. Finally, we rescale the pixel intensity distribution of the coating region to be in the range from 50 to 255. Figure 2(b) shows the pixel intensity distribution after the transformation. The intensity values below 50 represent pores or air regions where the coating material is not present. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[599,460,833,474]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Augmentation of Training Set ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[511,493,919,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our experimental dataset is limited to nine BSE images, as shown in Fig. 2. However, the GAN models require enormous amount of training images to generate high-resolution images as output. Extensive efforts are ongoing to develop models that can create high quality images with limited training data [10, 11]. Recent approaches, such as StyleGAN2 [6], require a smaller training set, however, still require substantial number of training images. We implement different strategies to augment the training dataset. We apply rotation and reflection operations on the raw images and add the new images to the dataset. The new images include additional variations of structural features that impact the thermal properties. We thus obtain a diverse set of images to train the FluxGAN model. However, it is essential that the new images include features that are consistent with the physical conditions displayed by the original images. This constraint imposes restrictions on the type of operations we could perform to create new images. For example, all experimental images of Fig. 2 (and also, Fig. 3(i)) show that the images have flatter bottom surfaces and uneven top surfaces. These features appear because the thermal spray coatings are fabricated on top of substrates. We only apply horizontal flip transformations but do not apply any vertical flip operations to maintain similar layer-like features in the new images. Additionally, when the droplets of melted material are sprayed in a regular interval, the material solidifies and forms layers in the top-to-bottom direction. As can be ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,919,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[81,65,490,255]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"seen from Fig. 2(ii), the layers are highly uneven. This is because the sprayed material might solidify at different rates in the sprayed microstructures during fabrication. Highly anisotropic features may appear when droplets of melted material are sprayed over already solidified splats. To ensure that the new images retain such characteristics, we apply only small angular rotations between -2.5 to +2.5 degrees, with 11 incremental steps. We set the top and bottom air regions to be 80 pixels wide and add extra space as needed so that the coating region stays within the image boundary, as shown in Fig. 3(ii). The augmented dataset contains a total of 198 (9 original × 11 rotated × 2 flipped) superimposed images. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[145,284,426,299]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Computation of Thermal Properties ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,316,488,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We compute the thermal properties of the coating microstructures using image-based FEM techniques, as implemented in COMSOL software [12]. We assume that the heat conduction direction is along the top-to-bottom direction of the coatings. We convert the microstructure images to masks by assigning all pixels with intensities $< 50$ to black color, representing air, and the pixels with intensities $\\geq 50$ to grey color, representing niobium. Figure 1(a) and (e) show an experimental image and the corresponding masked image, respectively. We use the masked images as input for image-based FEM simulations. We import the masked images to COMSOL and use the built-in function, $im(x,y) = \\{0,1\\}$ , to mark different regions within each image. The discrete values correspond to black and gray regions of the images, respectively. This creates rectangular simulation domains that have same dimensions as the input images. We use the image function, $im(x,y)$ , and the thermal conductivity values of air and Nb, to define spatially resolved thermal conductivities, $\\kappa_{\\mathrm{local}}(x,y)$ , in the rectangular simulation domain: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[151,628,488,670]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\kappa_ {\\text {l o c a l}} (x, y) = \\left\\{ \\begin{array}{l l} \\kappa_ {\\text {A i r}}, & \\text {i f} i m (x, y) = 0 \\\\ \\kappa_ {\\text {N b}}, & \\text {i f} i m (x, y) = 1 \\end{array} \\right. \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[81,681,490,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We choose thermal conductivity of niobium $(\\kappa_{\\mathrm{Nb}} = 54$ $\\mathrm{Wm^{-1}K^{-1}})$ for all grey pixels and thermal conductivity of air $(\\kappa_{\\mathrm{Air}} = 0.1~\\mathrm{Wm^{-1}K^{-1}})$ for all black pixels. We also define the local densities, $\\rho_{\\mathrm{local}}(x,y)$ , and local specific heat capacities, $C_\\mathrm{p}$ , $\\mathrm{local}(x,y)$ , using similar equations as Eq. 1. We choose $\\rho_{\\mathrm{Air,Nb}} = \\{1.225,8570\\}~\\mathrm{Kgm}^{-3}$ and $C_\\mathrm{p}^{\\mathrm{Air,Nb}} = \\{1008,260\\}~\\mathrm{JKg^{-1}K^{-1}}$ , respectively. However, the heat flux distribution is primarily determined by the local thermal conductivities, as expected. The thermal properties of porous materials are commonly calculated using effective models, such as the Maxwell-Eucken model [9]. These models only take the porosity of the structure into account and do not consider the distribution of pores and their shapes to calculate thermal properties. Instead, we compute the heat flux in the coatings using image-based FEM and Fourier's law: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[535,61,890,151]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0071/b1547f8f057c3313c29a690f92449df0a7f506886215e33f3ffefa39fab472d2.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[534,155,890,238]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0863/79384c430d4492e4f6ba6c451f866e734272f8e2817ce5c5a0a10beb56047c3d.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[534,239,893,327]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0568/2e9a20e2f8e0135e686b17b71f30f42dc0c1dfdd4fd2860b9bedcc471dbd865d.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[535,325,893,420]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0223/eff26f2930b9a773151638856c5d35b4ac2ea73c5696add668ade6f9aa8aadf1.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[535,424,885,521]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 3. Preparation of training images: (i) BSE image. Pixel intensity distribution of BSE images (a) before and (b) after image processing; Histogram shows the number of pixel counts for different pixel intensity in a monochrome channel. Heat flux along components, (c) $Q_{x}$ , and (d) $Q_{y}$ , for applied temperature gradients. Top horizontal axes labels show heat flux values and the bottom labels show graphical domain encoding for the monochrome channels. Three channel representations of (ii) structural and (iii-iv) heat flux data. The bottom label values of (b-d) are used as color scheme of images (ii-iv). The three channels are superimposed to create RGB images. (v) Tiles extracted from RGB images are used as training images. \"]","image_footnote":"[]","img_path":"images/0960/8c0e2d57c6985b8374f711f857b645719e92eca4884bcc2f1169e79ab01e4a7a.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,751,919,882]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathbf{q} = -d_z \\kappa_{\\mathrm{local}} \\nabla T$ . Here, $q$ is the heat flux along the temperature gradient $\\nabla T$ and $d_z = 1 \\mathrm{~m}$ is the thickness along $z$ direction. We only discuss the heat flux in the 2D $x - y$ plane of the coatings and report the values of $Q = q / d_z$ , in units of $\\mathrm{Wm}^{-2}$ . We find that the heat flux and the resulting effective thermal conductivity can be significantly different for two coatings with the same porosity but different pore distributions. Such variability cannot be captured by the effective models. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,883,918,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We assume that both the top and the bottom no-material regions are made of low thermal conductivity ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,918,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[86,65,488,455]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"material, i.e., air. We model the top region as heat source with temperature equal to $700\\mathrm{K}$ and the bottom region as heat sink with temperature $300\\mathrm{K}$ . Thus, we simulate an applied temperature bias of $400\\mathrm{K}$ along the top-to-bottom direction of the coatings, for all BSE masked images. We model the lateral boundaries of the simulation cells as perfect insulators. We define a rectangular grid for the FEM simulations of dimension, $p_y \\times p_x$ . Here $p_x$ and $p_y$ are the number of pixels along the $x$ and the $y$ directions of the images. We use an adaptive meshing scheme and carry out five refinements in COMSOL to identify a mesh grid that minimizes the $L_2$ norm of the squared error. The image function $im$ is defined on the grid and assigns the local material properties accordingly. We compute heat flux, $q$ , using these adaptive nodes and element shape functions. For each image, we iteratively solve for $q$ that satisfies the boundary conditions and local thermal conductivities. We assume $\\mathrm{d}_z = 1\\mathrm{m}$ in our calculations, thus, $Q$ have the same values as $q$ , but different units. We refer to $Q(x,y)$ as heat flux in the subsequent discussion. $Q(x,y)$ 's are defined on a rectangular grid of the same resolution as the input masked image. However, the grid is different for each image, depending on the original resolution of the experimental image and the applied transformations as described in the 'Augmentation of Training Set' section. The associated heat flux also vary significantly, as can be expected. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[86,458,488,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We show the components of heat flux along $x$ and $y$ directions in Fig. 3(c,d), respectively. The labels of the top horizontal axes show the heat flux values. We transform $Q_{x}$ and $Q_{y}$ to represent them in the graphical domain. We linearly scale $Q_{x}$ and $Q_{y}$ such that the middle $98\\%$ of the distribution falls in the range from 0 to 255. We assign the left and the right $1\\%$ of heat flux distribution to values of 0 and 255, respectively. We transform the $Q$ values using the following equations: $Q_{x} = Q_{x} / 10^{6} \\times 173 + 127$ ; $Q_{y} = Q_{y} / 10^{6} \\times 153 + 255$ . We obtain these equations by assigning the bounds of the middle $98\\%$ of the $Q$ -distributions to graphical encoding values. The bottom axes labels of Fig. 3 (c,d) correspond to the graphical domain encoding for the monochrome channels. Note that the FEM simulation domains have horizontal reflection symmetry. We leverage this aspect and obtain results for 99 additional images by horizontally reflecting the FEM-generated heat flux $Q(x,y)$ [W/m²]. In the reflected images, the $(x,y)$ values are flipped horizontally and the magnitudes of $Q_{x}$ change sign, however, the magnitudes of $Q_{y}$ stays the same. Thus, we obtain data for 198 images from the 99 FEM calculations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[165,823,406,835]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Preparation of Training Images ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[83,854,488,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We superimpose structural images and the corresponding heat flux maps into three-channel RGB images. The R, G, and B channels are the graphical encoding of $Q_{y}$ , $Q_{x}$ , and the structural images, as shown in Fig. 3(d), (c) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[555,63,879,296]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0168/32cde9c46d3f8ca4011ac6f65a549e72e4492b64a32db19ca1fe0b0db98c2d42.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[555,300,875,646]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 4. Schematic of the FluxGAN model workflow. Model architecture consists of (i) a generator, and (ii) a discriminator. (iii) Large-size images are generated by learning spatially extensible representations living in a latent space. Images in the first and the second columns are produced by varying global latent and styles respectively. Top, middle, and bottom images correspond to the green, red, and blue boxed regions in the implicit image (i), respectively. \"]","image_footnote":"[]","img_path":"images/0708/52b0f3437ea20aa53ac27c5cfe98d24a2943840f44a32d4961d0d3f1158b80fc.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[511,811,919,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and (b), respectively. We train the FluxGAN model on the relationship between the structural features of the coatings and the associated thermal properties. To this end, we create a training set by uniformly sampling overlapping square tiles of size $17.4\\mu \\mathrm{m} \\times 17.4\\mu \\mathrm{m}$ ( $64\\mathrm{px} \\times 64\\mathrm{px}$ ) from the RGB images. We split each RGB image into $19 \\times 13$ overlapping tiles and create a training set ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,918,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[81,65,491,196]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"that includes 48,906 ( $= 198 \\times 19 \\times 13$ ) RGB images. Figure 3(v) shows representative square tiles included in the training set. Each image is represented by an array of numbers. The dimension of the array is the height times the width of the tile, times the number of channels in the image: $64\\mathrm{px} \\times 64\\mathrm{px} \\times 3$ . The array elements are pixel intensities in the range from 0 to 255, that correspond to the graphical encoding of the heat flux maps and the structural images. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[161,228,413,242]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Unsupervised Learning of Styles ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,261,491,666]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We train the FluxGAN model using square $64\\mathrm{px} \\times 64\\mathrm{px}$ RGB patches, as discussed in the previous section. GAN models can learn from small patches and successfully generate new large-size images. However, the reconstruction of large scale holistic images can be challenging. For example, techniques such as consecutive image outpainting can result in discontinuous and repetitive structures [13, 14]. Several models have been proposed recently that can generate large images but they fail to maintain a global coherence in the generated images [15-17]. The recently proposed InfinityGAN approach has shown a superior ability to generate holistic large-size images after being trained on small patches [18]. The generated images show a great diversity and continuity along all spatial directions. We implement the InfinityGAN approach in our FluxGAN model to generate large coating images, learning from small patches. The approach generates large holistic images, also known as implicit images, with diverse local features. The InfinityGAN architecture adopts functionality from StyleGAN2 [6], which the FluxGAN model leverages to learn the different styles or the textures of the images, in an unsupervised manner. InfinityGAN synthesizes images of arbitrarily large-size by learning spatially extensible representations living in a latent space. The latent space is encoded by a global latent vector that guides the holistic layout of the infinite-pixel image, and a local latent tensor that expresses structural variations of small region patches. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,667,491,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We show a schematic of the FluxGAN model workflow in Fig. 4. The model consists of a generator that learns to generate plausible images (Fig. 4(i)), and a discriminator that learns to distinguish the generated fake images from real images (Fig. 4(ii)). The generator consists of two modules, a structure and a texture synthesizer. The structure synthesizer is a neural implicit function [19-22], that takes three sets of inputs: a global latent variable, a local latent variable and a continuous coordinate that samples the sub-regions of the implicit image. The texture synthesizer is a fully convolutional StyleGAN2 model [6], with all positional information removed. In addition to the same three inputs, a set of randomized noises are provided as input to the texture synthesizer, to model variations of fine-grained texture within the local structural representations. A mapping layer projects global latent onto a texture style vector, and the tex ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[537,75,658,166]","code_body":null,"code_caption":null,"image_caption":"[\"(i) 1 Style \"]","image_footnote":"[]","img_path":"images/0032/ab8929e957498c373c16877635e48542e421472e8f4a7f1cd1977166f91ade06.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[658,75,774,166]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0464/30de1b08b7e2b18271fc61825a5ceaab8b7e052fab4c7ffee263cdc36370c8c7.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[777,75,895,166]","code_body":null,"code_caption":null,"image_caption":"[\"-280μm 1024px \"]","image_footnote":"[]","img_path":"images/0784/1025c636fd856b634a4667ce8bde604627509cae7b0e56586e25a26a4249c05b.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[539,181,658,272]","code_body":null,"code_caption":null,"image_caption":"[\"(ii) 2 Styles \"]","image_footnote":"[]","img_path":"images/0961/97d2f33c8ce63f003755a137f2115da9a1fab70794776258c1cc7a6702f53434.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[658,167,776,272]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0121/5e35fcb255d74220a0970bee870248933c0e777fc181e88471272c94405f9f9b.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[777,167,895,272]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0915/06513a1e36028f1182223ef043f261af450ec9f4f0660f2b4d82916ce784a443.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[539,287,658,378]","code_body":null,"code_caption":null,"image_caption":"[\"(iii) 3 Styles \"]","image_footnote":"[]","img_path":"images/0778/18182db05e6273ebcea225ce6a0b8ddfb1a12683edcadb0818227b822efe7324.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[658,273,776,378]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0622/75acfef2ec5e1c00ae7164b0e803c418bc676805574969138c86fb8f6bc0f2e7.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[777,273,895,378]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0157/dae4db6acaf5050bace87adc32736e99a1d9c7dee79405df06e1baef1a48c117.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[539,393,658,484]","code_body":null,"code_caption":null,"image_caption":"[\"(iv) 6 Styles \"]","image_footnote":"[]","img_path":"images/0814/bfd2da93fafc42c483ec246230eb5e2444ac8045f89e04c3c581023a4f36f83e.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[658,393,776,484]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0222/c84f8d6d3537960f58e4c5ead2df5fb015a442d5962f1eda51217433390637e0.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[777,380,895,484]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 5. Representative input maps and output images of the FluxGAN model. The first column shows input maps and the second and the third columns show two representative images generated by the model for each input map, respectively. Increasing the number of styles and varying their spatial arrangement affects both the overall appearance and the local diversity of the generated images. \"]","image_footnote":"[]","img_path":"images/0894/a9fa17c8def1905d615ee9dfdb4a60a2c8e84acd68db0b6cba3d9b095682f724.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,637,919,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ture style is injected into all pixels in each layer of the global image via feature modulation. Similar to InfinityGAN, the model uses 256 and 512 dimensions for local and global latent vectors, respectively, for unsupervised learning of structure and texture variations. We use coordinate grid to specify the location of the local structural patches to be sampled. We use sine functions with period $T = 56$ to sample both $x$ and $y$ directions of the local latents. Our training dataset includes $64\\mathrm{px} \\times 64\\mathrm{px}$ RGB image tiles, as mentioned previously. However, the model does not know the positioning of these $64\\mathrm{px} \\times 64\\mathrm{px}$ tiles in the global image. To address the issue, the model uses smaller $37\\mathrm{px} \\times 37\\mathrm{px}$ patches and learns to coordinate the patches relative to each other, during training. We use the same architecture of the discriminator as implemented in StyleGAN2. The schematic of the discriminator workflow is shown in Fig. 4(ii). The discriminator compares generated $37\\mathrm{px} \\times 37\\mathrm{px}$ patches with those included in the training set images. We assess the quality ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,918,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[81,65,490,125]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of images created by the model during training and find that the model achieved the smallest value of the Fréchet inception distance (FID) metric [23] of 2.64 after 660,000 training steps. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,125,490,690]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 4(iii) shows representative output images that are generated based on single-style input maps. The input maps determine the different latent variables and drive the generation of the environments. Since the inputs are single-style maps, the model uses a single latent vector and generates all the regions of the microstructure. We vary the latent vector and compare the generated images, to examine the information encoded in the latent space. We obtain three sets of global latent vectors by using different random sampling from a unit Gaussian distribution. We use the three different latent vectors and keep all other variables (e.g., coordinates and styles) fixed, to obtain the three images shown in the first column of Fig. 4(iii). The structural environments of the images vary significantly when we change the global latent variables. The images show different regions of the coatings, such as the microstructure or the surface and air regions. Together the top surface, material, and bottom surface images constitute the large coating images. The images are representative of the regions marked with green, red, and blue boxes in Fig. 4(i). It is interesting to note that the heat flux patterns across the images appear similar in magnitude, especially in regions away from the pores. For each choice of the global latent, we vary the styles and obtain the images shown in the second column of Fig. 4(iii). The structural environments remain very similar between the set of images shown in each row, however, the magnitudes of the heat flux are varied. This result implies that the global latent variables encode the environment (e.g., structure) and the styles are highly related to the physical phenomenon of interest (e.g., heat flux maps). This insight can offer great practical advantage. For example, styles can inform changes of heating conditions or reveal strategies to design structural features such that heat flux can be guided away from sensitive regions of the microstructures. Thus, FluxGAN model trained on style-based descriptions offers great practical advantage for designing microstructures that satisfy target thermal properties. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[191,718,380,732]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"GENERATION PHASE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[202,750,370,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Unguided Generation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,782,490,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 5 shows representative inputs (first column) and the corresponding images generated as output of the model (second and third column). The model input specifies the overall height and width of the image, the types and the number of styles, the spatial positioning of styles, and merging functions to obtain smooth interfaces between the regions. We show visual representations of the four input maps with different spatial arrangements of styles, in the first column of Fig. 5(i-iv). The input ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[535,61,898,599]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 6. Comparison of structural features of generated (blue) and experimental images (red). We show the mean dependency (solid lines) and the range (shaded regions) for the chord-length distribution and the two-point correlation functions, in the second and the third column, respectively. \"]","image_footnote":"[]","img_path":"images/0432/43f3bc2213ab3781245655f6223f7880d09c4cd152ab568a1baf61f6d6ceb407.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,724,919,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"maps include one, two, three, and six randomly chosen styles, respectively. Note that the number of styles determines the global latent variables, and consequently, the overall appearance of the generated coating images, which is consistent with InfinityGAN spatial style fusion implementation. The images shown in the second and the third column of Fig. 5(i-iv) highlight the structural diversity in generated images for same input maps. We select $540~1024\\mathrm{px}\\times 1024\\mathrm{px}$ images generated with single-style and $50~512\\mathrm{px}\\times 512\\mathrm{px}$ images generated with each multi-style input map, and validate against experimental images using the procedure discussed in the following section. Although we show structural images in Fig. 5, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,918,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[81,65,488,109]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the model outputs are RGB images that contain both structural and heat flux information. We only show the structural channel for the ease of discussion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[145,142,426,156]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Validation of Structural Information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,175,490,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We compare the structural features of the generated images with those of the experimental BSE images. We analyze three features: pore size distribution, chord-length distribution, and two-point correlation functions. Figure 6(i-iv) shows the comparison between the features of the experimental images and the images generated from one, two, three and six styles input maps, respectively. The first column shows the density of pores of given area, defined by the ratio between the number of pores with the specific area and the total number of pores. We calculate the pore sizes by counting the number of black pixels inside each pore. The presence of the black pores enclosed within the gray material region can be particularly noted from the experimental image shown in Fig. 2(ii). The smallest pore is of size $1\\mathrm{px} \\times 1\\mathrm{px} \\sim 0.07\\mu \\mathrm{m}^2$ . This size pores are the highest in number in the coatings as can be noted from Fig. 6(a,d,g). This could be a systematic artifact of the images. Overall, the density of different size pores in all four classes of images match with those in the experimental images. This implies that the model is able to produce the anisotropic pore distributions characteristic of the original thermal spray coatings shown in the BSE images. The porous coatings include numerous interfaces between the material phases and the pore phases. If an imaginary line is drawn in the porous medium, the line will intersect multiple material-pore interfaces. The lengths between these intersections are referred to as chord lengths in the respective phases. The chord length distribution function is then defined by the probability of finding a chord of given length in one of the phases [24, 25]. These functions provide a quantitative measure of the structure of the porous media. The second column of Fig. 6 shows the comparison of the chord-length distributions in material phases of experimental (red lines) and generated images (blue lines). The solid and the dashed lines represent the chord-length distributions in the $x$ and $y$ direction, respectively. The results show that there is higher probability of finding longer chords in the $x$ direction compared to the $y$ direction in the images. This corresponds to the presence of layer-like features that can be noted from the experimental images, as shown in Fig. 2. The layer-like structures form along the vertical ( $y$ ) direction when the droplets of melted material are sprayed in a regular interval during the thermal spray process. We show the comparison between the spatial two-point correlation functions in the third column of Fig. 6. The spatial correlation function between two points $\\mathbf{r}_1$ and $\\mathbf{r}_2$ is defined as $\\langle f(\\mathbf{x} + \\mathbf{r}_1)f(\\mathbf{x} + \\mathbf{r}_2)\\rangle$ [25, 26], where and $\\langle .\\rangle$ indicates a volume average over the spatial coordinate $\\mathbf{x} = (x,y)$ . The characteristic function $f(\\mathbf{x})$ is either zero ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[535,61,895,377]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0949/14da7258b29b17203f85953c4315225792c6855f6971fa7326da210f8d68efa9.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[535,377,684,503]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0220/7451bbd2e4061937993b79a674e090ae1e3987f53f8189213f9803060b6f69ff.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[535,505,684,631]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0607/bc4866d20fdaeaccc2e0a876dc4b60c7f51dd1b83e662697bbe0fd76e2b6e66d.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[686,377,893,560]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0806/4cb62aee055efc2b4fc478fe6f0bf3b499aeae9fc0646cd48e09feb9fefeb806.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[686,560,895,632]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 7. Comparison of generated heat flux (blue) and FEM results (red). (i) Full size generated image with single-style input map. Average generated heat flux (blue) along (a) horizontal and (b) and vertical directions, and compared to FEM results (red). Selected red boxed region is enlarged for comparison between (ii) generated and (iii) FEM results. (iv) (a) Structural and (b-c) heat flux pixel intensity distributions of 540 similarly generated images. \"]","image_footnote":"[]","img_path":"images/0560/5600decd01547f0f92e7890cae544ca26ad20666da38a89a091e57c283170181.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,811,919,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"or one if the point lies in the material or the pore phase. We note a close match between the two-point correlation functions for all four cases. The result for the image generated with the six-style-input map is the closest to the one observed in BSE images. This can be attributed to the higher diversity of microstructures present in the images generated with six-style-input maps. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[906,34,918,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[106,63,460,728]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 8. Image outpainting with holistic heat flux distribution as input. (i) Bottom air region (green box) is supplied as input. (ii) Outpainted image (left) and corresponding FEM results (right). (iii) Interface region of (ii). (iv) (a) Horizontal and (b) vertical averages of generated (blue) heat flux in input region, compared to input (green) and FEM results (red). MAEs for ML-INPUT (blue) and ML-FEM (red) comparisons reported for microstructure shown in (ii). MAEs averaged over seven systems are shown in parentheses \"]","image_footnote":"[]","img_path":"images/0818/41e5e4d6abed40303d607cd1f6c44869222371effe1829f19e20a5efc6d88f40.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[612,66,821,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Heat Flux Data Validation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[511,103,919,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We validate the heat flux of the generated coatings against values computed with FEM for the same microstructures. It is essential that the structural environments and the applied heating conditions of the FEM models are similar to those of the generated coatings. As we illustrate in the above sections, we generate coatings with input maps that include spatial arrangement of random choice of styles. The styles are closely associated with the heat flux patterns in different regions of the coatings. The coatings generated with different input maps not only show highly variable heat flux in the microstructures but also different heating conditions in the surface regions. The heating conditions in coatings generated with arbitrarily chosen input maps may not be consistent with the fixed heating conditions imposed in the FEM models. As we discuss in the \"Computation of Thermal Properties\" section, we simulate a temperature bias of 400K to compute heat flux in all the BSE masks using FEM. To maintain similar heating conditions in generated structures and the FEM models, we provide only single-style-maps as input and generate coating images. We find that the trained FluxGAN model is able to generate full coating images that include material and air regions from sufficiently large $(1024\\mathrm{px} \\times 1024\\mathrm{px})$ single-style-maps. We show an example generated microstructure and the associated heat flux in Fig. 7(i). The yellow vector arrows represent the resultant of the horizontal $(Q_x)$ and the vertical $(Q_y)$ heat flux components. We produce masked images from the generated structural channel and compute the heat flux through the masked images using FEM calculations. We compute the average heat flux along the horizontal and the vertical directions of the coatings from the $Q_x$ and $Q_y$ values of the 1024 pixels of the square image. We show the comparison between the average generated (blue) and FEM-obtained (red) heat flux along the horizontal and the vertical directions, in Fig. 7(i)(a) and (b), respectively. The generated heat flux is in good agreement with FEM results, with mean absolute errors (MAE) of $0.009 - 0.012\\mathrm{MW/m^2}$ for $Q_x$ and $0.013 - 0.020\\mathrm{MW/m^2}$ for $Q_y$ components, respectively. Note that the average $Q_x$ is approximately zero and the average $Q_y$ is always negative. The $Q_y$ components have a dominant contribution to the overall heat flux, since we assume that the temperature gradient is applied along top-to-bottom (negative $y$ ) direction. We show an enlarged image of the $100\\mathrm{px} \\times 100\\mathrm{px}$ red boxed section within the large $1024\\mathrm{px} \\times 1024\\mathrm{px}$ in Fig. 7 (ii). The corresponding masked image and the FEM result in shown in Fig. 7 (iii). The close match between the heat flux patterns can be particularly noted from the two images. We analyze $5401024\\mathrm{px} \\times 1024\\mathrm{px}$ images generated with single-style-input maps. We show the pixel intensity distributions for the three channels in these 540 generated images in Fig. 7(iv). The distributions show high diversity and are consistent with those in the training set, see Fig. 3(b-d). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[898,34,919,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[210,66,361,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Guided Generation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[86,99,488,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Here, we illustrate how our FluxGAN model provides an expedited approach to design new coatings with target thermal properties. In the conventional approach for designing new coatings, one typically fabricates the coatings and then estimates the physical properties using experiments or computational modelling. The process is repeated till the fabricated microstructures satisfy target physical properties, as we outline in Fig. 1(ii). In contrast, the FluxGAN model directly guides the inverse design of coatings that satisfy target thermal properties. Given a target thermal property, the model generates rational designs of new microstructures that satisfy the properties. We demonstrate the targeted generation approach in Fig. 8. We provide the model with the description of physical phenomena in a particular region, e.g., the heat flux near the heat sink, indicated by the green boxes in the images of Fig. 8(i). The model input is a single $80\\mathrm{px} \\times 587\\mathrm{px}$ RGB image that we extract from one of the $410\\mathrm{px} \\times 587\\mathrm{px}$ images. The input image only contains information about the heat flux in the boxed air region where no material is present, referred to as $Q$ INPUT. The model uses outpainting technique to generate the microstructure, the top air region, and the associated heat flux ( $Q$ ML) throughout the large $400\\mathrm{px} \\times 587\\mathrm{px}$ size images. We show the resulting images in Fig. 8(i-ii). The model uses GAN inversion [27-32] to find the latent variables that match the input image and conditional coordination to independently generate spatially consistent micro-patches [17]. Note that the model is capable of generating different coating images shown in Fig. 8(i-ii), when supplied with the same input image. This is possible by selecting different latent variables during outpainting procedure. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[86,580,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, we calculate the heat flux associated with the generated microstructures using FEM, $Q$ FEM, for the same temperature bias of $400\\mathrm{K}$ . We show an outpainted image and the corresponding FEM results for the masked image in the left and the right columns of Fig. 8(ii), respectively. We show the comparison between $Q$ INPUT (green), $Q$ ML (blue) and $Q$ FEM (red) in Fig. 8(iv). Figure 8 (iv)(a) and (b) show the average horizontal and vertical heat flux, computed from the $Q_{x}$ and $Q_{y}$ values of the 80 and 587 pixels of the input region, respectively. The shaded regions represent the range of heat flux values observed in all seven generated images. The MAEs represent the average absolute distance between the two plotted dependencies. The FluxGAN generated heat flux match with $Q$ INPUT and FEM results, with great accuracy. The errors range from 0.003 to $0.01\\mathrm{MW / m}^2$ for all the results, or around $2\\%$ of the average heat flux value in the input region. The $Q_{y}$ components have a dominant contribution to the overall heat flux, compared to $Q_{x}$ . This is expected since we assume that the temperature gradient is applied along top-to-bottom $(y)$ direction. The $Q_{y}$ ML values show larger deviation at the boundaries since the FluxGAN model is unaware of in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[535,63,893,369]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0103/4bef010db61535822f3f3095465bae1f217aa85f7a4b72697cc1f0cf8a632d64.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[535,383,890,445]","code_body":null,"code_caption":null,"image_caption":"[\"Width: $160\\\\mu m$ 587px, Height: $109\\\\mu m$ 400px \",\"(iv) $Q_{x}$ ML $Q_{y}$ ML $\\\\equiv \\\\cdot Q_{x}$ INPUT \"]","image_footnote":"[]","img_path":"images/0130/027c0a24f23543b53e0b0814e5ad25422d73ca35a61ebe722107713f0c520670.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[535,460,893,587]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/1006/6b3e5949a40a825260d4c7d05e164055d2596109abc8a24a06d63a27180e4ae7.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[537,587,888,704]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 9. Image outpainting with artificially constructed heat flux distribution as input. (i) Input image. (ii) Example outpainted images (left) and corresponding FEM results (right). (iii) Interface region of representative image shown in (ii). (iv) (a) Horizontal and (b) vertical averages of generated (blue) heat flux in input region, compared to input (green) and FEM results (red). MAEs for ML-INPUT (blue) and ML-FEM (red) comparisons reported for bottom microstructure of (ii). Average MAEs of the three systems are shown in parentheses. \"]","image_footnote":"[]","img_path":"images/0097/b1433eab28463406042a2670dd0f3aeb4cbca7f6064e72b96014eceb97a99a52.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[898,34,916,45]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[81,65,491,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"sulating boundary conditions while the FEM results are obtained using this restriction. We marked three points of interest in the interface region with magenta circles, as shown in Fig. 8(iii). These points represent the location of the cusps at the bottom material-air interface and are next to dips at the surfaces. They are closest to the heat sink, as can be noted by following the thin green line that marks the top boundary of the input region. The heat flux arrows at this locations (Fig. 8(iii)) indicate that the heat is being guided sideways from the cusps, with the magnitudes being the highest among all values in the bottom air region (Fig. 8 (iv)(b)). Such characteristic heat flux patterns are associated with the different color environments around these points in all the input green boxed regions of Fig. 8(i). Consequently, similar cusp points can be noted from all generated microstructures of Fig. 8(i) and (ii). The common presence of these points in all generated microstructures refer to the fact that they all are rational designs that satisfy the target input heat flux. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,356,491,777]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To further challenge the FluxGAN model, we test its ability to generate images for an artificially constructed input. We construct the input image by periodically extending the red-boxed $80\\mathrm{px} \\times 80\\mathrm{px}$ region marked in the top panel of Fig. 9(i). The full panel shows the resulting input image of size $80\\mathrm{px} \\times 587\\mathrm{px}$ . We show three outpainted images and the corresponding FEM results in Fig. 9(ii). We show the comparison of the average horizontal and vertical heat flux, computed from the $Q_{x}$ and $Q_{y}$ values of the 80 and 587 pixels of the input region, in Fig. 9(iv)(a) and (b), respectively. The shaded regions represent the range of heat flux values observed in three different images. The periodic nature of heat flux can be particularly visible from the average vertical heat flux, shown in Fig. 9(iv)(b). The FluxGAN generated heat flux match with $Q$ INPUT and FEM results, with great accuracy. The MAEs of the FluxGAN results range from 0.002 to $0.011\\mathrm{MW/m^2}$ when compared with the INPUT and from 0.007 to $0.012\\mathrm{MW/m^2}$ when compared with the FEM results, respectively. Average vertical heat flux agrees with the FEM results in the input region within $3\\%$ error margin. These results demonstrate that the model is able to generate rational microstructures that best fit the criterion imposed by the input image. Note that the generated microstructures are highly diverse away from the periodic input region and do not show any visible repetitions. The diversity of generated images indicates that the model provides multiple designs of microstructures to satisfy target conditions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[127,808,444,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Extension to Three-Dimensional Domain ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,840,490,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although our study primarily focuses on 2D microstructures, here we discuss how we can leverage the FluxGAN model to generate 3D microstructures with high structural diversity. GANs can be trained to generate 3D volumes, which are useful for design optimization ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,65,921,559]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and detailed analysis of structural features and physical processes [4, 33, 34]. These models can be used for rapid generation of complex 3D structures over conventional approaches. A recent article used a bounded random walk algorithm to generate an interface, followed by seeding of random size particles to produce a two-phase material, resulting in large $128\\mathrm{px} \\times 10000\\mathrm{px}$ images. The images were used to train SliceGAN [33] algorithm and output 3D configurations. However, the lack of diversity in such approach allows the generator to trick the discriminators, resulting in unrealistic 3D representations. We demonstrate that this issue can be resolved by training the GAN models with images that include both structural and physical phenomena information. We propose a combined approach that implements both the FluxGAN and the SliceGAN algorithms to generate complex 3D microstructures and associated heat flux environments with high diversity. The SliceGAN approach generates a volume by assimilating 2D slices, each of which is refined to match the training set images. However, a large number of diverse 2D images is required for successful training, especially to generate complex, anisotropic 3D materials with high density of interfaces. We leverage the FluxGAN model to generate two large $64\\mathrm{px} \\times 320000\\mathrm{px}$ images ( $17.4\\mu \\mathrm{m} \\times 8.7\\mathrm{cm}$ coatings) for the surface and the material regions. We make random selections of $64\\mathrm{px} \\times$ $64\\mathrm{px}$ patches from the generated images and pass them to two perpendicular discriminators of SliceGAN. Figure 10(i) and (ii) show two perpendicular RGB slices for the surface and the material regions, respectively. Note that the heat flux components (red and green channels) are continuous across the two perpendicular slices and the blue channel produces matching structure in both the perpendicular planes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,566,921,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The objective of the generator of the SliceGAN model is to generate realistic volumes in which the 2D slices along $X$ and $Y$ directions pass the discriminator test. Note that the outputs from the generator include information in five channels: [BSE, $Q_{X}$ , $Q_{Y}$ , $Q_{X}^{\\perp}$ , $Q_{Y}^{\\perp}$ ]. The first channel contains structural information as learned from the experimental BSE images. The other two sets of channels include heat flux data. $(Q_{X}, Q_{Y})$ and $(Q_{X}^{\\perp}, Q_{Y}^{\\perp})$ refer to the heat flux components of the two perpendicular slices, represented in graphical domain. The generated information is passed to the two discriminators. Each of the two perpendicular discriminators receives three-channel RGB images and share a common structural channel (BSE). However, each discriminator receives a separate set of heat flux data, $(Q_{X}, Q_{Y})$ or $(Q_{X}^{\\perp}, Q_{Y}^{\\perp})$ . The model assimilates 64 slices in each of two perpendicular directions to produce $64 \\times 64 \\times 64$ voxel volumes, as shown in Fig. 10(iii) and (iv). For the generated 3D microstructures, we obtain the heat flux along the $Z$ -direction, $Q_{Z}$ , by averaging the vertical heat flux components $Q_{Y}$ and $Q_{Y}^{\\perp}$ obtained from both discriminators. The resulting volumes have a four-channel representation: [BSE, $Q_{X}$ , $Q_{X}^{\\perp}$ , $Q_{Z}$ ]. Finally, the SliceGAN model outputs two representative 3D con ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[898,34,919,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,63,875,232]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 10. Microstructure representation in 3D domain. Two discriminators are implemented to test perpendicular RGB image slices for (i) surface and (ii) material regions. Representative volumes generated for (iii) surface and (iv) material regions with superimposed heat flux. (v) Two representative 3D microstructures generated by combined FluxGAN-SliceGAN approach. \"]","image_footnote":"[]","img_path":"images/0629/4b509e3f770b93293fc5c71012e085a7c9ceb831f0dce7e5b111c9608181bc7a.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,328,488,503]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figurations of size $64 \\times 400 \\times 400$ voxels using the generated volumes, as shown in Fig. 10(v). The resultant microstructures shows great structural diversity in both the surface landscape as well as the cross section of inner material region, which are not accessible in the experimental and training images. The combined FluxGAN-SliceGAN approach shows remarkable ability to infer 3D representation of microstructure and associated physical phenomenon from a single 2D image. We attribute the high quality of the representation to both large size of the training image and the heat flux data included in the image channels. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[166,532,405,546]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUMMARY AND OUTLOOK ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,566,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We propose a generative ML model, FluxGAN, capable of generating arbitrary large images of microstructures and associated heat flux data. The model generates the information about heat flux that will be observed within the microstructures and the outside heat source or sink regions, if temperature gradients are applied externally. We train the model with RGB images in which the different color channels contain graphical domain representation of structural information from experimental images and heat flux data obtained from FEM calculations. In these images, the information about the structural features are superimposed with heat flux patterns that correspond to the structural features. During training, the model learns about the different combinations of structural features and heat flux patterns, referred to as styles, in an unsupervised manner. Once trained, the model generates large images for given inputs maps that specify spatial distribution of styles to be included in the output images. The generated microstructures show high diversity and include structural features that have characteristics similar to those present in the experimental images. We compare the generated heat flux with the results from separate FEM analyses on the corresponding generated microstructures. The FluxGAN generated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,328,919,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"heat flux show good agreement with FEM results. Furthermore, we demonstrate that the image generation can be guided by providing partial information to the model. We provide the model with the heat flux near the bottom heat sink region. The model shows remarkable ability to generate large microstructures, heat source regions and associated heat flux that are consistent with the input. The generated heat flux values lie within $3\\%$ of those obtained with separate FEM simulations. Thus, our FluxGAN model offers an expedited approach for inverse design of microstructures with target thermal properties. The images show high structural diversity as well. We illustrate that the FluxGAN generated images can be leveraged to produce complex 3D microstructures, in combination with the SliceGAN architecture. We generate 0.1 meter long continuous and structurally diverse 2D structural images and their associated heat flux environment, to construct the 3D representations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,589,919,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In conclusion, FluxGAN offers fast, inexpensive, and reliable approach for design and analysis of 2D and 3D microstructures. The model is capable of generating arbitrary large environments with constant computation cost. This aspect is particularly advantageous over the FEM approach where memory usage scales linearly with the number of degrees of freedom. Our approach is general and can be extended to any continuous physical phenomena represented in graphical domain. The ability of the model to render arbitrary large environments while trained on small size patches offers great practical advantage. For example, the model will be highly effective in providing description of physical phenomena at the micro-meso or even macro scale, or guiding characterization and fabrication of complex devices, such as micro-electronic chips with extreme design points. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[624,852,807,864]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DATA AVAILABILITY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[511,883,918,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare that the data supporting the findings of this study are available within the paper and its ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[898,34,919,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[181,109,392,123]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGEMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,141,490,316]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We are indebted to Dr. M. R. Kracum for providing us with the two-dimensional backscatter electron images of the niobium thermal sprayed coatings, sharing valuable insights regarding the outstanding challenges of thermal spray coatings, and several helpful discussions. We gratefully acknowledge funding from the research partnership initiative between the College of Engineering & Applied Science at the University of Colorado Boulder and the DOE-Sandia National Laboratories, Albuquerque, NM. This work utilized the Summit supercomputer, which is supported by the National Science Foundation (awards ACI-1532235 and ACI-1532236), the University of Col ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,65,921,111]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Orado Boulder, and Colorado State University. The Summit supercomputer is a joint effort of the University of Colorado Boulder and Colorado State University. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[596,137,836,150]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHOR CONTRIBUTIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[511,167,919,241]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A.K.P and M.S. contributed to the acquisition and the analysis of data and the creation of new scripts used in the study. S.N. contributed to the conception and the design of the work, the interpretation of data, drafting and revision of the article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[606,268,826,282]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COMPETING INTERESTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[511,301,831,316]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare no competing interests. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[86,369,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] L. Yang, D. Zhang, and G. E. Karniadakis, Physics-informed generative adversarial networks for stochastic differential equations, SIAM Journal on Scientific Computing 42, A292 (2020). \",\"[2] C. Jiang and A. B. Farimani, Deep learning convective flow using conditional generative adversarial networks, arXiv preprint arXiv:2005.06422 (2020). \",\"[3] H. Jiang, Z. Nie, R. Yeo, A. B. Farimani, and L. B. Kara, StressGAN: A generative deep learning model for two-dimensional stress distribution prediction, Journal of Applied Mechanics 88 (2021). \",\"[4] T. Hsu, W. K. Epping, H. Kim, H. W. Abernathy, G. A. Hackett, A. D. Rollett, P. A. Salvador, and E. A. Holm, Microstructure generation via generative adversarial network for heterogeneous, topologically complex 3d materials, Jom 73, 90 (2021). \",\"[5] P. C. Nguyen, N. N. Vlassis, B. Bahmani, W. Sun, H. Udaykumar, and S. S. Baek, Synthesizing controlled microstructures of porous media using generative adversarial networks and reinforcement learning, Scientific reports 12, 9034 (2022). \",\"[6] T. Karras, S. Laine, and T. Aila, A style-based generator architecture for generative adversarial networks, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2019) pp. 4401-4410. \",\"[7] X. Huang and S. Belongie, Arbitrary style transfer in real-time with adaptive instance normalization, in Proceedings of the IEEE international conference on computer vision (2017) pp. 1501-1510. \",\"[8] T. Karras, M. Aittala, J. Hellsten, S. Laine, J. Lehtinen, and T. Aila, Training generative adversarial networks with limited data, Advances in neural information processing systems 33, 12104 (2020). \",\"[9] J. Wang, J. K. Carson, M. F. North, and D. J. Cleland, A new approach to modelling the effective thermal conductivity of heterogeneous materials, International journal of heat and mass transfer 49, 3075 (2006). \",\"[10] S. Gurumurthy, R. Kiran Sarvadevabhatla, and R. Venkatesh Babu, Deligan: Generative adversarial networks for diverse and limited data, in Proceedings of the IEEE conference on computer vision and pattern \"]","page_idx":"13","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[514,369,919,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"recognition (2017) pp. 166-174. \",\"[11] I. Gulrajani, F. Ahmed, M. Arjovsky, V. Dumoulin, and A. C. Courville, Improved training of wasserstein gans, Advances in neural information processing systems 30 (2017). \",\"[12] C. Multiphysics, Introduction to comsol multiphysics (R), COMSOL Multiphysics, Burlington, MA, accessed Feb 9, 32 (1998). \",\"[13] R. Abdal, Y. Qin, and P. Wonka, Image2StyleGAN++, How to edit the embedded images?, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2020) pp. 8296-8305. \",\"[14] A. Liu, R. Tucker, V. Jampani, A. Makadia, N. Snavely, and A. Kanazawa, Infinite Nature: Perpetual view generation of natural scenes from a single image, in Proceedings of the IEEE/CVF International Conference on Computer Vision (2021) pp. 14458-14467. \",\"[15] T. R. Shaham, T. Dekel, and T. Michaeli, SinGAN: Learning a generative model from a single natural image, in Proceedings of the IEEE/CVF international conference on computer vision (2019) pp. 4570-4580. \",\"[16] A. Shocher, S. Bagon, P. Isola, and M. Irani, InGAN: Capturing and retargeting the\\\"dna\\\" of a natural image, in Proceedings of the IEEE/CVF International Conference on Computer Vision (2019) pp. 4492-4501. \",\"[17] C. H. Lin, C.-C. Chang, Y.-S. Chen, D.-C. Juan, W. Wei, and H.-T. Chen, COCO-GAN: Generation by parts via conditional coordinating, in Proceedings of the IEEE/CVF international conference on computer vision (2019) pp. 4512-4521. \",\"[18] C. H. Lin, H.-Y. Lee, Y.-C. Cheng, S. Tulyakov, and M.-H. Yang, InfinityGAN: Towards infinite-pixel image synthesis, arXiv preprint arXiv:2104.03963 (2021). \",\"[19] J. J. Park, P. Florence, J. Straub, R. Newcombe, and S. Lovegrove, DeepSDF: Learning continuous signed distance functions for shape representation, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2019) pp. 165-174. \",\"[20] L. Mescheder, M. Oechsle, M. Niemeyer, S. Nowozin, and A. Geiger, Occupancy Networks: Learning 3d reconstruction in function space, in Proceedings of the IEEE/CVF \"]","page_idx":"13","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[898,34,919,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[83,65,321,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplementary Information files. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[86,66,488,753]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"conference on computer vision and pattern recognition (2019) pp. 4460-4470. \",\"[21] B. Mildenhall, P. P. Srinivasan, M. Tancik, J. T. Barron, R. Ramamoorthi, and R. Ng, NERF: Representing scenes as neural radiance fields for view synthesis, Communications of the ACM 65, 99 (2021). \",\"[22] Y. Chen, S. Liu, and X. Wang, Learning continuous image representation with local implicit image function, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2021) pp. 8628-8638. \",\"[23] M. Heusel, H. Ramsauer, T. Unterthiner, B. Nessler, and S. Hochreiter, GANs trained by a two time-scale update rule converge to a local nash equilibrium, Advances in neural information processing systems 30 (2017). \",\"[24] S. Torquato and B. Lu, Chord-length distribution function for two-phase random media, Physical Review E 47, 2950 (1993). \",\"[25] S. Torquato, *Random heterogeneous materials* (Springer., 2013). \",\"[26] J. G. Berryman and S. C. Blair, Use of digital image analysis to estimate fluid permeability of porous materials: Application of two-point correlation functions, Journal of applied Physics 60, 1930 (1986). \",\"[27] A. Creswell and A. A. Bharath, Inverting the generator of a generative adversarial network, IEEE transactions on neural networks and learning systems 30, 1967 (2018). \",\"[28] F. Ma, U. Ayaz, and S. Karaman, Invertibility of convolutional generative networks from partial measurements, Advances in Neural Information Processing Systems 31 (2018). \",\"[29] R. Abdal, Y. Qin, and P. Wonka, Image2StyleGAN: How to embed images into the StyleGAN latent space?, in Proceedings of the IEEE/CVF international conference on computer vision (2019) pp. 4432-4441. \",\"[30] D. Bau, H. Strobelt, W. Peebles, J. Wulff, B. Zhou, J.-Y. Zhu, and A. Torralba, Semantic photo manipulation with a generative image prior, arXiv preprint arXiv:2005.07727 (2020). \",\"[31] J. Zhu, Y. Shen, D. Zhao, and B. Zhou, In-domain GAN inversion for real image editing, in European conference on computer vision (Springer, 2020) pp. 592-608. \",\"[32] Y.-C. Cheng, C. H. Lin, H.-Y. Lee, J. Ren, S. Tulyakov, and M.-H. Yang, InOut: Diverse image outpainting via gan inversion, in Proceedings of the IEEE/CVF Conference on Computer Vision and Pattern Recognition (2022) pp. 11431-11440. \",\"[33] S. Kench and S. J. Cooper, Generating three-dimensional structures from a two-dimensional slice with generative adversarial network-based dimensionality expansion, Nature Machine Intelligence 3, 299 (2021). \",\"[34] A. Henkes and H. Wessels, Three-dimensional microstructure generation using generative adversarial neu \"]","page_idx":"14","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[542,66,918,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ral networks in the context of continuum micromechanics, Computer Methods in Applied Mechanics and Engineering 400, 115497 (2022). ","text_format":null,"text_level":null,"type":"ref_text"},{"bbox":"[580,146,852,159]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUPPLEMENTARY MATERIALS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[511,179,919,364]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Here we discuss and compare computational costs associated with ML model generation and FEM validation. We generate a set of images using periodically extended $80 \\times 587$ pixels input image discussed in section Guided Generation. We build a progression of input images extending the length by up to 6 times. The resulting out-painted images have the sizes $400\\mathrm{px} \\times (\\mathrm{N} \\times 587)\\mathrm{px}$ , with $\\mathrm{N} = 1,2,3,4,5,6$ . We demonstrate convergence of FEM validation mean absolute error (MAE) for the $400\\mathrm{px} \\times 3522\\mathrm{px}$ outpainted image in Fig. 11(i). We show MAE for the total heat flux magnitude, namely, $Q = \\sqrt{Q_x^2 + Q_y^2}$ , $\\mathrm{MAE} = \\sum_{i=1}^{H \\times W} |Q_i^{ML} - Q_i^{FEM}| / (H \\times W)$ , ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,364,919,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $Q_{i}$ is the total heat flux magnitude at a given pixel, $H$ and $W$ are the height and width of an image. MAE converges quickly with the number of degrees of freedom (DoF) used for FEM calculation and saturates below $0.05\\mathrm{MW / m^2}$ after 1 million DoF. For the further calculations we fix DoF around that value. We also show calculation time (red solid line) and memory usage (green solid line) for FEM validation step. We observe their linear scaling with DoF. For comparison, the generation time (red dashed line) and memory usage (green dashed line) are also shown for ML model. In Fig. 11(ii) we compare ML generation and FEM calculation costs. Both FEM (red solid line) and ML (red dashed line) have similar linear time scaling with image size for the DoF fixed around 1 million. However, the memory usage is significantly higher for FEM (green solid line) compared to ML (green dashed line). We also show that MAE (blue solid line) stays consistently small (bellow $0.05\\mathrm{MW / m^2}$ ) for all image sizes. The highest time cost is associated with latent inversion (black dashed line). The low memory costs associated with ML are due to patch-by-path generation approach, where each patch $(37\\mathrm{px} \\times 37\\mathrm{px})$ is generated independently to produce large scale images. The time costs for ML generation shown here are for generating one patch at a time. This can be improved significantly since the model is capable of generating patches in batches, allowing for the highly parallelized output. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[898,34,918,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[125,61,470,333]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0985/01b6e41acb59de5e3571ae17d7c3b96d7ef7e8dae58c796bc918c04281b24bd7.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[473,61,879,328]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 11. Supplementary Materials Computation and generation costs. (i) MAE and computational costs as a function of number of degrees of freedom for $400\\\\mathrm{px} \\\\times 3522\\\\mathrm{px}$ image. MAEs are calculated for the magnitude of heat flux. For the time (red) and memory (green) axes solid lines correspond to FEM, dashed lines correspond to ML. (ii) MAE and computational costs as a function of image length. Color lines show time (red) and memory (green) costs of FEM validation (solid) and ML generation (dashed). MAEs for heat flux magnitude are shown in blue. Latent inversion time cost is shown in black dashed line. \"]","image_footnote":"[]","img_path":"images/0284/ff44d13374aaa7dcff45c6b3a57d2d97a1a28e2fc93381feba9b405c2884b817.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[898,34,919,46]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[94,61,908,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"FluxGAN: A Physics-Aware Generative Adversarial Network Model for Generating Microstructures That Maintain Target Heat Flux \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[250,112,750,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Artem K. Pimachev, $^{1}$ Manoj Settipalli, $^{1}$ and Sanghamitra Neogi $^{1}$ ,* \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[303,131,702,172]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Ann and H.J. Smead Aerospace Engineering Sciences, University of Colorado Boulder, Boulder, CO 80303, USA (Dated: October 10, 2023) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[169,179,831,405]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We propose a physics-aware generative adversarial network model, FluxGAN, capable of simultaneously generating high-quality images of large microstructures and description of their thermal properties. During the training phase, the model learns about the relationship between the local structural features and the physical processes, such as the heat flux in the microstructures, due to external temperature gradients. Once trained, the model generates new structural and associated heat flux environments, bypassing the computationally expensive modeling. Our model provides a cost effective and efficient approach over conventional modeling techniques, such as the finite element method (FEM), for describing the thermal properties of microstructures. The conventional approach requires computational modeling that scales with the size of the microstructure model, therefore limiting the simulation to a given size, resolution, and complexity of the model. In contrast, the FluxGAN model uses synthesis-by-part approach and generates arbitrary large size images at low computational cost. We demonstrate that the model can be utilized to generate designs of thermal sprayed coatings that satisfies target thermal properties. Furthermore, the model is capable of generating coating microstructures and physical processes in three-dimensional (3D) domain after being trained on two-dimensional (2D) examples. Our approach has the potential to transform the design and optimization of thermal sprayed coatings for various applications, including high-temperature and long-duration operation of gas turbines for aircraft or ground-based power generators. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[212,430,361,444]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,462,488,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In recent years, machine learning techniques, such as generative adversarial networks (GANs), are increasingly being used to explain deterministic multiphysics phenomena where the underlying physical model is complex or unknown. Physics-informed generative adversarial networks have been proposed for solving forward, inverse, and mixed stochastic problems using data from a limited number of scattered measurements [1]. Instead of relying solely on data for training, this approach encoded the governing physical laws in the GAN architecture in the form of stochastic differential equations. FluidGAN has been proposed for learning and predicting time-dependent convective flow coupled with energy transport [2]. StressGAN model was developed to generate mechanical stress distributions for various complex cases of geometry, load, and boundary conditions [3]. The model was shown to predict more accurate high-resolution stress distributions than a convolutional neural network model. In parallel, GANs have shown remarkable progress for creating high-resolution synthetic images, visually similar to their real counterparts, supported by revolutionary adverts in the graphical data domain. Until recently, training such model required enormous amount of training images and was highly unstable. GANs have been shown to be highly effective in generating realistic microstructural data that can be used to augment limited experimental data or simulate microstructures that are challenging to obtain experimentally [4, 5]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,429,919,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The style-based GAN (StyleGAN2) architecture [6], implemented the style transfer approach [7] with the adaptive discriminator augmentation (ADA) [8] mechanism, and demonstrated that high-quality images can be generated with limited training data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,510,921,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this study, we propose a new FluxGAN model that simultaneously generates high-quality microstructural images and high-resolution description of thermal properties of these microstructures. We adopt the StyleGAN2 architecture to develop the model and train the model using images that include both microstructural information and the associated physical (i.e., thermal) phenomena. We demonstrate the capabilities of our approach for the analysis and design of microstructure-controlled thermal properties of thermal sprayed coatings. The thermal sprayed coatings exhibit highly diverse structural environments, including pores with different shapes and sizes, and varied size grains aligned at different crystallographic orientations. The microstructural features strongly affect interface-sensitive material properties, such as thermal diffusivity. Additionally, the structural features could change and evolve due to sintering in high temperature environments. The presence of microstructural features is often quantified by the porosity parameter: (pore volume)/(total volume)×100 %. The variation of thermal properties of coatings has commonly been described in relation with porosity, using phenomenological models [9]. However, global parameter (e.g. porosity) based models may not accurately capture the physics of heat transfer across various microstructural features and feature interfaces. The complexity of structural features and their evolution makes it highly challenging to characterize the physical properties \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[22,232,57,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"arXiv:2310.04622v1 [cond-mat.dis-nn] 6 Oct 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[84,898,300,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"* sanghamitra.neogi@colorado.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[83,65,491,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of these coatings, especially after aging, using existing experimental and numerical approaches. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,95,491,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our proposed FluxGAN model provides highly accurate prediction of thermal phenomena in coatings with different microstructures that include different porosities, grain sizes, and crystallographic orientations. We use a small number of two-dimensional (2D) images of niobium thermal sprayed coatings, obtained with backscatter electron (BSE) imaging technique, as the 'true' image of the coating microstructures. We compute the thermal properties of the microstructures using the image-based finite element method (FEM). We train the FluxGAN model using superimposed images that include both microstructural and thermal property data. The FluxGAN model combines the physical properties predicted by FEM and the GAN architecture, for generating diverse microstructures with desired thermal properties. We use separate FEM simulations to validate the generated thermal data. The model uses synthesis-by-part approach and generates images of arbitrary size patch by patch, which requires constant memory usage. In contrast, the FEM memory usage and computational time scales with the image size. The combination of image-based FEM and GAN models offers a promising solution to overcome the limitations of traditional experimental and numerical methods. Our model provides a cost effective and efficient approach for describing the microstructure-controlled thermal properties of thermal sprayed coatings. The model establishes a direct relationship between structural features and thermal properties of coatings, which could be utilized to better control and optimize their thermal properties. We demonstrate that our model can be used to design thermal sprayed coatings that can maintain tailored heat flux that meets application-specific requirements. Our approach has the potential to transform the design and optimization of thermal sprayed coatings for various industrial applications, including high-temperature and long-duration operation of gas turbines for aircraft or ground-based power generators. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[240,662,333,674]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[222,691,351,705]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Model Overview \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,724,491,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 1(i) shows the overview of our physics-informed FluxGAN model. The model includes a training and a generation phase. We train the model with images that include information about structural as well as thermal properties of the microstructure. We obtain the 2D structural images, as shown in Fig. 1(a), using backscatter electron (BSE) imaging and simulate the thermal properties using FEM techniques. Figure 1(e) shows the spatial distribution of heat flux, $Q(x,y)$ , generated in the microstructure, due to the application of temperature gradient along the top-to-bottom direction. Figure 1(c) and (d) show the graphical domain representation of the heat flux components, $Q_{x}$ and $Q_{y}$ , respectively. We \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,65,921,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"create RGB images by superimposing the experimental structural images and the heat flux maps, as shown in Fig. 1(b). We provide the RGB images as input to the FluxGAN model. The model identifies the different features of the RGB training images, referred to as styles, in an unsupervised manner. The styles not only classify structural features but are strongly associated with heat flux patterns of the RGB images. In the unguided generation phase, the FluxGAN model requires minimal input from the user and generates a new image corresponding to the input. An example input is shown in Fig. 1(f). The input specifies the overall height and width of the image and the spatial map of styles to be included. The spatial map includes the number of styles that can be identified in the image (styles 1 and 2), the locations for regions with styles 1 and 2 (anchors), and the merging function that can be applied to obtain smooth interfaces between the regions. Figure 1(g) shows a representative microstructure, generated by the FluxGAN model. The generated image includes structural features that correspond to styles 1 and 2 as specified by the user input. The image also includes information about the heat flux that will be observed if the microstructure is subjected to temperature gradients along the top-to-bottom image direction. Thus, the FluxGAN model directly generates designs of representative microstructures and corresponding physical properties from a minimal user input. The model can even generate designs of new classes of structures that are not present in original experimental images. For example, different designs can be created by combining different styles, varying the positions of the styles in two-dimensional (2D) or three-dimensional (3D) spatial domains. Additionally, the model offers guided assignment of styles in the generated microstructures, based on the specifications of the input image. For example, given a known heat flux distribution in the heat source or sink region as input, the model allows for inverse design of microstructures that satisfies the target heat flux condition. We describe the different components of the FluxGAN model in the following sections. We demonstrate the effectiveness of the FluxGAN model by using single phase niobium (Nb) thermal spray coatings as an example. However, our model can be broadly applied to different materials and structures to assess how well they satisfy target physical properties. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,724,921,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The conventional approach for designing new coatings, as outlined in Fig. 1(ii), typically iterates through the following steps: (1) fabrication of coatings, (2) experimental characterization, (3) developing computational models based on experimental images, (4) physical property calculation, and repeat (1-4) till the fabricated structures satisfy target physical properties. Our FluxGAN model provides an expedited approach to inform the design of new microstructures that satisfy target physical properties, bypassing the expensive iterative process. In this study, we have chosen the styles in an arbitrary manner. However, the styles can be associated with specific physical conditions. For example, the different spray in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,919,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[267,61,746,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(i) Generative ML Framework (FluxGAN) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[127,83,225,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Training \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[127,107,880,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 1. Overview of FluxGAN model and its advantage over conventional approach: (i) The model includes a training and a generation phase. We train the model with (b) superimposed RGB images that include (a) experimental structural images and (c,d) heat flux data, simulated with FEM techniques. The model classifies the distinct features of the RGB images and assigns them as different styles. Once trained, the model generates images based on user input. (f) Spatial map of different styles as input. (g) The model generates new structural image superimposed with associated heat flux, that satisfies target thermal properties. (ii) In contrast, conventional design approach follows an expensive and iterative cycle until microstructures with target physical properties are obtained. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0693/fd25d1ecdaad443ecc7ac44c6c0b077001822f090c6e44ae27f04d79c0bde73f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,763,490,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"tervals in a thermal spray process could result in different structural features. The different features can also be associated with diverse environmental conditions, such as high temperatures or corrosion. As styles are strongly associated with the heat flux, physical meaning of styles can be regions of high or low thermal conductance and temperature hot spots, etc. A FluxGAN model aware of the relationship between the styles and synthesis or environmental conditions can offer great practical advantage. For example, the styles in generated images can \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,763,919,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"inform strategies to synthesize microstructures with target functionalities and also, provide information about the reliability of microstructure in diverse environmental conditions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,918,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[106,78,468,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(i) Width: $160\\\\\\\\mu \\\\\\\\mathrm{m}587\\\\\\\\mathrm{px}$ , Height: $112\\\\\\\\mu \\\\\\\\mathrm{m}410\\\\\\\\mathrm{px}$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0389/1125340f1ba0b30fd5e93a7ca4e0dd5324e3e807f366614a95d818a78bc83778.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[106,292,467,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(ii) Width: $50\\\\\\\\mu \\\\\\\\mathrm{m}$ \\\",\\\"FIG. 2. Experimental images of coating microstructures: (i) Raw BSE images of niobium thermal spray coatings. (ii) Magnified image of microstructure shows a wide variety of structural features, such as flat splats and porosities due to conditions during the synthesis process. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0353/cfedf6fc20e2b225fe4a9c6de4267b5f55a81faff3f30c3ead11c29e0c437b4a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[205,614,366,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TRAINING PHASE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[150,647,421,662]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Processing of Experimental Images \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,681,490,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 2 shows the 2D experimental BSE images of the Nb thermal spray coatings that we use to demonstrate the performance of the FluxGAN model. The dimension of each image is $112\\\\mu \\\\mathrm{m} \\\\times 160\\\\mu \\\\mathrm{m}$ ( $410\\\\mathrm{px} \\\\times 587\\\\mathrm{px}$ ). Three distinct regions can be visually identified from the images: the gray middle region that shows the presence of the coating microstructure, the top and bottom dark regions where no coating material is present and the two interface regions between the gray coating and the dark regions. We assume that the dark regions of the images represent presence of air. We show a magnified version of a representative coating microstructure in Fig. 2(ii). As can be noted, the microstructure includes distinct features, such as flat splats and globular and interfacial porosities. In addition to these features, a wide variety of small features can also be noted that are repre \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,66,919,429]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"sentative of materials properties or processing conditions. However, some features may appear due to difference in lighting conditions during imaging. Note that the FluxGAN model identifies the different styles of the training images in an unsupervised manner. To ensure that the microstructure images only include 'true' features, we preprocess the grayscale BSE images and remove features that appear due to irregular image brightness. The preprocessing is an essential step since our goal is to develop a model that can relate 'true' structural features with the corresponding physical properties. First, we obtain the pixel intensity distribution of the BSE images, by counting the number of pixels that has a given intensity in the range between 0 and 255. Figure 2(a) shows that the coating region of the images have intensities $\\\\geq$ 50 in this scale. The appearance of the distinct peaks can be attributed to different lighting conditions during imaging. We scale the intensities to values in the range between 0 and 1. We then shift the mean of the distribution to 0.5 using a power transformation. Finally, we rescale the pixel intensity distribution of the coating region to be in the range from 50 to 255. Figure 2(b) shows the pixel intensity distribution after the transformation. The intensity values below 50 represent pores or air regions where the coating material is not present. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[599,460,833,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Augmentation of Training Set \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,493,919,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our experimental dataset is limited to nine BSE images, as shown in Fig. 2. However, the GAN models require enormous amount of training images to generate high-resolution images as output. Extensive efforts are ongoing to develop models that can create high quality images with limited training data [10, 11]. Recent approaches, such as StyleGAN2 [6], require a smaller training set, however, still require substantial number of training images. We implement different strategies to augment the training dataset. We apply rotation and reflection operations on the raw images and add the new images to the dataset. The new images include additional variations of structural features that impact the thermal properties. We thus obtain a diverse set of images to train the FluxGAN model. However, it is essential that the new images include features that are consistent with the physical conditions displayed by the original images. This constraint imposes restrictions on the type of operations we could perform to create new images. For example, all experimental images of Fig. 2 (and also, Fig. 3(i)) show that the images have flatter bottom surfaces and uneven top surfaces. These features appear because the thermal spray coatings are fabricated on top of substrates. We only apply horizontal flip transformations but do not apply any vertical flip operations to maintain similar layer-like features in the new images. Additionally, when the droplets of melted material are sprayed in a regular interval, the material solidifies and forms layers in the top-to-bottom direction. As can be \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,919,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[81,65,490,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"seen from Fig. 2(ii), the layers are highly uneven. This is because the sprayed material might solidify at different rates in the sprayed microstructures during fabrication. Highly anisotropic features may appear when droplets of melted material are sprayed over already solidified splats. To ensure that the new images retain such characteristics, we apply only small angular rotations between -2.5 to +2.5 degrees, with 11 incremental steps. We set the top and bottom air regions to be 80 pixels wide and add extra space as needed so that the coating region stays within the image boundary, as shown in Fig. 3(ii). The augmented dataset contains a total of 198 (9 original × 11 rotated × 2 flipped) superimposed images. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[145,284,426,299]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Computation of Thermal Properties \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,316,488,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We compute the thermal properties of the coating microstructures using image-based FEM techniques, as implemented in COMSOL software [12]. We assume that the heat conduction direction is along the top-to-bottom direction of the coatings. We convert the microstructure images to masks by assigning all pixels with intensities $< 50$ to black color, representing air, and the pixels with intensities $\\\\geq 50$ to grey color, representing niobium. Figure 1(a) and (e) show an experimental image and the corresponding masked image, respectively. We use the masked images as input for image-based FEM simulations. We import the masked images to COMSOL and use the built-in function, $im(x,y) = \\\\{0,1\\\\}$ , to mark different regions within each image. The discrete values correspond to black and gray regions of the images, respectively. This creates rectangular simulation domains that have same dimensions as the input images. We use the image function, $im(x,y)$ , and the thermal conductivity values of air and Nb, to define spatially resolved thermal conductivities, $\\\\kappa_{\\\\mathrm{local}}(x,y)$ , in the rectangular simulation domain: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[151,628,488,670]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\kappa_ {\\\\text {l o c a l}} (x, y) = \\\\left\\\\{ \\\\begin{array}{l l} \\\\kappa_ {\\\\text {A i r}}, & \\\\text {i f} i m (x, y) = 0 \\\\\\\\ \\\\kappa_ {\\\\text {N b}}, & \\\\text {i f} i m (x, y) = 1 \\\\end{array} \\\\right. \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[81,681,490,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We choose thermal conductivity of niobium $(\\\\kappa_{\\\\mathrm{Nb}} = 54$ $\\\\mathrm{Wm^{-1}K^{-1}})$ for all grey pixels and thermal conductivity of air $(\\\\kappa_{\\\\mathrm{Air}} = 0.1~\\\\mathrm{Wm^{-1}K^{-1}})$ for all black pixels. We also define the local densities, $\\\\rho_{\\\\mathrm{local}}(x,y)$ , and local specific heat capacities, $C_\\\\mathrm{p}$ , $\\\\mathrm{local}(x,y)$ , using similar equations as Eq. 1. We choose $\\\\rho_{\\\\mathrm{Air,Nb}} = \\\\{1.225,8570\\\\}~\\\\mathrm{Kgm}^{-3}$ and $C_\\\\mathrm{p}^{\\\\mathrm{Air,Nb}} = \\\\{1008,260\\\\}~\\\\mathrm{JKg^{-1}K^{-1}}$ , respectively. However, the heat flux distribution is primarily determined by the local thermal conductivities, as expected. The thermal properties of porous materials are commonly calculated using effective models, such as the Maxwell-Eucken model [9]. These models only take the porosity of the structure into account and do not consider the distribution of pores and their shapes to calculate thermal properties. Instead, we compute the heat flux in the coatings using image-based FEM and Fourier's law: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[535,61,890,151]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0071/b1547f8f057c3313c29a690f92449df0a7f506886215e33f3ffefa39fab472d2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[534,155,890,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0863/79384c430d4492e4f6ba6c451f866e734272f8e2817ce5c5a0a10beb56047c3d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[534,239,893,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0568/2e9a20e2f8e0135e686b17b71f30f42dc0c1dfdd4fd2860b9bedcc471dbd865d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[535,325,893,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0223/eff26f2930b9a773151638856c5d35b4ac2ea73c5696add668ade6f9aa8aadf1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[535,424,885,521]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 3. Preparation of training images: (i) BSE image. Pixel intensity distribution of BSE images (a) before and (b) after image processing; Histogram shows the number of pixel counts for different pixel intensity in a monochrome channel. Heat flux along components, (c) $Q_{x}$ , and (d) $Q_{y}$ , for applied temperature gradients. Top horizontal axes labels show heat flux values and the bottom labels show graphical domain encoding for the monochrome channels. Three channel representations of (ii) structural and (iii-iv) heat flux data. The bottom label values of (b-d) are used as color scheme of images (ii-iv). The three channels are superimposed to create RGB images. (v) Tiles extracted from RGB images are used as training images. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0960/8c0e2d57c6985b8374f711f857b645719e92eca4884bcc2f1169e79ab01e4a7a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,751,919,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathbf{q} = -d_z \\\\kappa_{\\\\mathrm{local}} \\\\nabla T$ . Here, $q$ is the heat flux along the temperature gradient $\\\\nabla T$ and $d_z = 1 \\\\mathrm{~m}$ is the thickness along $z$ direction. We only discuss the heat flux in the 2D $x - y$ plane of the coatings and report the values of $Q = q / d_z$ , in units of $\\\\mathrm{Wm}^{-2}$ . We find that the heat flux and the resulting effective thermal conductivity can be significantly different for two coatings with the same porosity but different pore distributions. Such variability cannot be captured by the effective models. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,883,918,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We assume that both the top and the bottom no-material regions are made of low thermal conductivity \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,918,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[86,65,488,455]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"material, i.e., air. We model the top region as heat source with temperature equal to $700\\\\mathrm{K}$ and the bottom region as heat sink with temperature $300\\\\mathrm{K}$ . Thus, we simulate an applied temperature bias of $400\\\\mathrm{K}$ along the top-to-bottom direction of the coatings, for all BSE masked images. We model the lateral boundaries of the simulation cells as perfect insulators. We define a rectangular grid for the FEM simulations of dimension, $p_y \\\\times p_x$ . Here $p_x$ and $p_y$ are the number of pixels along the $x$ and the $y$ directions of the images. We use an adaptive meshing scheme and carry out five refinements in COMSOL to identify a mesh grid that minimizes the $L_2$ norm of the squared error. The image function $im$ is defined on the grid and assigns the local material properties accordingly. We compute heat flux, $q$ , using these adaptive nodes and element shape functions. For each image, we iteratively solve for $q$ that satisfies the boundary conditions and local thermal conductivities. We assume $\\\\mathrm{d}_z = 1\\\\mathrm{m}$ in our calculations, thus, $Q$ have the same values as $q$ , but different units. We refer to $Q(x,y)$ as heat flux in the subsequent discussion. $Q(x,y)$ 's are defined on a rectangular grid of the same resolution as the input masked image. However, the grid is different for each image, depending on the original resolution of the experimental image and the applied transformations as described in the 'Augmentation of Training Set' section. The associated heat flux also vary significantly, as can be expected. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[86,458,488,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We show the components of heat flux along $x$ and $y$ directions in Fig. 3(c,d), respectively. The labels of the top horizontal axes show the heat flux values. We transform $Q_{x}$ and $Q_{y}$ to represent them in the graphical domain. We linearly scale $Q_{x}$ and $Q_{y}$ such that the middle $98\\\\%$ of the distribution falls in the range from 0 to 255. We assign the left and the right $1\\\\%$ of heat flux distribution to values of 0 and 255, respectively. We transform the $Q$ values using the following equations: $Q_{x} = Q_{x} / 10^{6} \\\\times 173 + 127$ ; $Q_{y} = Q_{y} / 10^{6} \\\\times 153 + 255$ . We obtain these equations by assigning the bounds of the middle $98\\\\%$ of the $Q$ -distributions to graphical encoding values. The bottom axes labels of Fig. 3 (c,d) correspond to the graphical domain encoding for the monochrome channels. Note that the FEM simulation domains have horizontal reflection symmetry. We leverage this aspect and obtain results for 99 additional images by horizontally reflecting the FEM-generated heat flux $Q(x,y)$ [W/m²]. In the reflected images, the $(x,y)$ values are flipped horizontally and the magnitudes of $Q_{x}$ change sign, however, the magnitudes of $Q_{y}$ stays the same. Thus, we obtain data for 198 images from the 99 FEM calculations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[165,823,406,835]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Preparation of Training Images \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[83,854,488,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We superimpose structural images and the corresponding heat flux maps into three-channel RGB images. The R, G, and B channels are the graphical encoding of $Q_{y}$ , $Q_{x}$ , and the structural images, as shown in Fig. 3(d), (c) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[555,63,879,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0168/32cde9c46d3f8ca4011ac6f65a549e72e4492b64a32db19ca1fe0b0db98c2d42.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[555,300,875,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 4. Schematic of the FluxGAN model workflow. Model architecture consists of (i) a generator, and (ii) a discriminator. (iii) Large-size images are generated by learning spatially extensible representations living in a latent space. Images in the first and the second columns are produced by varying global latent and styles respectively. Top, middle, and bottom images correspond to the green, red, and blue boxed regions in the implicit image (i), respectively. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0708/52b0f3437ea20aa53ac27c5cfe98d24a2943840f44a32d4961d0d3f1158b80fc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[511,811,919,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and (b), respectively. We train the FluxGAN model on the relationship between the structural features of the coatings and the associated thermal properties. To this end, we create a training set by uniformly sampling overlapping square tiles of size $17.4\\\\mu \\\\mathrm{m} \\\\times 17.4\\\\mu \\\\mathrm{m}$ ( $64\\\\mathrm{px} \\\\times 64\\\\mathrm{px}$ ) from the RGB images. We split each RGB image into $19 \\\\times 13$ overlapping tiles and create a training set \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,918,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[81,65,491,196]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"that includes 48,906 ( $= 198 \\\\times 19 \\\\times 13$ ) RGB images. Figure 3(v) shows representative square tiles included in the training set. Each image is represented by an array of numbers. The dimension of the array is the height times the width of the tile, times the number of channels in the image: $64\\\\mathrm{px} \\\\times 64\\\\mathrm{px} \\\\times 3$ . The array elements are pixel intensities in the range from 0 to 255, that correspond to the graphical encoding of the heat flux maps and the structural images. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[161,228,413,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Unsupervised Learning of Styles \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,261,491,666]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We train the FluxGAN model using square $64\\\\mathrm{px} \\\\times 64\\\\mathrm{px}$ RGB patches, as discussed in the previous section. GAN models can learn from small patches and successfully generate new large-size images. However, the reconstruction of large scale holistic images can be challenging. For example, techniques such as consecutive image outpainting can result in discontinuous and repetitive structures [13, 14]. Several models have been proposed recently that can generate large images but they fail to maintain a global coherence in the generated images [15-17]. The recently proposed InfinityGAN approach has shown a superior ability to generate holistic large-size images after being trained on small patches [18]. The generated images show a great diversity and continuity along all spatial directions. We implement the InfinityGAN approach in our FluxGAN model to generate large coating images, learning from small patches. The approach generates large holistic images, also known as implicit images, with diverse local features. The InfinityGAN architecture adopts functionality from StyleGAN2 [6], which the FluxGAN model leverages to learn the different styles or the textures of the images, in an unsupervised manner. InfinityGAN synthesizes images of arbitrarily large-size by learning spatially extensible representations living in a latent space. The latent space is encoded by a global latent vector that guides the holistic layout of the infinite-pixel image, and a local latent tensor that expresses structural variations of small region patches. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,667,491,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We show a schematic of the FluxGAN model workflow in Fig. 4. The model consists of a generator that learns to generate plausible images (Fig. 4(i)), and a discriminator that learns to distinguish the generated fake images from real images (Fig. 4(ii)). The generator consists of two modules, a structure and a texture synthesizer. The structure synthesizer is a neural implicit function [19-22], that takes three sets of inputs: a global latent variable, a local latent variable and a continuous coordinate that samples the sub-regions of the implicit image. The texture synthesizer is a fully convolutional StyleGAN2 model [6], with all positional information removed. In addition to the same three inputs, a set of randomized noises are provided as input to the texture synthesizer, to model variations of fine-grained texture within the local structural representations. A mapping layer projects global latent onto a texture style vector, and the tex \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[537,75,658,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(i) 1 Style \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0032/ab8929e957498c373c16877635e48542e421472e8f4a7f1cd1977166f91ade06.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[658,75,774,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0464/30de1b08b7e2b18271fc61825a5ceaab8b7e052fab4c7ffee263cdc36370c8c7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[777,75,895,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"-280μm 1024px \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0784/1025c636fd856b634a4667ce8bde604627509cae7b0e56586e25a26a4249c05b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[539,181,658,272]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(ii) 2 Styles \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0961/97d2f33c8ce63f003755a137f2115da9a1fab70794776258c1cc7a6702f53434.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[658,167,776,272]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0121/5e35fcb255d74220a0970bee870248933c0e777fc181e88471272c94405f9f9b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[777,167,895,272]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0915/06513a1e36028f1182223ef043f261af450ec9f4f0660f2b4d82916ce784a443.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[539,287,658,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(iii) 3 Styles \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0778/18182db05e6273ebcea225ce6a0b8ddfb1a12683edcadb0818227b822efe7324.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[658,273,776,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0622/75acfef2ec5e1c00ae7164b0e803c418bc676805574969138c86fb8f6bc0f2e7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[777,273,895,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0157/dae4db6acaf5050bace87adc32736e99a1d9c7dee79405df06e1baef1a48c117.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[539,393,658,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(iv) 6 Styles \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0814/bfd2da93fafc42c483ec246230eb5e2444ac8045f89e04c3c581023a4f36f83e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[658,393,776,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0222/c84f8d6d3537960f58e4c5ead2df5fb015a442d5962f1eda51217433390637e0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[777,380,895,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 5. Representative input maps and output images of the FluxGAN model. The first column shows input maps and the second and the third columns show two representative images generated by the model for each input map, respectively. Increasing the number of styles and varying their spatial arrangement affects both the overall appearance and the local diversity of the generated images. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0894/a9fa17c8def1905d615ee9dfdb4a60a2c8e84acd68db0b6cba3d9b095682f724.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,637,919,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ture style is injected into all pixels in each layer of the global image via feature modulation. Similar to InfinityGAN, the model uses 256 and 512 dimensions for local and global latent vectors, respectively, for unsupervised learning of structure and texture variations. We use coordinate grid to specify the location of the local structural patches to be sampled. We use sine functions with period $T = 56$ to sample both $x$ and $y$ directions of the local latents. Our training dataset includes $64\\\\mathrm{px} \\\\times 64\\\\mathrm{px}$ RGB image tiles, as mentioned previously. However, the model does not know the positioning of these $64\\\\mathrm{px} \\\\times 64\\\\mathrm{px}$ tiles in the global image. To address the issue, the model uses smaller $37\\\\mathrm{px} \\\\times 37\\\\mathrm{px}$ patches and learns to coordinate the patches relative to each other, during training. We use the same architecture of the discriminator as implemented in StyleGAN2. The schematic of the discriminator workflow is shown in Fig. 4(ii). The discriminator compares generated $37\\\\mathrm{px} \\\\times 37\\\\mathrm{px}$ patches with those included in the training set images. We assess the quality \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,918,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[81,65,490,125]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of images created by the model during training and find that the model achieved the smallest value of the Fréchet inception distance (FID) metric [23] of 2.64 after 660,000 training steps. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,125,490,690]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 4(iii) shows representative output images that are generated based on single-style input maps. The input maps determine the different latent variables and drive the generation of the environments. Since the inputs are single-style maps, the model uses a single latent vector and generates all the regions of the microstructure. We vary the latent vector and compare the generated images, to examine the information encoded in the latent space. We obtain three sets of global latent vectors by using different random sampling from a unit Gaussian distribution. We use the three different latent vectors and keep all other variables (e.g., coordinates and styles) fixed, to obtain the three images shown in the first column of Fig. 4(iii). The structural environments of the images vary significantly when we change the global latent variables. The images show different regions of the coatings, such as the microstructure or the surface and air regions. Together the top surface, material, and bottom surface images constitute the large coating images. The images are representative of the regions marked with green, red, and blue boxes in Fig. 4(i). It is interesting to note that the heat flux patterns across the images appear similar in magnitude, especially in regions away from the pores. For each choice of the global latent, we vary the styles and obtain the images shown in the second column of Fig. 4(iii). The structural environments remain very similar between the set of images shown in each row, however, the magnitudes of the heat flux are varied. This result implies that the global latent variables encode the environment (e.g., structure) and the styles are highly related to the physical phenomenon of interest (e.g., heat flux maps). This insight can offer great practical advantage. For example, styles can inform changes of heating conditions or reveal strategies to design structural features such that heat flux can be guided away from sensitive regions of the microstructures. Thus, FluxGAN model trained on style-based descriptions offers great practical advantage for designing microstructures that satisfy target thermal properties. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,718,380,732]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"GENERATION PHASE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,750,370,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Unguided Generation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,782,490,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 5 shows representative inputs (first column) and the corresponding images generated as output of the model (second and third column). The model input specifies the overall height and width of the image, the types and the number of styles, the spatial positioning of styles, and merging functions to obtain smooth interfaces between the regions. We show visual representations of the four input maps with different spatial arrangements of styles, in the first column of Fig. 5(i-iv). The input \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[535,61,898,599]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 6. Comparison of structural features of generated (blue) and experimental images (red). We show the mean dependency (solid lines) and the range (shaded regions) for the chord-length distribution and the two-point correlation functions, in the second and the third column, respectively. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0432/43f3bc2213ab3781245655f6223f7880d09c4cd152ab568a1baf61f6d6ceb407.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,724,919,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"maps include one, two, three, and six randomly chosen styles, respectively. Note that the number of styles determines the global latent variables, and consequently, the overall appearance of the generated coating images, which is consistent with InfinityGAN spatial style fusion implementation. The images shown in the second and the third column of Fig. 5(i-iv) highlight the structural diversity in generated images for same input maps. We select $540~1024\\\\mathrm{px}\\\\times 1024\\\\mathrm{px}$ images generated with single-style and $50~512\\\\mathrm{px}\\\\times 512\\\\mathrm{px}$ images generated with each multi-style input map, and validate against experimental images using the procedure discussed in the following section. Although we show structural images in Fig. 5, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,918,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[81,65,488,109]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the model outputs are RGB images that contain both structural and heat flux information. We only show the structural channel for the ease of discussion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[145,142,426,156]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Validation of Structural Information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,175,490,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We compare the structural features of the generated images with those of the experimental BSE images. We analyze three features: pore size distribution, chord-length distribution, and two-point correlation functions. Figure 6(i-iv) shows the comparison between the features of the experimental images and the images generated from one, two, three and six styles input maps, respectively. The first column shows the density of pores of given area, defined by the ratio between the number of pores with the specific area and the total number of pores. We calculate the pore sizes by counting the number of black pixels inside each pore. The presence of the black pores enclosed within the gray material region can be particularly noted from the experimental image shown in Fig. 2(ii). The smallest pore is of size $1\\\\mathrm{px} \\\\times 1\\\\mathrm{px} \\\\sim 0.07\\\\mu \\\\mathrm{m}^2$ . This size pores are the highest in number in the coatings as can be noted from Fig. 6(a,d,g). This could be a systematic artifact of the images. Overall, the density of different size pores in all four classes of images match with those in the experimental images. This implies that the model is able to produce the anisotropic pore distributions characteristic of the original thermal spray coatings shown in the BSE images. The porous coatings include numerous interfaces between the material phases and the pore phases. If an imaginary line is drawn in the porous medium, the line will intersect multiple material-pore interfaces. The lengths between these intersections are referred to as chord lengths in the respective phases. The chord length distribution function is then defined by the probability of finding a chord of given length in one of the phases [24, 25]. These functions provide a quantitative measure of the structure of the porous media. The second column of Fig. 6 shows the comparison of the chord-length distributions in material phases of experimental (red lines) and generated images (blue lines). The solid and the dashed lines represent the chord-length distributions in the $x$ and $y$ direction, respectively. The results show that there is higher probability of finding longer chords in the $x$ direction compared to the $y$ direction in the images. This corresponds to the presence of layer-like features that can be noted from the experimental images, as shown in Fig. 2. The layer-like structures form along the vertical ( $y$ ) direction when the droplets of melted material are sprayed in a regular interval during the thermal spray process. We show the comparison between the spatial two-point correlation functions in the third column of Fig. 6. The spatial correlation function between two points $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ is defined as $\\\\langle f(\\\\mathbf{x} + \\\\mathbf{r}_1)f(\\\\mathbf{x} + \\\\mathbf{r}_2)\\\\rangle$ [25, 26], where and $\\\\langle .\\\\rangle$ indicates a volume average over the spatial coordinate $\\\\mathbf{x} = (x,y)$ . The characteristic function $f(\\\\mathbf{x})$ is either zero \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[535,61,895,377]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0949/14da7258b29b17203f85953c4315225792c6855f6971fa7326da210f8d68efa9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[535,377,684,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0220/7451bbd2e4061937993b79a674e090ae1e3987f53f8189213f9803060b6f69ff.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[535,505,684,631]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0607/bc4866d20fdaeaccc2e0a876dc4b60c7f51dd1b83e662697bbe0fd76e2b6e66d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[686,377,893,560]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0806/4cb62aee055efc2b4fc478fe6f0bf3b499aeae9fc0646cd48e09feb9fefeb806.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[686,560,895,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 7. Comparison of generated heat flux (blue) and FEM results (red). (i) Full size generated image with single-style input map. Average generated heat flux (blue) along (a) horizontal and (b) and vertical directions, and compared to FEM results (red). Selected red boxed region is enlarged for comparison between (ii) generated and (iii) FEM results. (iv) (a) Structural and (b-c) heat flux pixel intensity distributions of 540 similarly generated images. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0560/5600decd01547f0f92e7890cae544ca26ad20666da38a89a091e57c283170181.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,811,919,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"or one if the point lies in the material or the pore phase. We note a close match between the two-point correlation functions for all four cases. The result for the image generated with the six-style-input map is the closest to the one observed in BSE images. This can be attributed to the higher diversity of microstructures present in the images generated with six-style-input maps. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[906,34,918,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[106,63,460,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 8. Image outpainting with holistic heat flux distribution as input. (i) Bottom air region (green box) is supplied as input. (ii) Outpainted image (left) and corresponding FEM results (right). (iii) Interface region of (ii). (iv) (a) Horizontal and (b) vertical averages of generated (blue) heat flux in input region, compared to input (green) and FEM results (red). MAEs for ML-INPUT (blue) and ML-FEM (red) comparisons reported for microstructure shown in (ii). MAEs averaged over seven systems are shown in parentheses \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0818/41e5e4d6abed40303d607cd1f6c44869222371effe1829f19e20a5efc6d88f40.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[612,66,821,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Heat Flux Data Validation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,103,919,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We validate the heat flux of the generated coatings against values computed with FEM for the same microstructures. It is essential that the structural environments and the applied heating conditions of the FEM models are similar to those of the generated coatings. As we illustrate in the above sections, we generate coatings with input maps that include spatial arrangement of random choice of styles. The styles are closely associated with the heat flux patterns in different regions of the coatings. The coatings generated with different input maps not only show highly variable heat flux in the microstructures but also different heating conditions in the surface regions. The heating conditions in coatings generated with arbitrarily chosen input maps may not be consistent with the fixed heating conditions imposed in the FEM models. As we discuss in the \\\"Computation of Thermal Properties\\\" section, we simulate a temperature bias of 400K to compute heat flux in all the BSE masks using FEM. To maintain similar heating conditions in generated structures and the FEM models, we provide only single-style-maps as input and generate coating images. We find that the trained FluxGAN model is able to generate full coating images that include material and air regions from sufficiently large $(1024\\\\mathrm{px} \\\\times 1024\\\\mathrm{px})$ single-style-maps. We show an example generated microstructure and the associated heat flux in Fig. 7(i). The yellow vector arrows represent the resultant of the horizontal $(Q_x)$ and the vertical $(Q_y)$ heat flux components. We produce masked images from the generated structural channel and compute the heat flux through the masked images using FEM calculations. We compute the average heat flux along the horizontal and the vertical directions of the coatings from the $Q_x$ and $Q_y$ values of the 1024 pixels of the square image. We show the comparison between the average generated (blue) and FEM-obtained (red) heat flux along the horizontal and the vertical directions, in Fig. 7(i)(a) and (b), respectively. The generated heat flux is in good agreement with FEM results, with mean absolute errors (MAE) of $0.009 - 0.012\\\\mathrm{MW/m^2}$ for $Q_x$ and $0.013 - 0.020\\\\mathrm{MW/m^2}$ for $Q_y$ components, respectively. Note that the average $Q_x$ is approximately zero and the average $Q_y$ is always negative. The $Q_y$ components have a dominant contribution to the overall heat flux, since we assume that the temperature gradient is applied along top-to-bottom (negative $y$ ) direction. We show an enlarged image of the $100\\\\mathrm{px} \\\\times 100\\\\mathrm{px}$ red boxed section within the large $1024\\\\mathrm{px} \\\\times 1024\\\\mathrm{px}$ in Fig. 7 (ii). The corresponding masked image and the FEM result in shown in Fig. 7 (iii). The close match between the heat flux patterns can be particularly noted from the two images. We analyze $5401024\\\\mathrm{px} \\\\times 1024\\\\mathrm{px}$ images generated with single-style-input maps. We show the pixel intensity distributions for the three channels in these 540 generated images in Fig. 7(iv). The distributions show high diversity and are consistent with those in the training set, see Fig. 3(b-d). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[898,34,919,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[210,66,361,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Guided Generation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[86,99,488,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Here, we illustrate how our FluxGAN model provides an expedited approach to design new coatings with target thermal properties. In the conventional approach for designing new coatings, one typically fabricates the coatings and then estimates the physical properties using experiments or computational modelling. The process is repeated till the fabricated microstructures satisfy target physical properties, as we outline in Fig. 1(ii). In contrast, the FluxGAN model directly guides the inverse design of coatings that satisfy target thermal properties. Given a target thermal property, the model generates rational designs of new microstructures that satisfy the properties. We demonstrate the targeted generation approach in Fig. 8. We provide the model with the description of physical phenomena in a particular region, e.g., the heat flux near the heat sink, indicated by the green boxes in the images of Fig. 8(i). The model input is a single $80\\\\mathrm{px} \\\\times 587\\\\mathrm{px}$ RGB image that we extract from one of the $410\\\\mathrm{px} \\\\times 587\\\\mathrm{px}$ images. The input image only contains information about the heat flux in the boxed air region where no material is present, referred to as $Q$ INPUT. The model uses outpainting technique to generate the microstructure, the top air region, and the associated heat flux ( $Q$ ML) throughout the large $400\\\\mathrm{px} \\\\times 587\\\\mathrm{px}$ size images. We show the resulting images in Fig. 8(i-ii). The model uses GAN inversion [27-32] to find the latent variables that match the input image and conditional coordination to independently generate spatially consistent micro-patches [17]. Note that the model is capable of generating different coating images shown in Fig. 8(i-ii), when supplied with the same input image. This is possible by selecting different latent variables during outpainting procedure. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[86,580,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, we calculate the heat flux associated with the generated microstructures using FEM, $Q$ FEM, for the same temperature bias of $400\\\\mathrm{K}$ . We show an outpainted image and the corresponding FEM results for the masked image in the left and the right columns of Fig. 8(ii), respectively. We show the comparison between $Q$ INPUT (green), $Q$ ML (blue) and $Q$ FEM (red) in Fig. 8(iv). Figure 8 (iv)(a) and (b) show the average horizontal and vertical heat flux, computed from the $Q_{x}$ and $Q_{y}$ values of the 80 and 587 pixels of the input region, respectively. The shaded regions represent the range of heat flux values observed in all seven generated images. The MAEs represent the average absolute distance between the two plotted dependencies. The FluxGAN generated heat flux match with $Q$ INPUT and FEM results, with great accuracy. The errors range from 0.003 to $0.01\\\\mathrm{MW / m}^2$ for all the results, or around $2\\\\%$ of the average heat flux value in the input region. The $Q_{y}$ components have a dominant contribution to the overall heat flux, compared to $Q_{x}$ . This is expected since we assume that the temperature gradient is applied along top-to-bottom $(y)$ direction. The $Q_{y}$ ML values show larger deviation at the boundaries since the FluxGAN model is unaware of in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[535,63,893,369]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0103/4bef010db61535822f3f3095465bae1f217aa85f7a4b72697cc1f0cf8a632d64.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[535,383,890,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Width: $160\\\\\\\\mu m$ 587px, Height: $109\\\\\\\\mu m$ 400px \\\",\\\"(iv) $Q_{x}$ ML $Q_{y}$ ML $\\\\\\\\equiv \\\\\\\\cdot Q_{x}$ INPUT \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0130/027c0a24f23543b53e0b0814e5ad25422d73ca35a61ebe722107713f0c520670.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[535,460,893,587]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1006/6b3e5949a40a825260d4c7d05e164055d2596109abc8a24a06d63a27180e4ae7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[537,587,888,704]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 9. Image outpainting with artificially constructed heat flux distribution as input. (i) Input image. (ii) Example outpainted images (left) and corresponding FEM results (right). (iii) Interface region of representative image shown in (ii). (iv) (a) Horizontal and (b) vertical averages of generated (blue) heat flux in input region, compared to input (green) and FEM results (red). MAEs for ML-INPUT (blue) and ML-FEM (red) comparisons reported for bottom microstructure of (ii). Average MAEs of the three systems are shown in parentheses. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0097/b1433eab28463406042a2670dd0f3aeb4cbca7f6064e72b96014eceb97a99a52.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[898,34,916,45]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[81,65,491,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"sulating boundary conditions while the FEM results are obtained using this restriction. We marked three points of interest in the interface region with magenta circles, as shown in Fig. 8(iii). These points represent the location of the cusps at the bottom material-air interface and are next to dips at the surfaces. They are closest to the heat sink, as can be noted by following the thin green line that marks the top boundary of the input region. The heat flux arrows at this locations (Fig. 8(iii)) indicate that the heat is being guided sideways from the cusps, with the magnitudes being the highest among all values in the bottom air region (Fig. 8 (iv)(b)). Such characteristic heat flux patterns are associated with the different color environments around these points in all the input green boxed regions of Fig. 8(i). Consequently, similar cusp points can be noted from all generated microstructures of Fig. 8(i) and (ii). The common presence of these points in all generated microstructures refer to the fact that they all are rational designs that satisfy the target input heat flux. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,356,491,777]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To further challenge the FluxGAN model, we test its ability to generate images for an artificially constructed input. We construct the input image by periodically extending the red-boxed $80\\\\mathrm{px} \\\\times 80\\\\mathrm{px}$ region marked in the top panel of Fig. 9(i). The full panel shows the resulting input image of size $80\\\\mathrm{px} \\\\times 587\\\\mathrm{px}$ . We show three outpainted images and the corresponding FEM results in Fig. 9(ii). We show the comparison of the average horizontal and vertical heat flux, computed from the $Q_{x}$ and $Q_{y}$ values of the 80 and 587 pixels of the input region, in Fig. 9(iv)(a) and (b), respectively. The shaded regions represent the range of heat flux values observed in three different images. The periodic nature of heat flux can be particularly visible from the average vertical heat flux, shown in Fig. 9(iv)(b). The FluxGAN generated heat flux match with $Q$ INPUT and FEM results, with great accuracy. The MAEs of the FluxGAN results range from 0.002 to $0.011\\\\mathrm{MW/m^2}$ when compared with the INPUT and from 0.007 to $0.012\\\\mathrm{MW/m^2}$ when compared with the FEM results, respectively. Average vertical heat flux agrees with the FEM results in the input region within $3\\\\%$ error margin. These results demonstrate that the model is able to generate rational microstructures that best fit the criterion imposed by the input image. Note that the generated microstructures are highly diverse away from the periodic input region and do not show any visible repetitions. The diversity of generated images indicates that the model provides multiple designs of microstructures to satisfy target conditions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[127,808,444,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Extension to Three-Dimensional Domain \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,840,490,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although our study primarily focuses on 2D microstructures, here we discuss how we can leverage the FluxGAN model to generate 3D microstructures with high structural diversity. GANs can be trained to generate 3D volumes, which are useful for design optimization \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,65,921,559]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and detailed analysis of structural features and physical processes [4, 33, 34]. These models can be used for rapid generation of complex 3D structures over conventional approaches. A recent article used a bounded random walk algorithm to generate an interface, followed by seeding of random size particles to produce a two-phase material, resulting in large $128\\\\mathrm{px} \\\\times 10000\\\\mathrm{px}$ images. The images were used to train SliceGAN [33] algorithm and output 3D configurations. However, the lack of diversity in such approach allows the generator to trick the discriminators, resulting in unrealistic 3D representations. We demonstrate that this issue can be resolved by training the GAN models with images that include both structural and physical phenomena information. We propose a combined approach that implements both the FluxGAN and the SliceGAN algorithms to generate complex 3D microstructures and associated heat flux environments with high diversity. The SliceGAN approach generates a volume by assimilating 2D slices, each of which is refined to match the training set images. However, a large number of diverse 2D images is required for successful training, especially to generate complex, anisotropic 3D materials with high density of interfaces. We leverage the FluxGAN model to generate two large $64\\\\mathrm{px} \\\\times 320000\\\\mathrm{px}$ images ( $17.4\\\\mu \\\\mathrm{m} \\\\times 8.7\\\\mathrm{cm}$ coatings) for the surface and the material regions. We make random selections of $64\\\\mathrm{px} \\\\times$ $64\\\\mathrm{px}$ patches from the generated images and pass them to two perpendicular discriminators of SliceGAN. Figure 10(i) and (ii) show two perpendicular RGB slices for the surface and the material regions, respectively. Note that the heat flux components (red and green channels) are continuous across the two perpendicular slices and the blue channel produces matching structure in both the perpendicular planes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,566,921,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The objective of the generator of the SliceGAN model is to generate realistic volumes in which the 2D slices along $X$ and $Y$ directions pass the discriminator test. Note that the outputs from the generator include information in five channels: [BSE, $Q_{X}$ , $Q_{Y}$ , $Q_{X}^{\\\\perp}$ , $Q_{Y}^{\\\\perp}$ ]. The first channel contains structural information as learned from the experimental BSE images. The other two sets of channels include heat flux data. $(Q_{X}, Q_{Y})$ and $(Q_{X}^{\\\\perp}, Q_{Y}^{\\\\perp})$ refer to the heat flux components of the two perpendicular slices, represented in graphical domain. The generated information is passed to the two discriminators. Each of the two perpendicular discriminators receives three-channel RGB images and share a common structural channel (BSE). However, each discriminator receives a separate set of heat flux data, $(Q_{X}, Q_{Y})$ or $(Q_{X}^{\\\\perp}, Q_{Y}^{\\\\perp})$ . The model assimilates 64 slices in each of two perpendicular directions to produce $64 \\\\times 64 \\\\times 64$ voxel volumes, as shown in Fig. 10(iii) and (iv). For the generated 3D microstructures, we obtain the heat flux along the $Z$ -direction, $Q_{Z}$ , by averaging the vertical heat flux components $Q_{Y}$ and $Q_{Y}^{\\\\perp}$ obtained from both discriminators. The resulting volumes have a four-channel representation: [BSE, $Q_{X}$ , $Q_{X}^{\\\\perp}$ , $Q_{Z}$ ]. Finally, the SliceGAN model outputs two representative 3D con \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[898,34,919,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,63,875,232]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 10. Microstructure representation in 3D domain. Two discriminators are implemented to test perpendicular RGB image slices for (i) surface and (ii) material regions. Representative volumes generated for (iii) surface and (iv) material regions with superimposed heat flux. (v) Two representative 3D microstructures generated by combined FluxGAN-SliceGAN approach. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0629/4b509e3f770b93293fc5c71012e085a7c9ceb831f0dce7e5b111c9608181bc7a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,328,488,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figurations of size $64 \\\\times 400 \\\\times 400$ voxels using the generated volumes, as shown in Fig. 10(v). The resultant microstructures shows great structural diversity in both the surface landscape as well as the cross section of inner material region, which are not accessible in the experimental and training images. The combined FluxGAN-SliceGAN approach shows remarkable ability to infer 3D representation of microstructure and associated physical phenomenon from a single 2D image. We attribute the high quality of the representation to both large size of the training image and the heat flux data included in the image channels. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[166,532,405,546]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUMMARY AND OUTLOOK \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,566,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We propose a generative ML model, FluxGAN, capable of generating arbitrary large images of microstructures and associated heat flux data. The model generates the information about heat flux that will be observed within the microstructures and the outside heat source or sink regions, if temperature gradients are applied externally. We train the model with RGB images in which the different color channels contain graphical domain representation of structural information from experimental images and heat flux data obtained from FEM calculations. In these images, the information about the structural features are superimposed with heat flux patterns that correspond to the structural features. During training, the model learns about the different combinations of structural features and heat flux patterns, referred to as styles, in an unsupervised manner. Once trained, the model generates large images for given inputs maps that specify spatial distribution of styles to be included in the output images. The generated microstructures show high diversity and include structural features that have characteristics similar to those present in the experimental images. We compare the generated heat flux with the results from separate FEM analyses on the corresponding generated microstructures. The FluxGAN generated \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,328,919,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"heat flux show good agreement with FEM results. Furthermore, we demonstrate that the image generation can be guided by providing partial information to the model. We provide the model with the heat flux near the bottom heat sink region. The model shows remarkable ability to generate large microstructures, heat source regions and associated heat flux that are consistent with the input. The generated heat flux values lie within $3\\\\%$ of those obtained with separate FEM simulations. Thus, our FluxGAN model offers an expedited approach for inverse design of microstructures with target thermal properties. The images show high structural diversity as well. We illustrate that the FluxGAN generated images can be leveraged to produce complex 3D microstructures, in combination with the SliceGAN architecture. We generate 0.1 meter long continuous and structurally diverse 2D structural images and their associated heat flux environment, to construct the 3D representations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,589,919,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In conclusion, FluxGAN offers fast, inexpensive, and reliable approach for design and analysis of 2D and 3D microstructures. The model is capable of generating arbitrary large environments with constant computation cost. This aspect is particularly advantageous over the FEM approach where memory usage scales linearly with the number of degrees of freedom. Our approach is general and can be extended to any continuous physical phenomena represented in graphical domain. The ability of the model to render arbitrary large environments while trained on small size patches offers great practical advantage. For example, the model will be highly effective in providing description of physical phenomena at the micro-meso or even macro scale, or guiding characterization and fabrication of complex devices, such as micro-electronic chips with extreme design points. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[624,852,807,864]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DATA AVAILABILITY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,883,918,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare that the data supporting the findings of this study are available within the paper and its \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[898,34,919,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[181,109,392,123]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGEMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,141,490,316]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We are indebted to Dr. M. R. Kracum for providing us with the two-dimensional backscatter electron images of the niobium thermal sprayed coatings, sharing valuable insights regarding the outstanding challenges of thermal spray coatings, and several helpful discussions. We gratefully acknowledge funding from the research partnership initiative between the College of Engineering & Applied Science at the University of Colorado Boulder and the DOE-Sandia National Laboratories, Albuquerque, NM. This work utilized the Summit supercomputer, which is supported by the National Science Foundation (awards ACI-1532235 and ACI-1532236), the University of Col \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,65,921,111]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Orado Boulder, and Colorado State University. The Summit supercomputer is a joint effort of the University of Colorado Boulder and Colorado State University. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[596,137,836,150]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHOR CONTRIBUTIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,167,919,241]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A.K.P and M.S. contributed to the acquisition and the analysis of data and the creation of new scripts used in the study. S.N. contributed to the conception and the design of the work, the interpretation of data, drafting and revision of the article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[606,268,826,282]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COMPETING INTERESTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,301,831,316]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare no competing interests. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[86,369,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] L. Yang, D. Zhang, and G. E. Karniadakis, Physics-informed generative adversarial networks for stochastic differential equations, SIAM Journal on Scientific Computing 42, A292 (2020). \\\",\\\"[2] C. Jiang and A. B. Farimani, Deep learning convective flow using conditional generative adversarial networks, arXiv preprint arXiv:2005.06422 (2020). \\\",\\\"[3] H. Jiang, Z. Nie, R. Yeo, A. B. Farimani, and L. B. Kara, StressGAN: A generative deep learning model for two-dimensional stress distribution prediction, Journal of Applied Mechanics 88 (2021). \\\",\\\"[4] T. Hsu, W. K. Epping, H. Kim, H. W. Abernathy, G. A. Hackett, A. D. Rollett, P. A. Salvador, and E. A. Holm, Microstructure generation via generative adversarial network for heterogeneous, topologically complex 3d materials, Jom 73, 90 (2021). \\\",\\\"[5] P. C. Nguyen, N. N. Vlassis, B. Bahmani, W. Sun, H. Udaykumar, and S. S. Baek, Synthesizing controlled microstructures of porous media using generative adversarial networks and reinforcement learning, Scientific reports 12, 9034 (2022). \\\",\\\"[6] T. Karras, S. Laine, and T. Aila, A style-based generator architecture for generative adversarial networks, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2019) pp. 4401-4410. \\\",\\\"[7] X. Huang and S. Belongie, Arbitrary style transfer in real-time with adaptive instance normalization, in Proceedings of the IEEE international conference on computer vision (2017) pp. 1501-1510. \\\",\\\"[8] T. Karras, M. Aittala, J. Hellsten, S. Laine, J. Lehtinen, and T. Aila, Training generative adversarial networks with limited data, Advances in neural information processing systems 33, 12104 (2020). \\\",\\\"[9] J. Wang, J. K. Carson, M. F. North, and D. J. Cleland, A new approach to modelling the effective thermal conductivity of heterogeneous materials, International journal of heat and mass transfer 49, 3075 (2006). \\\",\\\"[10] S. Gurumurthy, R. Kiran Sarvadevabhatla, and R. Venkatesh Babu, Deligan: Generative adversarial networks for diverse and limited data, in Proceedings of the IEEE conference on computer vision and pattern \\\"]\",\n \"page_idx\": \"13\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[514,369,919,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"recognition (2017) pp. 166-174. \\\",\\\"[11] I. Gulrajani, F. Ahmed, M. Arjovsky, V. Dumoulin, and A. C. Courville, Improved training of wasserstein gans, Advances in neural information processing systems 30 (2017). \\\",\\\"[12] C. Multiphysics, Introduction to comsol multiphysics (R), COMSOL Multiphysics, Burlington, MA, accessed Feb 9, 32 (1998). \\\",\\\"[13] R. Abdal, Y. Qin, and P. Wonka, Image2StyleGAN++, How to edit the embedded images?, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2020) pp. 8296-8305. \\\",\\\"[14] A. Liu, R. Tucker, V. Jampani, A. Makadia, N. Snavely, and A. Kanazawa, Infinite Nature: Perpetual view generation of natural scenes from a single image, in Proceedings of the IEEE/CVF International Conference on Computer Vision (2021) pp. 14458-14467. \\\",\\\"[15] T. R. Shaham, T. Dekel, and T. Michaeli, SinGAN: Learning a generative model from a single natural image, in Proceedings of the IEEE/CVF international conference on computer vision (2019) pp. 4570-4580. \\\",\\\"[16] A. Shocher, S. Bagon, P. Isola, and M. Irani, InGAN: Capturing and retargeting the\\\\\\\"dna\\\\\\\" of a natural image, in Proceedings of the IEEE/CVF International Conference on Computer Vision (2019) pp. 4492-4501. \\\",\\\"[17] C. H. Lin, C.-C. Chang, Y.-S. Chen, D.-C. Juan, W. Wei, and H.-T. Chen, COCO-GAN: Generation by parts via conditional coordinating, in Proceedings of the IEEE/CVF international conference on computer vision (2019) pp. 4512-4521. \\\",\\\"[18] C. H. Lin, H.-Y. Lee, Y.-C. Cheng, S. Tulyakov, and M.-H. Yang, InfinityGAN: Towards infinite-pixel image synthesis, arXiv preprint arXiv:2104.03963 (2021). \\\",\\\"[19] J. J. Park, P. Florence, J. Straub, R. Newcombe, and S. Lovegrove, DeepSDF: Learning continuous signed distance functions for shape representation, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2019) pp. 165-174. \\\",\\\"[20] L. Mescheder, M. Oechsle, M. Niemeyer, S. Nowozin, and A. Geiger, Occupancy Networks: Learning 3d reconstruction in function space, in Proceedings of the IEEE/CVF \\\"]\",\n \"page_idx\": \"13\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[898,34,919,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[83,65,321,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplementary Information files. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[86,66,488,753]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"conference on computer vision and pattern recognition (2019) pp. 4460-4470. \\\",\\\"[21] B. Mildenhall, P. P. Srinivasan, M. Tancik, J. T. Barron, R. Ramamoorthi, and R. Ng, NERF: Representing scenes as neural radiance fields for view synthesis, Communications of the ACM 65, 99 (2021). \\\",\\\"[22] Y. Chen, S. Liu, and X. Wang, Learning continuous image representation with local implicit image function, in Proceedings of the IEEE/CVF conference on computer vision and pattern recognition (2021) pp. 8628-8638. \\\",\\\"[23] M. Heusel, H. Ramsauer, T. Unterthiner, B. Nessler, and S. Hochreiter, GANs trained by a two time-scale update rule converge to a local nash equilibrium, Advances in neural information processing systems 30 (2017). \\\",\\\"[24] S. Torquato and B. Lu, Chord-length distribution function for two-phase random media, Physical Review E 47, 2950 (1993). \\\",\\\"[25] S. Torquato, *Random heterogeneous materials* (Springer., 2013). \\\",\\\"[26] J. G. Berryman and S. C. Blair, Use of digital image analysis to estimate fluid permeability of porous materials: Application of two-point correlation functions, Journal of applied Physics 60, 1930 (1986). \\\",\\\"[27] A. Creswell and A. A. Bharath, Inverting the generator of a generative adversarial network, IEEE transactions on neural networks and learning systems 30, 1967 (2018). \\\",\\\"[28] F. Ma, U. Ayaz, and S. Karaman, Invertibility of convolutional generative networks from partial measurements, Advances in Neural Information Processing Systems 31 (2018). \\\",\\\"[29] R. Abdal, Y. Qin, and P. Wonka, Image2StyleGAN: How to embed images into the StyleGAN latent space?, in Proceedings of the IEEE/CVF international conference on computer vision (2019) pp. 4432-4441. \\\",\\\"[30] D. Bau, H. Strobelt, W. Peebles, J. Wulff, B. Zhou, J.-Y. Zhu, and A. Torralba, Semantic photo manipulation with a generative image prior, arXiv preprint arXiv:2005.07727 (2020). \\\",\\\"[31] J. Zhu, Y. Shen, D. Zhao, and B. Zhou, In-domain GAN inversion for real image editing, in European conference on computer vision (Springer, 2020) pp. 592-608. \\\",\\\"[32] Y.-C. Cheng, C. H. Lin, H.-Y. Lee, J. Ren, S. Tulyakov, and M.-H. Yang, InOut: Diverse image outpainting via gan inversion, in Proceedings of the IEEE/CVF Conference on Computer Vision and Pattern Recognition (2022) pp. 11431-11440. \\\",\\\"[33] S. Kench and S. J. Cooper, Generating three-dimensional structures from a two-dimensional slice with generative adversarial network-based dimensionality expansion, Nature Machine Intelligence 3, 299 (2021). \\\",\\\"[34] A. Henkes and H. Wessels, Three-dimensional microstructure generation using generative adversarial neu \\\"]\",\n \"page_idx\": \"14\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[542,66,918,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ral networks in the context of continuum micromechanics, Computer Methods in Applied Mechanics and Engineering 400, 115497 (2022). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"ref_text\"\n },\n {\n \"bbox\": \"[580,146,852,159]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUPPLEMENTARY MATERIALS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,179,919,364]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Here we discuss and compare computational costs associated with ML model generation and FEM validation. We generate a set of images using periodically extended $80 \\\\times 587$ pixels input image discussed in section Guided Generation. We build a progression of input images extending the length by up to 6 times. The resulting out-painted images have the sizes $400\\\\mathrm{px} \\\\times (\\\\mathrm{N} \\\\times 587)\\\\mathrm{px}$ , with $\\\\mathrm{N} = 1,2,3,4,5,6$ . We demonstrate convergence of FEM validation mean absolute error (MAE) for the $400\\\\mathrm{px} \\\\times 3522\\\\mathrm{px}$ outpainted image in Fig. 11(i). We show MAE for the total heat flux magnitude, namely, $Q = \\\\sqrt{Q_x^2 + Q_y^2}$ , $\\\\mathrm{MAE} = \\\\sum_{i=1}^{H \\\\times W} |Q_i^{ML} - Q_i^{FEM}| / (H \\\\times W)$ , \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,364,919,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $Q_{i}$ is the total heat flux magnitude at a given pixel, $H$ and $W$ are the height and width of an image. MAE converges quickly with the number of degrees of freedom (DoF) used for FEM calculation and saturates below $0.05\\\\mathrm{MW / m^2}$ after 1 million DoF. For the further calculations we fix DoF around that value. We also show calculation time (red solid line) and memory usage (green solid line) for FEM validation step. We observe their linear scaling with DoF. For comparison, the generation time (red dashed line) and memory usage (green dashed line) are also shown for ML model. In Fig. 11(ii) we compare ML generation and FEM calculation costs. Both FEM (red solid line) and ML (red dashed line) have similar linear time scaling with image size for the DoF fixed around 1 million. However, the memory usage is significantly higher for FEM (green solid line) compared to ML (green dashed line). We also show that MAE (blue solid line) stays consistently small (bellow $0.05\\\\mathrm{MW / m^2}$ ) for all image sizes. The highest time cost is associated with latent inversion (black dashed line). The low memory costs associated with ML are due to patch-by-path generation approach, where each patch $(37\\\\mathrm{px} \\\\times 37\\\\mathrm{px})$ is generated independently to produce large scale images. The time costs for ML generation shown here are for generating one patch at a time. This can be improved significantly since the model is capable of generating patches in batches, allowing for the highly parallelized output. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[898,34,918,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[125,61,470,333]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0985/01b6e41acb59de5e3571ae17d7c3b96d7ef7e8dae58c796bc918c04281b24bd7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[473,61,879,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 11. Supplementary Materials Computation and generation costs. (i) MAE and computational costs as a function of number of degrees of freedom for $400\\\\\\\\mathrm{px} \\\\\\\\times 3522\\\\\\\\mathrm{px}$ image. MAEs are calculated for the magnitude of heat flux. For the time (red) and memory (green) axes solid lines correspond to FEM, dashed lines correspond to ML. (ii) MAE and computational costs as a function of image length. Color lines show time (red) and memory (green) costs of FEM validation (solid) and ML generation (dashed). MAEs for heat flux magnitude are shown in blue. Latent inversion time cost is shown in black dashed line. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0284/ff44d13374aaa7dcff45c6b3a57d2d97a1a28e2fc93381feba9b405c2884b817.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[898,34,919,46]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.48550/arxiv.2310.04622"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Physics"},"sha256":{"kind":"string","value":"5bc16491c54d614198b5ac0246996b5bb5ccf415147dac325fb132c339b18b0a"},"title":{"kind":"string","value":"FluxGAN: A Physics-Aware Generative Adversarial Network Model for Generating Microstructures That Maintain Target Heat Flux"}}},{"rowIdx":154,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Ma, Chao|Li, Mingsong"},"content_list":{"kind":"list like","value":[{"bbox":"[63,79,144,158]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0800/3cfcc9935e33e61e6454ba4674611b0ece9a45b498c18114bddae97c9ffef1c6.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[373,76,611,89]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Contents lists available at ScienceDirect ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[383,107,601,124]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[334,145,650,160]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"journal homepage: www.elsevier.com/locate/gsf ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[838,66,937,160]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0940/f5ee484e19bf9151a069c92133d9ca74c88261b4175e902b0a160c41ef16456c.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,184,174,199]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Research Paper ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,206,714,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Astronomical time scale of the Turonian constrained by multiple paleoclimate proxies ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,262,273,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chao Ma $^{a,\\ast}$ , Mingsong Li $^{b}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,288,505,310]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"$^{a}$ Department of Computer Science, University of Idaho, Moscow, ID, 83843, USA \",\"$^{b}$ Department of Geosciences, The Pennsylvania State University, University Park, PA, 16802, USA \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[58,339,194,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLEINFO ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,364,213,375]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Handling editor: Wen-Jiao Xiao ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,387,109,397]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,399,141,409]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Astrochronology ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,409,176,419]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Astronomical time scale ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,419,119,430]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Uncertainty ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,431,115,440]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cretaceous ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,442,105,451]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Turonian ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,453,129,462]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Demerara rise ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[334,340,435,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ABSTRACT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[332,364,939,606]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the clocks that record the Earth history is (quasi-) periodic astronomical cycles. These cycles influence the climate that can be ultimately stored in sedimentary rocks. By cracking these (quasi-) periodic sedimentation signals, high resolution astronomical time scale (ATS) can be obtained. Paleoclimate proxies are widely used to extract astronomical cycles. However different proxies may respond differently to astronomical signals and nonastronomical noises including tectonics, diagenesis, and measurement error among others. Astronomical time scale constructed based on a single proxy where its signal-to-noise ratio is low may have uncertainty that is difficult to evaluate but can be revealed by utilizing other proxies. Here, we test eight astronomical age models using two astrochronological methods from four paleoclimate proxies (i.e., color reflection $\\mathrm{L}^*$ and $\\mathbf{b}^*$ , natural gamma radiation, and bulk density) from the Turonian to the Coniacian of the Cretaceous Period at the Demerara Rise in the equatorial Atlantic. The two astrochronological methods are time calibration using long eccentricity bandpass filtering (E1 bandpass) and tracking the long eccentricity from evolutive harmonic analysis (tracking EHA). The statistical mean and standard deviation of four age models from the four proxies are calculated to construct one integrated age model with age uncertainty in each method. Results demonstrate that extracting astronomical signals from multiple paleoclimate proxies is a valid method to estimate age model uncertainties. Anchored at the Cenomanian/Turonian boundary with an age of $93.9\\pm 0.15$ Ma from biostratigraphy, the ages for CC11/CC12 (calcareous nannofossil zones), Turonian/Coniacian (CC12/CC13), CC13/CC14, and Coniacian/Santonian boundaries are $91.25\\pm 0.20$ Ma, $89.87\\pm 0.20$ Ma, $86.36\\pm 0.33$ Ma, and $86.03\\pm 0.32$ Ma in E1 bandpass method, compared with $91.17\\pm 0.36$ Ma, $89.74\\pm 0.38$ Ma, $86.13\\pm 1.31$ Ma, and $85.80\\pm 1.33$ Ma respectively in tracking EHA method. These results are consistent with previous studies within error and provide a reliable estimation of uncertainties of the ages. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,641,164,655]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,668,487,802]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhythmic sedimentary rocks that record astronomical cycles (i.e., orbital eccentricity, obliquity and precession of the Earth) can be used as a high-resolution ruler measuring the geological time scale (Gradstein et al., 2012; Ma et al., 2014; Eldrett et al., 2015a; Hinnov, 2018). The study of the astronomical cycles in sedimentary sequences is called astrochronology while the time scale constructed from astrochronology is called astronomical time scale (Hinnov, 2018). Uncertainties associated with astronomical time scale has been considered in recent studies (Kuiper et al., 2008; Li et al., 2016; Ma et al., 2017, 2019; Meyers et al., 2012; Sageman et al., 2014; Westerhold et al., 2012). Meyers et al. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,641,937,788]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(2012) applied Bayesian method to constrain the uncertainty of astrochronology and radioisotopic ages of ash beds in the mid-Cretaceous. Uncertainties of astronomical time scale in the upper Cretaceous from Sageman et al. (2014) considered the age uncertainty derived from biostratigraphic and lithostratigraphic correlation. De Vleeschouwer and Parnell (2014) estimated age uncertainty for the Devonian by applying Bayesian method to astrochronology and radioisotopic geochronology. Ma et al. (2017) evaluated the age uncertainty derived from the radioisotopic dating and uncertainty associated with different ash beds as anchors in astrochronology for upper Cretaceous strata. All these studies rely on results from single paleoclimate proxy. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[527,788,937,800]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paleoclimate proxies may have different response to astronomical ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,844,305,854]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E-mail address: chao@uidaho.edu (C. Ma). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,856,499,867]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Peer-review under responsibility of China University of Geosciences (Beijing). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[366,12,591,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[400,42,596,55]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,831,203,842]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"* Corresponding author. ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[57,877,292,889]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1016/j.gsf.2020.01.013 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,890,579,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received 28 June 2019; Received in revised form 2 December 2019; Accepted 26 January 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,902,179,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Available online xxxx ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,912,937,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1674-9871/© 2020 China University of Geosciences (Beijing) and Peking University. Production and hosting by Elsevier B.V. This is an open access article under the ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,928,290,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[63,957,932,984]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Please cite this article as: Ma, C., Li, M., Astronomical time scale of the Turonian constrained by multiple paleoclimate proxies, Geoscience Frontiers, https://doi.org/10.1016/j.gsf.2020.01.013 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[90,66,455,281]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. Paleogeographic map for the Late Cretaceous (90 Ma) (modified from Ron Blakey http://jan.ucc.nau.edu/rcb7/ and the Colorado Plateau Geosystems Inc.). Black star shows the location of ODP Site 1259, Demerara Rise. \"]","image_footnote":"[]","img_path":"images/0764/5677d332844ad98aa5dc2714ca1baff2e48d327ebb71f124e487d712216586f8.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,341,485,446]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"forcing and non-astronomical noise (Li et al., 2019; Ma et al., 2019). For example, some proxies (e.g., grayscale) may have a linear relationship with $\\mathrm{CaCO_3}$ content (Eldrett et al., 2015a) while other proxies may have a logarithm relationship (Lockclair and Sageman, 2008). Some proxies may be dominated by astronomical forcing while other proxies may be largely influenced by non-orbital noise. Consequently, astronomical time scale constructed from a single proxy may have uncertainty that cannot be fully assessed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,448,485,617]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Testing multiple paleoclimate proxies may solve this problem especially at geological records where the preservation of paleoclimate signals is complicated. Recognition of astronomical forcing in variations of rock properties from Site 1259 of Cretaceous Demerara Rise in the equatorial Atlantic of $85 - 94\\mathrm{Ma}$ is not straightforward: color reflection, bulk density and natural gamma radiation (NGR) that reflect clay content in the Demerara Rise do not correlate linearly (Supplemental Fig. S1). For a full assessment of the uncertainty of astronomical time scale from multiple proxies, we applied two astrochronological methods to four paleoclimate proxies and constructed an astronomical time scale for the Turonian throughout Coniacian at the Demerara Rise $(85 - 94\\mathrm{Ma})$ . The result compares with previous studies within error and provides insight into the uncertainties in astronomical time scales. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,633,218,645]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Material and method ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,660,142,672]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1. Material ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,686,485,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Submarine plateau of the Demerara Rise is located at about $5^{\\circ}\\mathrm{N}$ off the coasts of Surinam and French Guyana (Fig. 1; Erbacher et al., 2004). Five sites (1257-1261) of ODP Leg 207 have recovered Cretaceous sediments from the Albian to the Campanian. Among these, the most complete stratigraphy at Site 1259 (GPS: $9^{\\circ}18'\\mathrm{N}$ , $54^{\\circ}12'\\mathrm{W}$ ) records one of major global carbon perturbation events, known as Oceanic Anoxic Event 2 (OAE2) and its aftermath (Erbacher et al., 2004). Sediments of the Turonian throughout the Coniacian at Site 1259 are mainly laminated black shale interbedded with carbonate-rich shale (Fig. 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,805,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Site 1259 has three holes: A, B, and C, all of which have their own depth in meters below seafloor (mbsf) that can be converted to meters composite depth (mcd). Here we converted all depth to mbsf of Hole A based on the converting table by Erbacher et al. (2004) because Hole A is the most complete and widely used profile (Erbacher et al., 2005). Data in depth converting table (Erbacher et al., 2004) were used as tie points and the depths between these tie points were linearly interpolated. Data from Hole B and C were converted to the mbsf of Hole A, thus data from Hole A, B, and C were composed to new data that cover most of the studied interval (Fig. 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,249]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Biostratigraphy of calcareous nannofossils (Hardas and Mutterlose, 2006; Bornemann et al., 2008) and chemostratigraphy (Erbacher et al., 2005) have been studied at Site 1259, which was utilized as a preliminary time frame for this cyclostratigraphic investigation. Accordingly, the Cenomanian/Turonian (C/T) boundary is between the first occurrence (FO) of the calcareous nannofossil Q. Intermedium at $545.40\\mathrm{m}$ and the FO of E. octopetalus at $544.70\\mathrm{m}$ of Site 1259, and the C/T boundary is closer to the FO of Q. Intermedium $(545.4\\mathrm{m}$ of Site 1259) (Erbacher et al., 2005; Hardas and Mutterlose, 2006; Bornemann et al., 2008). Thus, the depth of the C/T boundary is between $545.40\\mathrm{m}$ and $545.05\\mathrm{m}$ (the middle of two above FOs). We assigned the C/T boundary at $545.23\\mathrm{m}$ , the mid-point between $545.40\\mathrm{m}$ and $545.05\\mathrm{m}$ . The standard deviation (SD) of the depth of C/T boundary is defined based on the standard deviation of uniform distribution as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,261,937,293]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nS D = \\sqrt {\\frac {\\left(D _ {2} - D _ {1}\\right) ^ {2}}{1 2}} \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[507,303,937,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $D_{2}$ is the lower FO $(545.40\\mathrm{m})$ and $D_{1}$ is the upper FO $(545.05\\mathrm{m})$ . Therefore, the $SD$ is $0.10\\mathrm{m}$ in this case. The Turonian/Coniacian boundary is defined by the FO of M. furcatus (CC12/CC13) at $512.45\\mathrm{mcd}$ (Bornemann et al., 2008), which is equivalent to $510.7\\mathrm{mbsf}$ (Erbacher et al., 2004). The Coniacian/Santonian boundary is constrained between FO of L. grillii $(499.3\\mathrm{mcd})$ and FO of M. decussata $(501.2\\mathrm{mcd})$ (Bornemann et al., 2008), which is between $497.55\\mathrm{m}$ and $499.45\\mathrm{mbsf}$ (Erbacher et al., 2004). Thus, following the method above, the position for the Coniacian/Santonian boundary is $498.50\\mathrm{m}$ with a standard deviation of $0.55\\mathrm{m}$ . Calcareous nannofossil zones investigated in this study are the base of CC12 (CC11/CC12), the base of CC13 (CC12/CC13) and the base of CC14 (CC13/CC14), which correspond to depths of 521.51 mcd $(519.76\\mathrm{mbsf})$ , $512.45\\mathrm{mcd}$ $(510.7\\mathrm{mbsf})$ , and $501.2\\mathrm{mcd}$ $(499.50\\mathrm{mbsf})$ , respectively. Because no ash beds were found in this interval at Demerara Rise, the Cenomanian/Turonian boundary $(93.9 \\pm 0.15\\mathrm{Ma}$ , Meyers et al., 2012) in the Western Interior Basin, USA was chosen as the anchor for our ATS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,529,937,805]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Multiple paleoclimate proxies are from IODP Log Processing and Database (Erbacher et al., 2004) for Site 1259, including color reflection $\\mathrm{L}^*$ and $\\mathbf{b}^*$ , natural gamma radiation (NGR), and bulk density. These four proxies were used because they either have been proven carrying astronomical signals in the mid-Cretaceous of the Demerara Rise (e.g., $\\mathrm{L}^*$ and $\\mathbf{b}^*$ , Nederbragt et al., 2007) or have great potential to carry astronomical signals (e.g., density and gamma radiation, Li et al., 2019). Details of measurement methods for these proxies can be seen in Blum (1997). Rock color can be digitalized using a three-dimension color model such as the CIE LAB ( $\\mathrm{L}^*$ , $\\mathbf{a}^*$ , and $\\mathbf{b}^*$ ) color system (Robertson, 1977; Li et al., 2019). $\\mathrm{L}^*$ denotes lightness reflecting the richness of calcium carbonate, which is primarily influenced by carbonate productivity (Eldrett et al., 2015a, b). $\\mathbf{b}^*$ represents yellowness (positive values for yellow and negative values for blue), which may reflect iron-bearing minerals and bottom-water redox conditions (Li et al., 2019). These two proxies have been proven carrying astronomical signals in the Demerara Rise (Nederbragt et al., 2007). Changes in NGR and density in marine sediments represent variations in clay content; shale-rich beds show high NGR and low density while carbonate-rich beds show low NGR and high density. These data were collected from 497.25 to 550.48 mbsf, with a sampling resolution of $0.025\\mathrm{m}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,831,655,843]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2. Time series analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,857,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study applied a set of quantitative and statistical methods in time series analysis. Multi-taper method (MTM, Thomas, 1982) power spectral analysis and F-test evaluation were used to identify significant frequencies in paleoclimate proxies. Evolutive harmonic analysis (EHA) was performed to track spatial frequencies that are associated with astronomical frequencies with moving-window MTM analysis, which is to ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[766,42,937,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[114,66,884,501]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2. Stratigraphy, lithology, and proxy data at Site 1259. Biozones are from Bornemann et al. (2008). Data of Lightness, b*, density and NGR (natural gamma radiation) are from Erbacher et al. (2014) and $\\\\delta^{13}\\\\mathrm{C}_{\\\\mathrm{org}}$ are from Erbacher et al. (2015). \\\"Sant.\\\"-Santonian. \\\"Camp.\\\"-Campanian. \\\"Calc. nf.\\\"-Calcareous nanofossils. \\\"Litho.\\\"-lithology. \"]","image_footnote":"[]","img_path":"images/0692/0d4ba109fa2e8538906bab41cc294f5e3d0f8d09f2afc2ee89eaa6a41b50216a.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[60,566,485,856]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"track variations of the sedimentation rates (Meyers et al., 2001; Ma et al., 2014; Eldrett et al., 2015a). Average spectral misfit (ASM, Meyers et al., 2007) was used to search for the optimal sedimentation rate via fitting the spatial frequencies to orbital frequencies and the null hypothesis of no astronomical forcing was tested with Monte Carlo realizations. To evaluate age models derived from different astrochronological techniques, we adopted two methods of constructing astronomical time scale based on the most stable long eccentricity cycle (Laskar et al., 2004): (1) time calibration using bandpass filtering of the recognized long eccentricity cycles (E1 bandpass, Li et al., 2016; Wu et al., 2018) and (2) tracking the long eccentricity from the EHA result (tracking EHA, Ma et al., 2018). Linearly detrending was first conducted to $\\mathrm{L}^*$ , $\\mathbf{b}^*$ , density, and NGR series. Then the EHA method was applied to the four datasets, with a moving window of $5\\mathrm{m}$ and a step of $0.1\\mathrm{m}$ (Fig. 3). Sedimentation rates were derived by tracking significant long eccentricity signal from EHA manually based on frequencies that are higher than $80\\%$ F-test probability (bottom panels in Fig. 3) and consistent with the long eccentricity frequencies identified from ASM results (Table 2). In the E1 bandpass method, long eccentricity cycles were extracted by using Gaussian bandpass filter from the four proxies based on the frequencies identified in ASM. All these analyses were performed using \"astrochron\" package in R (Meyers, 2014). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,871,129,882]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,897,203,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. Time series analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,923,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strong and straight frequency peaks revealed in EHA plots suggest a ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,566,937,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"relatively stable sedimentation rate (cf. Meyers et al., 2001). Based on characteristics of the EHA plots, the datasets were divided into four intervals (see black and white boxes in Fig. 3) to perform MTM power spectral analysis for the extraction of significant frequencies. These four intervals were: $497.25 - 510\\mathrm{m}$ , $510 - 520\\mathrm{m}$ , $520 - 530\\mathrm{m}$ , and $530 - 550.48\\mathrm{m}$ . Because of the different stability of frequencies in the EHA result of $\\mathbf{L}^*$ , the actual intervals from $510\\mathrm{m}$ to $530\\mathrm{m}$ in the ASM tests for $\\mathbf{L}^*$ were $510 - 517\\mathrm{m}$ and $517 - 530\\mathrm{m}$ (Fig. 3, Table 2 and Supplementary Figs. S1-S17). Significant frequencies passing the F-test with confidence level of $\\geq 80\\% - 95\\%$ (except the interval of $510 - 520\\mathrm{m}$ for the NGR, where an F-test confidence level of $\\geq 75\\%$ was used, Supplementary Materials) were tested with the ASM method. The null hypothesis of no astronomical forcing $(H_0)$ and the value of sedimentation rates were evaluated. The null hypothesis test in the ASM of all four intervals in the four proxies demonstrated that astronomical forcing had a significant impact on the paleoclimate proxies (see Supplementary Figs. S1-S17). There is only one ASM test of the interval $(497.25 - 510\\mathrm{m})$ for NGR that did not reject the null hypothesis. Sedimentation rates for the four intervals from the four proxies are listed in Table 1. By applying the sedimentation rates, astronomical cyclicities are listed in Table 2, based on which the astronomical signals were tracked on EHA results (red or white dashed lines in Fig. 3). The ASM results also guided the long eccentricity bandpass. The bandpass ranges of the four intervals of $497.25 - 510\\mathrm{m}$ , $510 - 520\\mathrm{m}$ , $520 - 530\\mathrm{m}$ , and $530 - 550.48\\mathrm{m}$ are $0.7 - 0.9$ cycle/m, $0.18 - 0.55$ cycle/m, $0.24 - 0.47$ cycle/m, and $0.07 - 0.29$ cycle/m, respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[766,42,937,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[65,66,929,802]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3. EHA results for $\\\\mathrm{L}^*$ (first column), $\\\\mathbf{b}^{*}$ (second column), density (third column), and NGR (fourth column). The first row of the plots shows evolutive power spectral analysis (EPSA) in log power. The second row shows the normalized amplitude of EHA. The third row shows the normalized, filtered amplitude $(80\\\\%)$ of EHA. The colored bars at the bottom for the second and third rows are the same. Red and white dotted lines indicate the trace of orbital frequencies, which are labeled with E1 (long eccentricity), E2-3 (short eccentricity), O1 (long obliquity), O2 (short obliquity), P1 (long precession), and P2 (short precession). The black (top row) and white (middle and bottom rows) boxes are the four intervals for separate ASM analyses. \"]","image_footnote":"[]","img_path":"images/0910/d6b7c26670c17bc100025207db1b4d97ce6996f94f4e9020dc057b081d07ebe0.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[768,42,937,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[58,90,487,187]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0558/700ec294c315bbff6331b5a90825dfa686cfa29d72797d22589202554026c9dd.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Interval (m)</td><td>Sedimentation rate (cm/ kyr)</td><td rowspan=\"2\">Interval (m)</td><td colspan=\"3\">Sedimentation rate (cm/ kyr)</td></tr><tr><td>L*</td><td>b*</td><td>Density</td><td>NGR</td></tr><tr><td>497.25–510</td><td>0.35</td><td>497.25–510</td><td>0.34</td><td>0.28</td><td></td></tr><tr><td>510–517</td><td>0.64</td><td>510–520</td><td>0.65</td><td>0.70</td><td>0.85</td></tr><tr><td>517–530</td><td>0.78</td><td>520–530</td><td>0.63</td><td>0.66</td><td>0.60</td></tr><tr><td>530–550.48</td><td>1.43</td><td>530–550.48</td><td>1.10</td><td>1.53</td><td>1.50</td></tr></table>","table_caption":"[\"Table 1 Sedimentation rates obtained from the ASM test. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[58,205,315,218]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Construction of ATS and its uncertainty ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,230,485,441]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"405 kyr long eccentricity cycle is considered as the most stable astronomical cycle in Earth's history (Hinnov, 2018; Laskar et al., 2004; Ma et al., 2017), therefore, long eccentricity cycle was used for the construction of the ATS in this study. According to the ASM results (Tables 1 and 2), long eccentricity cycles tracked from the EHA results (Fig. 3) and long eccentricity bandpass were utilized for determining the sedimentation rate (Fig. 4). Sedimentation rates ranged from 2 to $0.2\\mathrm{cm / kyr}$ at Site 1269 from the Turonian to the Coniacian. Sedimentation rates were relatively high $(0.8 - 2\\mathrm{cm / kyr})$ in the early Turonian, then reached to a regional low sedimentation rate at around $0.5 - 1\\mathrm{cm / kyr}$ during the middle Turonian. It returned $\\sim 1\\mathrm{cm / kyr}$ during the latest Turonian and decreased to a relatively low rate of $\\sim 0.3\\mathrm{cm / kyr}$ during the Coniacian. Floating ATS was built by applying the sedimentation rates to each proxy. Finally, the absolute astronomical time scales of the four proxies were constructed by pinning the floating ATS to the Cenomanian/Turonian (C/T) boundary of $93.9\\pm 0.15$ Ma (Fig. 4). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,442,485,548]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The ATS enabled the determination of the mean and uncertainty of ages for stage and biozone boundaries of the Turonian-Coniacian interval (Table 3). Age models for the two methods (tracking EHA and E1 bandpass) were calculated separately. Statistical mean and standard deviation were calculated based on the four age models in each method (Table 3). We considered two sources of uncertainties: one was from ATS itself and the other one was from the anchor. Quadrature method was applied to combine uncertainties from the four age models in each ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,223]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"method and a 0.15-Myr uncertainty of the anchor. The total uncertainty was calculated by taking the square root of the sum of the variance from all sources. For example, the age for the Turonian/Coniacian boundary is $89.74 \\pm 0.35$ Ma based on four astrochronologies in the tracking EHA method (Table 3). Considering an 0.15-Myr uncertainty of the anchor, the total uncertainty is 0.38 Myr [obtained from sqrt(0.15 × 0.15 + 0.35 × 0.35)]. Thus, ages for the boundaries of CC11/CC12, Turonian/Coniacian (CC12/CC13), CC13/CC14, and Coniacian/Santonian are $91.17 \\pm 0.36$ Ma, $89.74 \\pm 0.38$ Ma, $86.13 \\pm 1.31$ Ma, and $85.80 \\pm 1.33$ Ma, respectively from tracking EHA method, comparing with $91.25 \\pm 0.20$ , $89.87 \\pm 0.20$ Ma, $86.36 \\pm 0.33$ Ma, and $86.03 \\pm 0.32$ Ma based on E1 bandpass method (Table 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,237,601,249]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,264,754,276]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4.1. Comparison with previous age models ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,288,937,540]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The consistency between key boundary ages in previous studies and our results demonstrates that our methods of estimating age model and uncertainties from multiple proxies are robust. The age of Turonian/ Coniacian boundary (TCB, which is equivalent to CC12/CC13 boundary) is constrained to $89.74 \\pm 0.41$ Ma by integrating biostratigraphy, radioisotopic geochronology, and cyclostratigraphy in Sageman et al. (2014). Eldrett et al. (2015a) applied similar methods as those used in Sageman et al. (2014) but on a different sedimentary record. They obtained the age for the TCB is $89.72 \\pm 0.17$ Ma. The radioisotopic ages used as anchors in Eldrett et al. (2015a) are from the ash beds in the studied core itself. In comparison, ages of ash beds in Sageman et al. (2014) are from the stratigraphic-correlated outcrop. This is one reason that the TCB age in Eldrett et al. (2015a) has smaller uncertainty. These two previous ages match well with the age of the same boundary obtained in our study: $89.74 \\pm 0.38$ Ma from the tracking EHA method and $89.87 \\pm 0.20$ Ma based on the E1 bandpass method. The age for the Coniacian/Santonian boundary (CSB) is $86.49 \\pm 0.44$ Ma in Sageman et al. (2014), which is within the range of the $85.80 \\pm 1.33$ Ma based on the tracking EHA method and $86.03 \\pm 0.32$ Ma from the E1 bandpass ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,590,939,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0666/57648ba202141c7421f56d0c91daf8735c1d17d58daf295768827b7fd8320b8e.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Astronomical parameter</td><td colspan=\"6\">Astronomically forced frequencies (cycles/m)</td></tr><tr><td>Depth (m)</td><td>L*</td><td>Depth (m)</td><td>b*</td><td>Density</td><td>NGR</td></tr><tr><td>E1</td><td>497.25–510 m</td><td>0.75</td><td>497.25–510 m</td><td>0.84</td><td>0.85</td><td></td></tr><tr><td>E2</td><td></td><td>2.20</td><td></td><td>2.19</td><td>2.80</td><td></td></tr><tr><td>E3</td><td></td><td>3.03</td><td></td><td>3.02</td><td>3.60</td><td></td></tr><tr><td>O1</td><td></td><td>5.75</td><td></td><td>5.98</td><td>7.40</td><td></td></tr><tr><td>O2</td><td></td><td>7.64</td><td></td><td>7.75</td><td>9.30</td><td></td></tr><tr><td>P1</td><td></td><td>12.66</td><td></td><td>12.99</td><td>15.83</td><td></td></tr><tr><td>P2</td><td></td><td>15.46</td><td></td><td>16.06</td><td>19.18</td><td></td></tr><tr><td>E1</td><td>510–517 m</td><td>0.50</td><td>510–520 m</td><td>0.37</td><td>0.38</td><td>0.23</td></tr><tr><td>E2</td><td></td><td>1.09</td><td></td><td>1.33</td><td>1.17</td><td>1.09</td></tr><tr><td>E3</td><td></td><td>1.83</td><td></td><td>1.66</td><td>1.50</td><td>1.27</td></tr><tr><td>O1</td><td></td><td>3.12</td><td></td><td>3.08</td><td>2.94</td><td>2.39</td></tr><tr><td>O2</td><td></td><td>4.09</td><td></td><td>4.03</td><td>3.89</td><td>3.12</td></tr><tr><td>P1</td><td></td><td>7.09</td><td></td><td>6.84</td><td>6.38</td><td>5.22</td></tr><tr><td>P2</td><td></td><td>8.40</td><td></td><td>8.10</td><td>7.82</td><td>6.46</td></tr><tr><td>E1</td><td>517–530 m</td><td>0.37</td><td>520–530 m</td><td>0.37</td><td>0.36</td><td>0.34</td></tr><tr><td>E2</td><td></td><td>1.12</td><td></td><td>1.23</td><td>1.19</td><td>1.41</td></tr><tr><td>E3</td><td></td><td>1.36</td><td></td><td>1.60</td><td>1.61</td><td>1.71</td></tr><tr><td>O1</td><td></td><td>2.72</td><td></td><td>3.10</td><td>3.05</td><td>3.34</td></tr><tr><td>O2</td><td></td><td>3.31</td><td></td><td>4.23</td><td>4.21</td><td>4.39</td></tr><tr><td>P1</td><td></td><td>5.67</td><td></td><td>7.18</td><td>6.85</td><td>7.39</td></tr><tr><td>P2</td><td></td><td>6.87</td><td></td><td>8.66</td><td>8.29</td><td>9.16</td></tr><tr><td>E1</td><td>530–550.48 m</td><td>0.17</td><td>530–550.48 m</td><td>0.24</td><td>0.16</td><td>0.12</td></tr><tr><td>E2</td><td></td><td>0.51</td><td></td><td>0.75</td><td>0.52</td><td>null</td></tr><tr><td>E3</td><td></td><td>0.74</td><td></td><td>0.93</td><td>0.75</td><td>0.75</td></tr><tr><td>O1</td><td></td><td>1.39</td><td></td><td>1.81</td><td>1.40</td><td>1.40</td></tr><tr><td>O2</td><td></td><td>1.87</td><td></td><td>2.39</td><td>1.70</td><td>1.56</td></tr><tr><td>P1</td><td></td><td>3.09</td><td></td><td>4.05</td><td>2.92</td><td>3.02</td></tr><tr><td>P2</td><td></td><td>3.84</td><td></td><td>4.97</td><td>3.52</td><td>3.61</td></tr></table>","table_caption":"[\"Table 2 Astronomically forced frequency (E1: long eccentricity, E2 and E3: short eccentricity, O1 and O2: obliquity, P1 and P2: precession). \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[768,42,937,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[115,66,887,503]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4. Age models and sedimentation rate histories. Age models using both tracking EHA and E1 bandpass methods were based on four proxies of L\\\\* (red), b\\\\* (blue), NGR (purple), and density (light green) proxies. \"]","image_footnote":"[]","img_path":"images/0509/d4aa371bbd2c2e45c58d5dc505e2cb665f3efaf75da5c9a9a05aa07543d35073.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,552,186,564]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"method in our study. ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,564,485,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However, there are also some inconsistencies in the age models between previous work and this study. The age for the C11/C12 boundary was constrained as $93.11 \\pm 0.17$ Ma in Eldrett et al. (2015a), which is $\\sim 2$ Ma older than the age of $91.17 \\pm 0.32$ Ma from the tracking EHA method and $91.25 \\pm 0.20$ Ma based on the E1 bandpass method in our study. The CC12/CC13 boundary was used as an indicator of the TCB at the Cretaceous Demerara Rise (Bornneman et al., 2008). Recent work suggests that the TCB in Texas may occur near the middle of the CC13 biozone (Corbett et al., 2014). The Turonian/Coniacian boundary is defined by the base of the Scaphites preventtricosus ammonite biozone, which is coincident with the CC14/CC13 boundary (Gradstein et al., 2012). These suggest that calcareous nannofossil biostratigraphy may not be as stable ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,552,937,576]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"as ammonite biostratigraphy for the age model construction in the Upper Cretaceous. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,578,937,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our age model is different from a previous study at the same core (Jones et al., 2018). They constructed an age model for the stratigraphy of core 1259A from $508\\mathrm{m}$ to $530\\mathrm{m}$ of Site 1259 based on cyclostratigraphy of calcium carbonate data and chemostratigraphy of carbon isotope (Supplementary Fig. S2). Their depth unit is meter composite depth (mcd), which is $\\sim 1.75\\mathrm{m}$ deeper than mbsf of Hole A in our study. The sedimentation rate model by Jones et al. (2018) has a substantial difference from 512 mbsf to 520 mbsf, which is $\\sim 0.2\\mathrm{cm / kyr}$ , while the sedimentation rate in our study is $0.64 - 0.85\\mathrm{cm / kyr}$ . Other than this interval, sedimentation rate models in these two studies are similar (Supplementary Fig. S2). Because there is no anchor in their age model at ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,764,937,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0835/6ceec89df8726cc658f3067690235f365d8415f04c182f3b9c03531ac46bf0a0.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Boundaries</td><td colspan=\"5\">Age Models (Ma)</td><td rowspan=\"2\">Mean (Ma)</td><td rowspan=\"2\">Age Model Uncertaintyb(2σ) (Ma)</td><td rowspan=\"2\">Total Uncertaintyc(Ma)</td><td rowspan=\"2\">Age (Ma) (from Sageman et al., 2014)</td><td rowspan=\"2\">Age (Ma) (from Eldrett et al., 2015a)</td></tr><tr><td>Modelsa</td><td>L*</td><td>b*</td><td>Density</td><td>NGR</td></tr><tr><td rowspan=\"2\">CC11/CC12</td><td>A</td><td>91.02</td><td>91.23</td><td>91.06</td><td>91.37</td><td>91.17</td><td>0.32</td><td>0.36</td><td>No data</td><td>93.11 ± 0.17</td></tr><tr><td>B</td><td>91.19</td><td>91.28</td><td>91.42</td><td>91.09</td><td>91.25</td><td>0.13</td><td>0.20</td><td></td><td></td></tr><tr><td rowspan=\"2\">Turonian/Coniacian (CC12/CC13)</td><td>A</td><td>89.68</td><td>89.53</td><td>89.82</td><td>89.94</td><td>89.74</td><td>0.35</td><td>0.38</td><td>89.74 ± 0.41</td><td>89.72 ± 0.17</td></tr><tr><td>B</td><td>89.73</td><td>89.90</td><td>90.05</td><td>89.78</td><td>89.87</td><td>0.13</td><td>0.20</td><td></td><td></td></tr><tr><td rowspan=\"2\">CC13/CC14</td><td>A</td><td>86.49</td><td>85.53</td><td>85.64</td><td>86.87</td><td>86.13</td><td>1.31</td><td>1.31</td><td>No data</td><td>No data</td></tr><tr><td>B</td><td>86.30</td><td>86.33</td><td>86.44</td><td>86.38</td><td>86.36</td><td>0.29</td><td>0.33</td><td></td><td></td></tr><tr><td rowspan=\"2\">Coniacian/Santonian</td><td>A</td><td>86.18</td><td>85.23</td><td>85.25</td><td>86.54</td><td>85.80</td><td>1.33</td><td>1.33</td><td>86.49 ± 0.44</td><td>No data</td></tr><tr><td>B</td><td>85.98</td><td>85.97</td><td>86.11</td><td>86.08</td><td>86.03</td><td>0.28</td><td>0.32</td><td></td><td></td></tr></table>","table_caption":"[\"Table 3 Age for stage and biozone boundaries. \"]","table_footnote":"[\"a A. Tracking EHA method; B. E1 bandpass method. \",\"b Uncertainty $(2\\\\sigma)$ from different age models based on different proxies. \",\"Total uncertainty derived by adding age model uncertainty and anchor (C/T boundary) uncertainty in quadrature. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[766,42,937,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Site 1259, we align two extreme age models based on their floating astronomical time scale to our age models (Supplementary Fig. S2). The age model of Jones et al. (2018) (left light blue curve in Supplementary Fig. S2) assigns a $100 - 200\\mathrm{kyr}$ duration to the interval from 528 mbsf to 545 mbsf at Site 1259, which implies that the sedimentation rate for this interval is $8.5 - 17~\\mathrm{cm / kyr}$ , an unreasonable range for the shale deposition of this interval at Demerara Rise. Another scenario (right light blue curve in Supplementary Fig. S2) would make the TCB be $88.6\\mathrm{Ma}$ , which is 1000 kyr younger than previous studies (Sageman et al., 2014; Eldrett et al., 2015a). Consequently, we argue that our age model is more practical. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,225,247,238]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4.2. Signal and noise evaluation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,250,485,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In cyclostratigraphic study, the signal usually refers to astronomical-related climate oscillations (i.e., eccentricity, obliquity, and precession cycles) while the noise frequently refers to the residual oscillations or non-orbital related components. In a statistical sense, ASM results and sedimentation rate histories from all four proxies in both methods of E1 bandpass and tracking EHA are similar along with the record (Tables 1 and 2, Fig. 4). All of them indicate that these proxy oscillations are of the astronomical origin at Site 1259 of the Demerara Rise. For the $\\mathrm{L}^*$ within the interval of $510\\mathrm{m}$ to $530\\mathrm{m}$ , subdivision for ASM tests is different from the other three proxies. And the ASM-derived sedimentation rates of the $\\mathrm{L}^*$ series at the $520 - 530\\mathrm{m}$ interval are higher than those derived from the other three proxies. This may be caused by the low signal-to-noise ratio in the $\\mathrm{L}^*$ record, which could reduce the relative power of astronomical signals at this interval. Proxy's oscillations during the Coniacian may have a low signal-to-noise ratio, indicated by no reliable ASM result in the NGR data (Table 2). Different proxies in the same stratigraphy display different degrees of signal-to-noise ratio; even in some intervals, a specified proxy may not preserve strong astronomical signals due to strong noise. In a few intervals of a specified proxy in this study, identified astronomical cycles have lower confidence levels. For instance, the confidence level (CL) of filtering spatial frequencies that were analyzed in ASM for NGR within the interval of $510 - 520\\mathrm{m}$ is $75\\%$ , while the CLs of the similar spatial frequencies in $\\mathrm{L}^*$ , $\\mathbf{b}^*$ and density are $90\\%$ , $80\\%$ , and $90\\%$ respectively. We can imagine that if only NGR was used in this interval, the result may be questionable because of the high probability of false-positive frequencies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,593,485,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sources of noise in paleoclimate oscillations fall into two categories: syndepositional noise and postdepositional noise. The syndepositional noise happens during the depositional processes, including basinal uplift/subsidence, volcanic eruptions, earthquakes, and autogenic processes, among others (Li et al., 2018). These noises could be recorded in most of the proxies that display comparable noise profiles. For example, ash beds should be removed from all proxies before the evaluation of astronomical signals. Postdepositional noise includes sources from bioturbation, compaction, and diagenesis that take place after the deposition of sediments (Weedon, 2003). Various types of diagenesis (e.g., oxygenation and remineralization) may affect different proxies in sedimentary rocks. The $\\mathrm{L}^*$ that reflects the carbonate versus organic matter may be affected by the remineralization of carbonate. The $\\mathbf{b}^*$ that reflects iron-bearing minerals and bottom water redox conditions could also be affected by the redox conditions after deposition (Li et al., 2019). Three main sources of natural gamma radiation are radiogenic isotopes of potassium (K), uranium (U) and thorium (Th) (Ruffell and Worden, 2000). Post-depositional migration of organic matter could affect the radiogenic source of U, thus natural gamma radiation (Li et al., 2019). Bulk density indicates changes in lithology and porosity (Blum, 1997). Post-depositional processes such as different compaction and mineral alternation lead to elevated \"noise\" in density data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,883,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Taken together, cyclostratigrapher should be careful when conducting cyclostratigraphic studies based on a single proxy. Identifying the same astronomical cycles from multiple proxies in the same strata is shown here to be a practical way to overcome the risks of low signal-to ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,92]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"noise ratio and false-positive frequencies identified as astronomical signals. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,110,794,123]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4.3. Challenges and opportunities of our methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,136,937,427]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There are two main methods of constructing an astronomical time scale for deep time beyond $50\\mathrm{Ma}$ : tracking a specific orbital frequency from the EHA method (Eldrett et al., 2015; Ma et al., 2017) and bandpass filtering of a specific orbital cycle (Li et al., 2016; Wu et al., 2018). Both have their own limitations. Paleoclimate proxies are not only influenced by astronomical forcing, non-astronomical forcing may lead to very low signal-to-noise ratio, which has influences on both tracking EHA and bandpass methods. The tracking EHA method has subjective uncertainties in tracking frequencies from the EHA plot: (1) it is manually tracked and (2) the tracked frequencies must be larger than a given confidence level. Clearly, this method subjectively introduces uncertainties to the construction of sedimentation rates and age models. Cyclostratigraphers have to make choices of tracked frequency peaks based on their experience. This uncertainty is impossible to quantify when only one proxy data is used. In comparison, approaches of the bandpass filtering have subjective uncertainties as well (Sinnesael et al., 2019). There are no universally accepted choices of frequency bands for the filtering of a specific astronomical signal (Zeeden et al., 2018). Different filtering settings, which usually depend on cyclostratigraphers' decision, may result in different age models. In sum, the subjective uncertainties in both methods are affected by the knowledge and experience of the cyclostratographer (Sinnesael et al., 2019). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,441,605,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5. Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,467,937,679]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Consistency of time series analyses on four proxies $(\\mathrm{L}^{*},\\mathrm{b}^{*}$ , density, and NGR) using two methods (tracking EHA and E1 bandpass methods) demonstrates the existence of astronomical forcing during the Turonian throughout the Santonian at the Demerara Rise in the equatorial Atlantic. Results of the astronomical time scale based on four proxies in both methods are different, demonstrating different paleoclimate proxies may preserve different signal-to-noise ratios in the aspect of astronomical forcing. This issue can be addressed from the statistical uncertainty of these astronomical time scales based on four proxies in both methods. The final uncertainty of the astronomical time scales was obtained by the quadrature algorithm applied to uncertainties from proxies and uncertainty from the anchor. The calibrated ages of the boundaries of CC11/ CC12, Turonian/Coniacian (CC12/CC13), CC13/CC14 and Coniacian/ Santonian compare well with previous studies (Sageman et al., 2014; Eldrett et al., 2015a). Future works could be quantifying non-astronomical noises in different paleoclimate proxies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,697,729,709]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Declaration of competing interest ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,723,937,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,776,633,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgement ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,803,937,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We thank James Eldrett and Stephen R. Meyers for their discussions. We also thank two anonymous reviewers for their constructive comments that improved this paper. This study was supported by NSF CAREER award to Stephen R. Meyers (EAR-1151438) and partially supported by the NSF Grant with No. 1835717. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,883,729,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Appendix A. Supplementary data ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,910,936,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplementary data to this article can be found online at https://doi.org/10.1016/j.gsf.2020.01.013. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[766,42,937,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[58,66,132,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,90,482,633]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Blum, P., 1997. 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Intercalibration of radioisotopic and astrochronologic time scales for the Cenomanian-Turonian boundary interval, Western Interior Basin, USA. Geology 40 (1), 7-10. \",\"Nederbragt, A.J., Thurow, J., Pearce, R., 2007. Sediment composition and cyclicity in the mid-cretaceous at Demerara Rise, ODP Leg 207. In: Proceedings of the Ocean Drilling Program, Scientific Results, vol 207, pp. 1-31. \",\"Robertson, A.R., 1977. The CIE 1976 color-difference formulae. Color Res. Appl. 2 (1), 7-11. \",\"Ruffell, A., Worden, R., 2000. Palaeoclimate analysis using spectral gamma-ray data from the Aptian (Cretaceous) of southern England and southern France. Palaeogeogr. Palaeoclimatol. Palaeoecol. 155 (3-4), 265-283. \",\"Sageman, B.B., Singer, B.S., Meyers, S.R., Siewert, S.E., Walaszczyk, I., Condon, D.J., Jicha, B.R., Obradovich, J.D., Sawyer, D.A., 2014. Integrating 40Ar/39Ar, U-Pb, and astronomical clocks in the cretaceous niobrara formation, western Interior Basin, USA. Bulletin 126 (7-8), 956-973. \",\"Sinnaesel, M., De Vleeschouwer, D., Zeeden, C., Batenburg, S.J., Da Silva, A.-C., de Winter, N.J., Dinarès-Turell, J., Drury, A.J., Gambacorta, G., Hilgen, F.J., Hinnov, L.A., Hudson, A.J.L., Kemp, D.B., Lantink, M.L., Laurin, J., Li, M., Liebrand, D., Ma, C., Meyers, S.R., Monkenbusch, J., Montanari, A., Nohl, T., Pälike, H., Pas, D., Ruhl, M., Thibault, N., Vahlenkamp, M., Valero, L., Wouters, S., Wu, H., Claeys, P., 2019. The Cyclostratigraphy Intercomparison Project (CIP): consistency, merits and pitfalls. Earth Sci. Rev. 199, 102965. https://doi.org/10.1016/j.earscriv.2019.102965. \",\"Thomson, D.J., 1982. Spectrum estimation and harmonic analysis. Proc. IEEE 70 (9), 1055-1096. \",\"Weedon, G.P., 2003. Time Series Analysis and Cyclostratigraphy: Examining Stratigraphic Records of Environmental Cycles. Cambridge University Press. \",\"Westerhold, T., Röhl, U., Laskar, J., 2012. Time scale controversy: accurate orbital calibration of the early Paleogene. G-cubed 13 (6). \",\"Wu, H., Fang, Q., Wang, X., Hinnov, L.A., Qi, Y., Shen, S.Z., Yang, T., Li, H., Chen, J., Zhang, S., 2018. An 34 my astronomical time scale for the uppermost Mississippian through Pennsylvanian of the Carboniferous System of the Paleo-Tethyan realm. Geology 47 (1), 83-86. \",\"Zeeden, C., Kaboth, S., Hilgen, F.J., Laskar, J., 2018. Taner filter settings and automatic correlation optimisation for cyclostratigraphic studies. Comput. Geosci. 119, 18-28. \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[366,12,589,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE IN PRESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,42,122,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Ma, M. Li ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[766,42,937,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Geoscience Frontiers xxx (xxxx) xxx ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[63,79,144,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0800/3cfcc9935e33e61e6454ba4674611b0ece9a45b498c18114bddae97c9ffef1c6.jpg\",\n \"list_items\": null,\n \"page_idx\": 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\",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[334,145,650,160]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"journal homepage: www.elsevier.com/locate/gsf \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[838,66,937,160]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0940/f5ee484e19bf9151a069c92133d9ca74c88261b4175e902b0a160c41ef16456c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n 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\"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,399,141,409]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Astrochronology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,409,176,419]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Astronomical time scale \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,419,119,430]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Uncertainty \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,431,115,440]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cretaceous \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,442,105,451]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Turonian \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,453,129,462]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Demerara rise \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[334,340,435,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ABSTRACT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[332,364,939,606]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the clocks that record the Earth history is (quasi-) periodic astronomical cycles. These cycles influence the climate that can be ultimately stored in sedimentary rocks. By cracking these (quasi-) periodic sedimentation signals, high resolution astronomical time scale (ATS) can be obtained. Paleoclimate proxies are widely used to extract astronomical cycles. However different proxies may respond differently to astronomical signals and nonastronomical noises including tectonics, diagenesis, and measurement error among others. Astronomical time scale constructed based on a single proxy where its signal-to-noise ratio is low may have uncertainty that is difficult to evaluate but can be revealed by utilizing other proxies. Here, we test eight astronomical age models using two astrochronological methods from four paleoclimate proxies (i.e., color reflection $\\\\mathrm{L}^*$ and $\\\\mathbf{b}^*$ , natural gamma radiation, and bulk density) from the Turonian to the Coniacian of the Cretaceous Period at the Demerara Rise in the equatorial Atlantic. The two astrochronological methods are time calibration using long eccentricity bandpass filtering (E1 bandpass) and tracking the long eccentricity from evolutive harmonic analysis (tracking EHA). The statistical mean and standard deviation of four age models from the four proxies are calculated to construct one integrated age model with age uncertainty in each method. Results demonstrate that extracting astronomical signals from multiple paleoclimate proxies is a valid method to estimate age model uncertainties. Anchored at the Cenomanian/Turonian boundary with an age of $93.9\\\\pm 0.15$ Ma from biostratigraphy, the ages for CC11/CC12 (calcareous nannofossil zones), Turonian/Coniacian (CC12/CC13), CC13/CC14, and Coniacian/Santonian boundaries are $91.25\\\\pm 0.20$ Ma, $89.87\\\\pm 0.20$ Ma, $86.36\\\\pm 0.33$ Ma, and $86.03\\\\pm 0.32$ Ma in E1 bandpass method, compared with $91.17\\\\pm 0.36$ Ma, $89.74\\\\pm 0.38$ Ma, $86.13\\\\pm 1.31$ Ma, and $85.80\\\\pm 1.33$ Ma respectively in tracking EHA method. These results are consistent with previous studies within error and provide a reliable estimation of uncertainties of the ages. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,641,164,655]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,668,487,802]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhythmic sedimentary rocks that record astronomical cycles (i.e., orbital eccentricity, obliquity and precession of the Earth) can be used as a high-resolution ruler measuring the geological time scale (Gradstein et al., 2012; Ma et al., 2014; Eldrett et al., 2015a; Hinnov, 2018). The study of the astronomical cycles in sedimentary sequences is called astrochronology while the time scale constructed from astrochronology is called astronomical time scale (Hinnov, 2018). Uncertainties associated with astronomical time scale has been considered in recent studies (Kuiper et al., 2008; Li et al., 2016; Ma et al., 2017, 2019; Meyers et al., 2012; Sageman et al., 2014; Westerhold et al., 2012). Meyers et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,641,937,788]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(2012) applied Bayesian method to constrain the uncertainty of astrochronology and radioisotopic ages of ash beds in the mid-Cretaceous. Uncertainties of astronomical time scale in the upper Cretaceous from Sageman et al. (2014) considered the age uncertainty derived from biostratigraphic and lithostratigraphic correlation. De Vleeschouwer and Parnell (2014) estimated age uncertainty for the Devonian by applying Bayesian method to astrochronology and radioisotopic geochronology. Ma et al. (2017) evaluated the age uncertainty derived from the radioisotopic dating and uncertainty associated with different ash beds as anchors in astrochronology for upper Cretaceous strata. All these studies rely on results from single paleoclimate proxy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[527,788,937,800]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paleoclimate proxies may have different response to astronomical \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,844,305,854]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E-mail address: chao@uidaho.edu (C. Ma). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,856,499,867]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Peer-review under responsibility of China University of Geosciences (Beijing). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[366,12,591,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[400,42,596,55]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,831,203,842]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"* Corresponding author. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[57,877,292,889]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1016/j.gsf.2020.01.013 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,890,579,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received 28 June 2019; Received in revised form 2 December 2019; Accepted 26 January 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,902,179,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Available online xxxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,912,937,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1674-9871/© 2020 China University of Geosciences (Beijing) and Peking University. Production and hosting by Elsevier B.V. This is an open access article under the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,928,290,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[63,957,932,984]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Please cite this article as: Ma, C., Li, M., Astronomical time scale of the Turonian constrained by multiple paleoclimate proxies, Geoscience Frontiers, https://doi.org/10.1016/j.gsf.2020.01.013 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[90,66,455,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. Paleogeographic map for the Late Cretaceous (90 Ma) (modified from Ron Blakey http://jan.ucc.nau.edu/rcb7/ and the Colorado Plateau Geosystems Inc.). Black star shows the location of ODP Site 1259, Demerara Rise. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0764/5677d332844ad98aa5dc2714ca1baff2e48d327ebb71f124e487d712216586f8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,341,485,446]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"forcing and non-astronomical noise (Li et al., 2019; Ma et al., 2019). For example, some proxies (e.g., grayscale) may have a linear relationship with $\\\\mathrm{CaCO_3}$ content (Eldrett et al., 2015a) while other proxies may have a logarithm relationship (Lockclair and Sageman, 2008). Some proxies may be dominated by astronomical forcing while other proxies may be largely influenced by non-orbital noise. Consequently, astronomical time scale constructed from a single proxy may have uncertainty that cannot be fully assessed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,448,485,617]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Testing multiple paleoclimate proxies may solve this problem especially at geological records where the preservation of paleoclimate signals is complicated. Recognition of astronomical forcing in variations of rock properties from Site 1259 of Cretaceous Demerara Rise in the equatorial Atlantic of $85 - 94\\\\mathrm{Ma}$ is not straightforward: color reflection, bulk density and natural gamma radiation (NGR) that reflect clay content in the Demerara Rise do not correlate linearly (Supplemental Fig. S1). For a full assessment of the uncertainty of astronomical time scale from multiple proxies, we applied two astrochronological methods to four paleoclimate proxies and constructed an astronomical time scale for the Turonian throughout Coniacian at the Demerara Rise $(85 - 94\\\\mathrm{Ma})$ . The result compares with previous studies within error and provides insight into the uncertainties in astronomical time scales. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,633,218,645]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Material and method \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,660,142,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1. Material \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,686,485,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Submarine plateau of the Demerara Rise is located at about $5^{\\\\circ}\\\\mathrm{N}$ off the coasts of Surinam and French Guyana (Fig. 1; Erbacher et al., 2004). Five sites (1257-1261) of ODP Leg 207 have recovered Cretaceous sediments from the Albian to the Campanian. Among these, the most complete stratigraphy at Site 1259 (GPS: $9^{\\\\circ}18'\\\\mathrm{N}$ , $54^{\\\\circ}12'\\\\mathrm{W}$ ) records one of major global carbon perturbation events, known as Oceanic Anoxic Event 2 (OAE2) and its aftermath (Erbacher et al., 2004). Sediments of the Turonian throughout the Coniacian at Site 1259 are mainly laminated black shale interbedded with carbonate-rich shale (Fig. 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,805,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Site 1259 has three holes: A, B, and C, all of which have their own depth in meters below seafloor (mbsf) that can be converted to meters composite depth (mcd). Here we converted all depth to mbsf of Hole A based on the converting table by Erbacher et al. (2004) because Hole A is the most complete and widely used profile (Erbacher et al., 2005). Data in depth converting table (Erbacher et al., 2004) were used as tie points and the depths between these tie points were linearly interpolated. Data from Hole B and C were converted to the mbsf of Hole A, thus data from Hole A, B, and C were composed to new data that cover most of the studied interval (Fig. 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,249]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Biostratigraphy of calcareous nannofossils (Hardas and Mutterlose, 2006; Bornemann et al., 2008) and chemostratigraphy (Erbacher et al., 2005) have been studied at Site 1259, which was utilized as a preliminary time frame for this cyclostratigraphic investigation. Accordingly, the Cenomanian/Turonian (C/T) boundary is between the first occurrence (FO) of the calcareous nannofossil Q. Intermedium at $545.40\\\\mathrm{m}$ and the FO of E. octopetalus at $544.70\\\\mathrm{m}$ of Site 1259, and the C/T boundary is closer to the FO of Q. Intermedium $(545.4\\\\mathrm{m}$ of Site 1259) (Erbacher et al., 2005; Hardas and Mutterlose, 2006; Bornemann et al., 2008). Thus, the depth of the C/T boundary is between $545.40\\\\mathrm{m}$ and $545.05\\\\mathrm{m}$ (the middle of two above FOs). We assigned the C/T boundary at $545.23\\\\mathrm{m}$ , the mid-point between $545.40\\\\mathrm{m}$ and $545.05\\\\mathrm{m}$ . The standard deviation (SD) of the depth of C/T boundary is defined based on the standard deviation of uniform distribution as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,261,937,293]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nS D = \\\\sqrt {\\\\frac {\\\\left(D _ {2} - D _ {1}\\\\right) ^ {2}}{1 2}} \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[507,303,937,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $D_{2}$ is the lower FO $(545.40\\\\mathrm{m})$ and $D_{1}$ is the upper FO $(545.05\\\\mathrm{m})$ . Therefore, the $SD$ is $0.10\\\\mathrm{m}$ in this case. The Turonian/Coniacian boundary is defined by the FO of M. furcatus (CC12/CC13) at $512.45\\\\mathrm{mcd}$ (Bornemann et al., 2008), which is equivalent to $510.7\\\\mathrm{mbsf}$ (Erbacher et al., 2004). The Coniacian/Santonian boundary is constrained between FO of L. grillii $(499.3\\\\mathrm{mcd})$ and FO of M. decussata $(501.2\\\\mathrm{mcd})$ (Bornemann et al., 2008), which is between $497.55\\\\mathrm{m}$ and $499.45\\\\mathrm{mbsf}$ (Erbacher et al., 2004). Thus, following the method above, the position for the Coniacian/Santonian boundary is $498.50\\\\mathrm{m}$ with a standard deviation of $0.55\\\\mathrm{m}$ . Calcareous nannofossil zones investigated in this study are the base of CC12 (CC11/CC12), the base of CC13 (CC12/CC13) and the base of CC14 (CC13/CC14), which correspond to depths of 521.51 mcd $(519.76\\\\mathrm{mbsf})$ , $512.45\\\\mathrm{mcd}$ $(510.7\\\\mathrm{mbsf})$ , and $501.2\\\\mathrm{mcd}$ $(499.50\\\\mathrm{mbsf})$ , respectively. Because no ash beds were found in this interval at Demerara Rise, the Cenomanian/Turonian boundary $(93.9 \\\\pm 0.15\\\\mathrm{Ma}$ , Meyers et al., 2012) in the Western Interior Basin, USA was chosen as the anchor for our ATS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,529,937,805]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Multiple paleoclimate proxies are from IODP Log Processing and Database (Erbacher et al., 2004) for Site 1259, including color reflection $\\\\mathrm{L}^*$ and $\\\\mathbf{b}^*$ , natural gamma radiation (NGR), and bulk density. These four proxies were used because they either have been proven carrying astronomical signals in the mid-Cretaceous of the Demerara Rise (e.g., $\\\\mathrm{L}^*$ and $\\\\mathbf{b}^*$ , Nederbragt et al., 2007) or have great potential to carry astronomical signals (e.g., density and gamma radiation, Li et al., 2019). Details of measurement methods for these proxies can be seen in Blum (1997). Rock color can be digitalized using a three-dimension color model such as the CIE LAB ( $\\\\mathrm{L}^*$ , $\\\\mathbf{a}^*$ , and $\\\\mathbf{b}^*$ ) color system (Robertson, 1977; Li et al., 2019). $\\\\mathrm{L}^*$ denotes lightness reflecting the richness of calcium carbonate, which is primarily influenced by carbonate productivity (Eldrett et al., 2015a, b). $\\\\mathbf{b}^*$ represents yellowness (positive values for yellow and negative values for blue), which may reflect iron-bearing minerals and bottom-water redox conditions (Li et al., 2019). These two proxies have been proven carrying astronomical signals in the Demerara Rise (Nederbragt et al., 2007). Changes in NGR and density in marine sediments represent variations in clay content; shale-rich beds show high NGR and low density while carbonate-rich beds show low NGR and high density. These data were collected from 497.25 to 550.48 mbsf, with a sampling resolution of $0.025\\\\mathrm{m}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,831,655,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2. Time series analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,857,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study applied a set of quantitative and statistical methods in time series analysis. Multi-taper method (MTM, Thomas, 1982) power spectral analysis and F-test evaluation were used to identify significant frequencies in paleoclimate proxies. Evolutive harmonic analysis (EHA) was performed to track spatial frequencies that are associated with astronomical frequencies with moving-window MTM analysis, which is to \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[766,42,937,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,66,884,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2. Stratigraphy, lithology, and proxy data at Site 1259. Biozones are from Bornemann et al. (2008). Data of Lightness, b*, density and NGR (natural gamma radiation) are from Erbacher et al. (2014) and $\\\\\\\\delta^{13}\\\\\\\\mathrm{C}_{\\\\\\\\mathrm{org}}$ are from Erbacher et al. (2015). \\\\\\\"Sant.\\\\\\\"-Santonian. \\\\\\\"Camp.\\\\\\\"-Campanian. \\\\\\\"Calc. nf.\\\\\\\"-Calcareous nanofossils. \\\\\\\"Litho.\\\\\\\"-lithology. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0692/0d4ba109fa2e8538906bab41cc294f5e3d0f8d09f2afc2ee89eaa6a41b50216a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[60,566,485,856]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"track variations of the sedimentation rates (Meyers et al., 2001; Ma et al., 2014; Eldrett et al., 2015a). Average spectral misfit (ASM, Meyers et al., 2007) was used to search for the optimal sedimentation rate via fitting the spatial frequencies to orbital frequencies and the null hypothesis of no astronomical forcing was tested with Monte Carlo realizations. To evaluate age models derived from different astrochronological techniques, we adopted two methods of constructing astronomical time scale based on the most stable long eccentricity cycle (Laskar et al., 2004): (1) time calibration using bandpass filtering of the recognized long eccentricity cycles (E1 bandpass, Li et al., 2016; Wu et al., 2018) and (2) tracking the long eccentricity from the EHA result (tracking EHA, Ma et al., 2018). Linearly detrending was first conducted to $\\\\mathrm{L}^*$ , $\\\\mathbf{b}^*$ , density, and NGR series. Then the EHA method was applied to the four datasets, with a moving window of $5\\\\mathrm{m}$ and a step of $0.1\\\\mathrm{m}$ (Fig. 3). Sedimentation rates were derived by tracking significant long eccentricity signal from EHA manually based on frequencies that are higher than $80\\\\%$ F-test probability (bottom panels in Fig. 3) and consistent with the long eccentricity frequencies identified from ASM results (Table 2). In the E1 bandpass method, long eccentricity cycles were extracted by using Gaussian bandpass filter from the four proxies based on the frequencies identified in ASM. All these analyses were performed using \\\"astrochron\\\" package in R (Meyers, 2014). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,871,129,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,897,203,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. Time series analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,923,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strong and straight frequency peaks revealed in EHA plots suggest a \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,566,937,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"relatively stable sedimentation rate (cf. Meyers et al., 2001). Based on characteristics of the EHA plots, the datasets were divided into four intervals (see black and white boxes in Fig. 3) to perform MTM power spectral analysis for the extraction of significant frequencies. These four intervals were: $497.25 - 510\\\\mathrm{m}$ , $510 - 520\\\\mathrm{m}$ , $520 - 530\\\\mathrm{m}$ , and $530 - 550.48\\\\mathrm{m}$ . Because of the different stability of frequencies in the EHA result of $\\\\mathbf{L}^*$ , the actual intervals from $510\\\\mathrm{m}$ to $530\\\\mathrm{m}$ in the ASM tests for $\\\\mathbf{L}^*$ were $510 - 517\\\\mathrm{m}$ and $517 - 530\\\\mathrm{m}$ (Fig. 3, Table 2 and Supplementary Figs. S1-S17). Significant frequencies passing the F-test with confidence level of $\\\\geq 80\\\\% - 95\\\\%$ (except the interval of $510 - 520\\\\mathrm{m}$ for the NGR, where an F-test confidence level of $\\\\geq 75\\\\%$ was used, Supplementary Materials) were tested with the ASM method. The null hypothesis of no astronomical forcing $(H_0)$ and the value of sedimentation rates were evaluated. The null hypothesis test in the ASM of all four intervals in the four proxies demonstrated that astronomical forcing had a significant impact on the paleoclimate proxies (see Supplementary Figs. S1-S17). There is only one ASM test of the interval $(497.25 - 510\\\\mathrm{m})$ for NGR that did not reject the null hypothesis. Sedimentation rates for the four intervals from the four proxies are listed in Table 1. By applying the sedimentation rates, astronomical cyclicities are listed in Table 2, based on which the astronomical signals were tracked on EHA results (red or white dashed lines in Fig. 3). The ASM results also guided the long eccentricity bandpass. The bandpass ranges of the four intervals of $497.25 - 510\\\\mathrm{m}$ , $510 - 520\\\\mathrm{m}$ , $520 - 530\\\\mathrm{m}$ , and $530 - 550.48\\\\mathrm{m}$ are $0.7 - 0.9$ cycle/m, $0.18 - 0.55$ cycle/m, $0.24 - 0.47$ cycle/m, and $0.07 - 0.29$ cycle/m, respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[766,42,937,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[65,66,929,802]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3. EHA results for $\\\\\\\\mathrm{L}^*$ (first column), $\\\\\\\\mathbf{b}^{*}$ (second column), density (third column), and NGR (fourth column). The first row of the plots shows evolutive power spectral analysis (EPSA) in log power. The second row shows the normalized amplitude of EHA. The third row shows the normalized, filtered amplitude $(80\\\\\\\\%)$ of EHA. The colored bars at the bottom for the second and third rows are the same. Red and white dotted lines indicate the trace of orbital frequencies, which are labeled with E1 (long eccentricity), E2-3 (short eccentricity), O1 (long obliquity), O2 (short obliquity), P1 (long precession), and P2 (short precession). The black (top row) and white (middle and bottom rows) boxes are the four intervals for separate ASM analyses. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0910/d6b7c26670c17bc100025207db1b4d97ce6996f94f4e9020dc057b081d07ebe0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[768,42,937,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[58,90,487,187]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0558/700ec294c315bbff6331b5a90825dfa686cfa29d72797d22589202554026c9dd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Interval (m)</td><td>Sedimentation rate (cm/ kyr)</td><td rowspan=\\\"2\\\">Interval (m)</td><td colspan=\\\"3\\\">Sedimentation rate (cm/ kyr)</td></tr><tr><td>L*</td><td>b*</td><td>Density</td><td>NGR</td></tr><tr><td>497.25–510</td><td>0.35</td><td>497.25–510</td><td>0.34</td><td>0.28</td><td></td></tr><tr><td>510–517</td><td>0.64</td><td>510–520</td><td>0.65</td><td>0.70</td><td>0.85</td></tr><tr><td>517–530</td><td>0.78</td><td>520–530</td><td>0.63</td><td>0.66</td><td>0.60</td></tr><tr><td>530–550.48</td><td>1.43</td><td>530–550.48</td><td>1.10</td><td>1.53</td><td>1.50</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1 Sedimentation rates obtained from the ASM test. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[58,205,315,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Construction of ATS and its uncertainty \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,230,485,441]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"405 kyr long eccentricity cycle is considered as the most stable astronomical cycle in Earth's history (Hinnov, 2018; Laskar et al., 2004; Ma et al., 2017), therefore, long eccentricity cycle was used for the construction of the ATS in this study. According to the ASM results (Tables 1 and 2), long eccentricity cycles tracked from the EHA results (Fig. 3) and long eccentricity bandpass were utilized for determining the sedimentation rate (Fig. 4). Sedimentation rates ranged from 2 to $0.2\\\\mathrm{cm / kyr}$ at Site 1269 from the Turonian to the Coniacian. Sedimentation rates were relatively high $(0.8 - 2\\\\mathrm{cm / kyr})$ in the early Turonian, then reached to a regional low sedimentation rate at around $0.5 - 1\\\\mathrm{cm / kyr}$ during the middle Turonian. It returned $\\\\sim 1\\\\mathrm{cm / kyr}$ during the latest Turonian and decreased to a relatively low rate of $\\\\sim 0.3\\\\mathrm{cm / kyr}$ during the Coniacian. Floating ATS was built by applying the sedimentation rates to each proxy. Finally, the absolute astronomical time scales of the four proxies were constructed by pinning the floating ATS to the Cenomanian/Turonian (C/T) boundary of $93.9\\\\pm 0.15$ Ma (Fig. 4). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,442,485,548]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The ATS enabled the determination of the mean and uncertainty of ages for stage and biozone boundaries of the Turonian-Coniacian interval (Table 3). Age models for the two methods (tracking EHA and E1 bandpass) were calculated separately. Statistical mean and standard deviation were calculated based on the four age models in each method (Table 3). We considered two sources of uncertainties: one was from ATS itself and the other one was from the anchor. Quadrature method was applied to combine uncertainties from the four age models in each \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"method and a 0.15-Myr uncertainty of the anchor. The total uncertainty was calculated by taking the square root of the sum of the variance from all sources. For example, the age for the Turonian/Coniacian boundary is $89.74 \\\\pm 0.35$ Ma based on four astrochronologies in the tracking EHA method (Table 3). Considering an 0.15-Myr uncertainty of the anchor, the total uncertainty is 0.38 Myr [obtained from sqrt(0.15 × 0.15 + 0.35 × 0.35)]. Thus, ages for the boundaries of CC11/CC12, Turonian/Coniacian (CC12/CC13), CC13/CC14, and Coniacian/Santonian are $91.17 \\\\pm 0.36$ Ma, $89.74 \\\\pm 0.38$ Ma, $86.13 \\\\pm 1.31$ Ma, and $85.80 \\\\pm 1.33$ Ma, respectively from tracking EHA method, comparing with $91.25 \\\\pm 0.20$ , $89.87 \\\\pm 0.20$ Ma, $86.36 \\\\pm 0.33$ Ma, and $86.03 \\\\pm 0.32$ Ma based on E1 bandpass method (Table 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,237,601,249]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,264,754,276]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4.1. Comparison with previous age models \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,288,937,540]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The consistency between key boundary ages in previous studies and our results demonstrates that our methods of estimating age model and uncertainties from multiple proxies are robust. The age of Turonian/ Coniacian boundary (TCB, which is equivalent to CC12/CC13 boundary) is constrained to $89.74 \\\\pm 0.41$ Ma by integrating biostratigraphy, radioisotopic geochronology, and cyclostratigraphy in Sageman et al. (2014). Eldrett et al. (2015a) applied similar methods as those used in Sageman et al. (2014) but on a different sedimentary record. They obtained the age for the TCB is $89.72 \\\\pm 0.17$ Ma. The radioisotopic ages used as anchors in Eldrett et al. (2015a) are from the ash beds in the studied core itself. In comparison, ages of ash beds in Sageman et al. (2014) are from the stratigraphic-correlated outcrop. This is one reason that the TCB age in Eldrett et al. (2015a) has smaller uncertainty. These two previous ages match well with the age of the same boundary obtained in our study: $89.74 \\\\pm 0.38$ Ma from the tracking EHA method and $89.87 \\\\pm 0.20$ Ma based on the E1 bandpass method. The age for the Coniacian/Santonian boundary (CSB) is $86.49 \\\\pm 0.44$ Ma in Sageman et al. (2014), which is within the range of the $85.80 \\\\pm 1.33$ Ma based on the tracking EHA method and $86.03 \\\\pm 0.32$ Ma from the E1 bandpass \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,590,939,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0666/57648ba202141c7421f56d0c91daf8735c1d17d58daf295768827b7fd8320b8e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Astronomical parameter</td><td colspan=\\\"6\\\">Astronomically forced frequencies (cycles/m)</td></tr><tr><td>Depth (m)</td><td>L*</td><td>Depth (m)</td><td>b*</td><td>Density</td><td>NGR</td></tr><tr><td>E1</td><td>497.25–510 m</td><td>0.75</td><td>497.25–510 m</td><td>0.84</td><td>0.85</td><td></td></tr><tr><td>E2</td><td></td><td>2.20</td><td></td><td>2.19</td><td>2.80</td><td></td></tr><tr><td>E3</td><td></td><td>3.03</td><td></td><td>3.02</td><td>3.60</td><td></td></tr><tr><td>O1</td><td></td><td>5.75</td><td></td><td>5.98</td><td>7.40</td><td></td></tr><tr><td>O2</td><td></td><td>7.64</td><td></td><td>7.75</td><td>9.30</td><td></td></tr><tr><td>P1</td><td></td><td>12.66</td><td></td><td>12.99</td><td>15.83</td><td></td></tr><tr><td>P2</td><td></td><td>15.46</td><td></td><td>16.06</td><td>19.18</td><td></td></tr><tr><td>E1</td><td>510–517 m</td><td>0.50</td><td>510–520 m</td><td>0.37</td><td>0.38</td><td>0.23</td></tr><tr><td>E2</td><td></td><td>1.09</td><td></td><td>1.33</td><td>1.17</td><td>1.09</td></tr><tr><td>E3</td><td></td><td>1.83</td><td></td><td>1.66</td><td>1.50</td><td>1.27</td></tr><tr><td>O1</td><td></td><td>3.12</td><td></td><td>3.08</td><td>2.94</td><td>2.39</td></tr><tr><td>O2</td><td></td><td>4.09</td><td></td><td>4.03</td><td>3.89</td><td>3.12</td></tr><tr><td>P1</td><td></td><td>7.09</td><td></td><td>6.84</td><td>6.38</td><td>5.22</td></tr><tr><td>P2</td><td></td><td>8.40</td><td></td><td>8.10</td><td>7.82</td><td>6.46</td></tr><tr><td>E1</td><td>517–530 m</td><td>0.37</td><td>520–530 m</td><td>0.37</td><td>0.36</td><td>0.34</td></tr><tr><td>E2</td><td></td><td>1.12</td><td></td><td>1.23</td><td>1.19</td><td>1.41</td></tr><tr><td>E3</td><td></td><td>1.36</td><td></td><td>1.60</td><td>1.61</td><td>1.71</td></tr><tr><td>O1</td><td></td><td>2.72</td><td></td><td>3.10</td><td>3.05</td><td>3.34</td></tr><tr><td>O2</td><td></td><td>3.31</td><td></td><td>4.23</td><td>4.21</td><td>4.39</td></tr><tr><td>P1</td><td></td><td>5.67</td><td></td><td>7.18</td><td>6.85</td><td>7.39</td></tr><tr><td>P2</td><td></td><td>6.87</td><td></td><td>8.66</td><td>8.29</td><td>9.16</td></tr><tr><td>E1</td><td>530–550.48 m</td><td>0.17</td><td>530–550.48 m</td><td>0.24</td><td>0.16</td><td>0.12</td></tr><tr><td>E2</td><td></td><td>0.51</td><td></td><td>0.75</td><td>0.52</td><td>null</td></tr><tr><td>E3</td><td></td><td>0.74</td><td></td><td>0.93</td><td>0.75</td><td>0.75</td></tr><tr><td>O1</td><td></td><td>1.39</td><td></td><td>1.81</td><td>1.40</td><td>1.40</td></tr><tr><td>O2</td><td></td><td>1.87</td><td></td><td>2.39</td><td>1.70</td><td>1.56</td></tr><tr><td>P1</td><td></td><td>3.09</td><td></td><td>4.05</td><td>2.92</td><td>3.02</td></tr><tr><td>P2</td><td></td><td>3.84</td><td></td><td>4.97</td><td>3.52</td><td>3.61</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2 Astronomically forced frequency (E1: long eccentricity, E2 and E3: short eccentricity, O1 and O2: obliquity, P1 and P2: precession). \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[768,42,937,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[115,66,887,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4. Age models and sedimentation rate histories. Age models using both tracking EHA and E1 bandpass methods were based on four proxies of L\\\\\\\\* (red), b\\\\\\\\* (blue), NGR (purple), and density (light green) proxies. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0509/d4aa371bbd2c2e45c58d5dc505e2cb665f3efaf75da5c9a9a05aa07543d35073.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,552,186,564]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"method in our study. \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,564,485,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However, there are also some inconsistencies in the age models between previous work and this study. The age for the C11/C12 boundary was constrained as $93.11 \\\\pm 0.17$ Ma in Eldrett et al. (2015a), which is $\\\\sim 2$ Ma older than the age of $91.17 \\\\pm 0.32$ Ma from the tracking EHA method and $91.25 \\\\pm 0.20$ Ma based on the E1 bandpass method in our study. The CC12/CC13 boundary was used as an indicator of the TCB at the Cretaceous Demerara Rise (Bornneman et al., 2008). Recent work suggests that the TCB in Texas may occur near the middle of the CC13 biozone (Corbett et al., 2014). The Turonian/Coniacian boundary is defined by the base of the Scaphites preventtricosus ammonite biozone, which is coincident with the CC14/CC13 boundary (Gradstein et al., 2012). These suggest that calcareous nannofossil biostratigraphy may not be as stable \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,552,937,576]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"as ammonite biostratigraphy for the age model construction in the Upper Cretaceous. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,578,937,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our age model is different from a previous study at the same core (Jones et al., 2018). They constructed an age model for the stratigraphy of core 1259A from $508\\\\mathrm{m}$ to $530\\\\mathrm{m}$ of Site 1259 based on cyclostratigraphy of calcium carbonate data and chemostratigraphy of carbon isotope (Supplementary Fig. S2). Their depth unit is meter composite depth (mcd), which is $\\\\sim 1.75\\\\mathrm{m}$ deeper than mbsf of Hole A in our study. The sedimentation rate model by Jones et al. (2018) has a substantial difference from 512 mbsf to 520 mbsf, which is $\\\\sim 0.2\\\\mathrm{cm / kyr}$ , while the sedimentation rate in our study is $0.64 - 0.85\\\\mathrm{cm / kyr}$ . Other than this interval, sedimentation rate models in these two studies are similar (Supplementary Fig. S2). Because there is no anchor in their age model at \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,764,937,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0835/6ceec89df8726cc658f3067690235f365d8415f04c182f3b9c03531ac46bf0a0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Boundaries</td><td colspan=\\\"5\\\">Age Models (Ma)</td><td rowspan=\\\"2\\\">Mean (Ma)</td><td rowspan=\\\"2\\\">Age Model Uncertaintyb(2σ) (Ma)</td><td rowspan=\\\"2\\\">Total Uncertaintyc(Ma)</td><td rowspan=\\\"2\\\">Age (Ma) (from Sageman et al., 2014)</td><td rowspan=\\\"2\\\">Age (Ma) (from Eldrett et al., 2015a)</td></tr><tr><td>Modelsa</td><td>L*</td><td>b*</td><td>Density</td><td>NGR</td></tr><tr><td rowspan=\\\"2\\\">CC11/CC12</td><td>A</td><td>91.02</td><td>91.23</td><td>91.06</td><td>91.37</td><td>91.17</td><td>0.32</td><td>0.36</td><td>No data</td><td>93.11 ± 0.17</td></tr><tr><td>B</td><td>91.19</td><td>91.28</td><td>91.42</td><td>91.09</td><td>91.25</td><td>0.13</td><td>0.20</td><td></td><td></td></tr><tr><td rowspan=\\\"2\\\">Turonian/Coniacian (CC12/CC13)</td><td>A</td><td>89.68</td><td>89.53</td><td>89.82</td><td>89.94</td><td>89.74</td><td>0.35</td><td>0.38</td><td>89.74 ± 0.41</td><td>89.72 ± 0.17</td></tr><tr><td>B</td><td>89.73</td><td>89.90</td><td>90.05</td><td>89.78</td><td>89.87</td><td>0.13</td><td>0.20</td><td></td><td></td></tr><tr><td rowspan=\\\"2\\\">CC13/CC14</td><td>A</td><td>86.49</td><td>85.53</td><td>85.64</td><td>86.87</td><td>86.13</td><td>1.31</td><td>1.31</td><td>No data</td><td>No data</td></tr><tr><td>B</td><td>86.30</td><td>86.33</td><td>86.44</td><td>86.38</td><td>86.36</td><td>0.29</td><td>0.33</td><td></td><td></td></tr><tr><td rowspan=\\\"2\\\">Coniacian/Santonian</td><td>A</td><td>86.18</td><td>85.23</td><td>85.25</td><td>86.54</td><td>85.80</td><td>1.33</td><td>1.33</td><td>86.49 ± 0.44</td><td>No data</td></tr><tr><td>B</td><td>85.98</td><td>85.97</td><td>86.11</td><td>86.08</td><td>86.03</td><td>0.28</td><td>0.32</td><td></td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3 Age for stage and biozone boundaries. \\\"]\",\n \"table_footnote\": \"[\\\"a A. Tracking EHA method; B. E1 bandpass method. \\\",\\\"b Uncertainty $(2\\\\\\\\sigma)$ from different age models based on different proxies. \\\",\\\"Total uncertainty derived by adding age model uncertainty and anchor (C/T boundary) uncertainty in quadrature. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[766,42,937,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Site 1259, we align two extreme age models based on their floating astronomical time scale to our age models (Supplementary Fig. S2). The age model of Jones et al. (2018) (left light blue curve in Supplementary Fig. S2) assigns a $100 - 200\\\\mathrm{kyr}$ duration to the interval from 528 mbsf to 545 mbsf at Site 1259, which implies that the sedimentation rate for this interval is $8.5 - 17~\\\\mathrm{cm / kyr}$ , an unreasonable range for the shale deposition of this interval at Demerara Rise. Another scenario (right light blue curve in Supplementary Fig. S2) would make the TCB be $88.6\\\\mathrm{Ma}$ , which is 1000 kyr younger than previous studies (Sageman et al., 2014; Eldrett et al., 2015a). Consequently, we argue that our age model is more practical. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,225,247,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4.2. Signal and noise evaluation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,250,485,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In cyclostratigraphic study, the signal usually refers to astronomical-related climate oscillations (i.e., eccentricity, obliquity, and precession cycles) while the noise frequently refers to the residual oscillations or non-orbital related components. In a statistical sense, ASM results and sedimentation rate histories from all four proxies in both methods of E1 bandpass and tracking EHA are similar along with the record (Tables 1 and 2, Fig. 4). All of them indicate that these proxy oscillations are of the astronomical origin at Site 1259 of the Demerara Rise. For the $\\\\mathrm{L}^*$ within the interval of $510\\\\mathrm{m}$ to $530\\\\mathrm{m}$ , subdivision for ASM tests is different from the other three proxies. And the ASM-derived sedimentation rates of the $\\\\mathrm{L}^*$ series at the $520 - 530\\\\mathrm{m}$ interval are higher than those derived from the other three proxies. This may be caused by the low signal-to-noise ratio in the $\\\\mathrm{L}^*$ record, which could reduce the relative power of astronomical signals at this interval. Proxy's oscillations during the Coniacian may have a low signal-to-noise ratio, indicated by no reliable ASM result in the NGR data (Table 2). Different proxies in the same stratigraphy display different degrees of signal-to-noise ratio; even in some intervals, a specified proxy may not preserve strong astronomical signals due to strong noise. In a few intervals of a specified proxy in this study, identified astronomical cycles have lower confidence levels. For instance, the confidence level (CL) of filtering spatial frequencies that were analyzed in ASM for NGR within the interval of $510 - 520\\\\mathrm{m}$ is $75\\\\%$ , while the CLs of the similar spatial frequencies in $\\\\mathrm{L}^*$ , $\\\\mathbf{b}^*$ and density are $90\\\\%$ , $80\\\\%$ , and $90\\\\%$ respectively. We can imagine that if only NGR was used in this interval, the result may be questionable because of the high probability of false-positive frequencies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,593,485,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sources of noise in paleoclimate oscillations fall into two categories: syndepositional noise and postdepositional noise. The syndepositional noise happens during the depositional processes, including basinal uplift/subsidence, volcanic eruptions, earthquakes, and autogenic processes, among others (Li et al., 2018). These noises could be recorded in most of the proxies that display comparable noise profiles. For example, ash beds should be removed from all proxies before the evaluation of astronomical signals. Postdepositional noise includes sources from bioturbation, compaction, and diagenesis that take place after the deposition of sediments (Weedon, 2003). Various types of diagenesis (e.g., oxygenation and remineralization) may affect different proxies in sedimentary rocks. The $\\\\mathrm{L}^*$ that reflects the carbonate versus organic matter may be affected by the remineralization of carbonate. The $\\\\mathbf{b}^*$ that reflects iron-bearing minerals and bottom water redox conditions could also be affected by the redox conditions after deposition (Li et al., 2019). Three main sources of natural gamma radiation are radiogenic isotopes of potassium (K), uranium (U) and thorium (Th) (Ruffell and Worden, 2000). Post-depositional migration of organic matter could affect the radiogenic source of U, thus natural gamma radiation (Li et al., 2019). Bulk density indicates changes in lithology and porosity (Blum, 1997). Post-depositional processes such as different compaction and mineral alternation lead to elevated \\\"noise\\\" in density data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,883,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Taken together, cyclostratigrapher should be careful when conducting cyclostratigraphic studies based on a single proxy. Identifying the same astronomical cycles from multiple proxies in the same strata is shown here to be a practical way to overcome the risks of low signal-to \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,92]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"noise ratio and false-positive frequencies identified as astronomical signals. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,110,794,123]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4.3. Challenges and opportunities of our methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,136,937,427]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There are two main methods of constructing an astronomical time scale for deep time beyond $50\\\\mathrm{Ma}$ : tracking a specific orbital frequency from the EHA method (Eldrett et al., 2015; Ma et al., 2017) and bandpass filtering of a specific orbital cycle (Li et al., 2016; Wu et al., 2018). Both have their own limitations. Paleoclimate proxies are not only influenced by astronomical forcing, non-astronomical forcing may lead to very low signal-to-noise ratio, which has influences on both tracking EHA and bandpass methods. The tracking EHA method has subjective uncertainties in tracking frequencies from the EHA plot: (1) it is manually tracked and (2) the tracked frequencies must be larger than a given confidence level. Clearly, this method subjectively introduces uncertainties to the construction of sedimentation rates and age models. Cyclostratigraphers have to make choices of tracked frequency peaks based on their experience. This uncertainty is impossible to quantify when only one proxy data is used. In comparison, approaches of the bandpass filtering have subjective uncertainties as well (Sinnesael et al., 2019). There are no universally accepted choices of frequency bands for the filtering of a specific astronomical signal (Zeeden et al., 2018). Different filtering settings, which usually depend on cyclostratigraphers' decision, may result in different age models. In sum, the subjective uncertainties in both methods are affected by the knowledge and experience of the cyclostratographer (Sinnesael et al., 2019). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,441,605,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5. Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,467,937,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Consistency of time series analyses on four proxies $(\\\\mathrm{L}^{*},\\\\mathrm{b}^{*}$ , density, and NGR) using two methods (tracking EHA and E1 bandpass methods) demonstrates the existence of astronomical forcing during the Turonian throughout the Santonian at the Demerara Rise in the equatorial Atlantic. Results of the astronomical time scale based on four proxies in both methods are different, demonstrating different paleoclimate proxies may preserve different signal-to-noise ratios in the aspect of astronomical forcing. This issue can be addressed from the statistical uncertainty of these astronomical time scales based on four proxies in both methods. The final uncertainty of the astronomical time scales was obtained by the quadrature algorithm applied to uncertainties from proxies and uncertainty from the anchor. The calibrated ages of the boundaries of CC11/ CC12, Turonian/Coniacian (CC12/CC13), CC13/CC14 and Coniacian/ Santonian compare well with previous studies (Sageman et al., 2014; Eldrett et al., 2015a). Future works could be quantifying non-astronomical noises in different paleoclimate proxies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,697,729,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Declaration of competing interest \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,723,937,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,776,633,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgement \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,803,937,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We thank James Eldrett and Stephen R. Meyers for their discussions. We also thank two anonymous reviewers for their constructive comments that improved this paper. This study was supported by NSF CAREER award to Stephen R. Meyers (EAR-1151438) and partially supported by the NSF Grant with No. 1835717. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,883,729,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Appendix A. Supplementary data \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,910,936,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplementary data to this article can be found online at https://doi.org/10.1016/j.gsf.2020.01.013. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[766,42,937,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[58,66,132,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,90,482,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Blum, P., 1997. Physical properties handbook. In: ODP Tech. Note, 26. https://doi.org/10.2973/odp.tn.26.1997. \\\",\\\"Bornemann, A., Norris, R.D., Friedrich, O., Beckmann, B., Schouten, S., Damsté, J.S.S., Vogel, J., Hofmann, P., Wagner, T., 2008. Isotopic evidence for glaciation during the Cretaceous supergreenhouse. Science 319 (5860), 189-192. \\\",\\\"Corbett, M.J., Watkins, D.K., Pospichal, J.J., 2014. A quantitative analysis of calcareous nannofossil bioevents of the Late Cretaceous (Late Cenomanian-Coniacian) Western Interior Seaway and their reliability in established zonation schemes. Mar. Micropaleontol. 109, 30-45. \\\",\\\"De Vleeschouwer, D., Parnell, A.C., 2014. Reducing time-scale uncertainty for the Devonian by integrating astrochronology and Bayesian statistics. Geology 42 (6), 491-494. \\\",\\\"Eldrett, J.S., Ma, C., Bergman, S.C., Lutz, B., Gregory, F.J., Dodsworth, P., Phipps, M., Hardas, P., Minisini, D., Ozkan, A., Ramezani, J., 2015a. 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Ocean Drilling Program, College Station, TX. https://doi.org/10.2973/odp.procr.ir.207.2004. \\\",\\\"Gradstein, F.M., Ogg, J.G., Schmitz, M.D., Ogg, G., 2012. The Geologic Time Scale 2012. Elsevier, Amsterdam, p. 1144. \\\",\\\"Hardas, P., Mutterlose, J., 2006. Calcareous nannofossil biostratigraphy of the cenomanian/turonian boundary interval of ODP Leg 207 at the Demerara Rise. Rev. Micropaleontol. 49 (3), 165-179. \\\",\\\"Hinnov, L.A., 2018. Cyclostratigraphy and astrochronology in 2018. Cyclostratigr. Astrochronol. 3 (1). \\\",\\\"Jones, M.M., Sageman, B.B., Meyers, S.R., 2018. Turonian sea level and paleoclimatic events in astronomically tuned records from the tropical north Atlantic and western interior seaway. Paleoceanogr. Paleoclimatol. 33 (5), 470-492. \\\",\\\"Kuiper, K.F., Deino, A., Hilgen, F.J., Krijgsman, W., Renne, P.R., Wijbrans, A.J., 2008. Synchronizing rock clocks of Earth history. 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Rev. 189, 125-146. \\\",\\\"Locklair, R.E., Sageman, B.B., 2008. *Cyclostratigraphy of the upper cretaceous niobrara formation*, western interior, USA: a coniacian-santonian orbital timescale. Earth Planet Sci. Lett. 269 (3-4), 540-553. \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[512,66,934,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Ma, C., Meyers, S.R., Sageman, B.B., 2019. Testing Late Cretaceous astronomical solutions in a 15 million year astrochronologic record from North America. Earth Planet Sci. Lett. 513, 1-11. \\\",\\\"Ma, C., Meyers, S.R., Sageman, B.B., 2017a. Theory of chaotic orbital variations confirmed by Cretaceous geological evidence. Nature 542 (7642), 468. \\\",\\\"Ma, C., Meyers, S.R., Sageman, B.B., Singer, B.S., Jicha, B.R., 2014. Testing the astronomical time scale for oceanic anoxic event 2, and its extension into Genomanian strata of the Western Interior Basin (USA). Geol. Soc. Am. Bull. 126 (7-8), 974-989. \\\",\\\"Ma, P., Wang, C., Meng, J., Ma, C., Zhao, X., Li, Y., Wang, M., 2017b. Late Oligocene-early Miocene evolution of the Lunpola Basin, central Tibetan Plateau, evidences from successive lacustrine records. Gondwana Res. 48, 224-236. \\\",\\\"Meyers, S.R., Sageman, B.B., Hinnov, L.A., 2001. Integrated quantitative stratigraphy of the Cenomanian-Turonian Bridge Creek Limestone Member using evolutive harmonic analysis and stratigraphic modeling. J. Sediment. Res. 71 (4), 628-644. \\\",\\\"Meyers, S.R., Sageman, B.B., 2007. Quantification of deep-time orbital forcing by average spectral misfit. Am. J. Sci. 307 (5), 773-792. \\\",\\\"Meyers, S.R., Siewert, S.E., Singer, B.S., Sageman, B.B., Condon, D.J., Obradovich, J.D., Jicha, B.R., Sawyer, D.A., 2012. Intercalibration of radioisotopic and astrochronologic time scales for the Cenomanian-Turonian boundary interval, Western Interior Basin, USA. Geology 40 (1), 7-10. \\\",\\\"Nederbragt, A.J., Thurow, J., Pearce, R., 2007. Sediment composition and cyclicity in the mid-cretaceous at Demerara Rise, ODP Leg 207. In: Proceedings of the Ocean Drilling Program, Scientific Results, vol 207, pp. 1-31. \\\",\\\"Robertson, A.R., 1977. The CIE 1976 color-difference formulae. Color Res. Appl. 2 (1), 7-11. \\\",\\\"Ruffell, A., Worden, R., 2000. Palaeoclimate analysis using spectral gamma-ray data from the Aptian (Cretaceous) of southern England and southern France. Palaeogeogr. Palaeoclimatol. Palaeoecol. 155 (3-4), 265-283. \\\",\\\"Sageman, B.B., Singer, B.S., Meyers, S.R., Siewert, S.E., Walaszczyk, I., Condon, D.J., Jicha, B.R., Obradovich, J.D., Sawyer, D.A., 2014. Integrating 40Ar/39Ar, U-Pb, and astronomical clocks in the cretaceous niobrara formation, western Interior Basin, USA. Bulletin 126 (7-8), 956-973. \\\",\\\"Sinnaesel, M., De Vleeschouwer, D., Zeeden, C., Batenburg, S.J., Da Silva, A.-C., de Winter, N.J., Dinarès-Turell, J., Drury, A.J., Gambacorta, G., Hilgen, F.J., Hinnov, L.A., Hudson, A.J.L., Kemp, D.B., Lantink, M.L., Laurin, J., Li, M., Liebrand, D., Ma, C., Meyers, S.R., Monkenbusch, J., Montanari, A., Nohl, T., Pälike, H., Pas, D., Ruhl, M., Thibault, N., Vahlenkamp, M., Valero, L., Wouters, S., Wu, H., Claeys, P., 2019. The Cyclostratigraphy Intercomparison Project (CIP): consistency, merits and pitfalls. Earth Sci. Rev. 199, 102965. https://doi.org/10.1016/j.earscriv.2019.102965. \\\",\\\"Thomson, D.J., 1982. Spectrum estimation and harmonic analysis. Proc. IEEE 70 (9), 1055-1096. \\\",\\\"Weedon, G.P., 2003. Time Series Analysis and Cyclostratigraphy: Examining Stratigraphic Records of Environmental Cycles. Cambridge University Press. \\\",\\\"Westerhold, T., Röhl, U., Laskar, J., 2012. Time scale controversy: accurate orbital calibration of the early Paleogene. G-cubed 13 (6). \\\",\\\"Wu, H., Fang, Q., Wang, X., Hinnov, L.A., Qi, Y., Shen, S.Z., Yang, T., Li, H., Chen, J., Zhang, S., 2018. An 34 my astronomical time scale for the uppermost Mississippian through Pennsylvanian of the Carboniferous System of the Paleo-Tethyan realm. Geology 47 (1), 83-86. \\\",\\\"Zeeden, C., Kaboth, S., Hilgen, F.J., Laskar, J., 2018. Taner filter settings and automatic correlation optimisation for cyclostratigraphic studies. Comput. Geosci. 119, 18-28. \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[366,12,589,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE IN PRESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,42,122,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Ma, M. Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[766,42,937,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Geoscience Frontiers xxx (xxxx) xxx \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1016/j.gsf.2020.01.013"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Earth and Atmospheric Sciences"},"sha256":{"kind":"string","value":"6575e916481063fa98a23b8fbb4837abac2565f0df52a633facb59ea47f5d138"},"title":{"kind":"string","value":"Astronomical time scale of the Turonian constrained by multiple paleoclimate proxies"}}},{"rowIdx":155,"cells":{"abstract":{"kind":"string","value":"\n \nReal-time transrectal ultrasound (TRUS) image guidance during robot-assisted laparoscopic radical prostatectomy has the potential to enhance surgery outcomes. Whether conventional or photoacoustic TRUS is used, the robotic system and the TRUS must be registered to each other. Accurate registration can be performed using photoacoustic (PA markers). However, this requires a manual search by an assistant [19]. This paper introduces the first automatic search for PA markers using a transrectal ultrasound robot. This effectively reduces the challenges associated with the da Vinci-TRUS registration. This paper investigated the performance of three search algorithms in simulation and experiment: Weighted Average (WA), Golden Section Search (GSS), and Ternary Search (TS). For validation, a surgical prostate scenario was mimicked and various ex vivo tissues were tested. As a result, the WA algorithm can achieve 0.53 degree average error after 9 data acquisitions, while the TS and GSS algorithm can achieve 0.29 degree and 0.48 degree average errors after 28 data acquisitions.\n "},"author":{"kind":"string","value":"Hyunwoo Song|Hamid Moradi|Shuojue Yang|Septimiu E. Salcudean|Emad M. Boctor|Zijian Wu"},"content_list":{"kind":"list like","value":[{"bbox":"[187,117,769,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Automatic Search for Photoacoustic Marker Using Automated Transrectal Ultrasound ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,178,759,213]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ZIJIAN WU $^{1\\dagger}$ , HAMID MORADI $^{2\\dagger}$ , SHUOJUE YANG $^{3}$ , HYUNWOO SONG $^{1,4}$ , EMAD M. BOCTOR $^{1,4*}$ , AND SEPTIMIU E. SALCUBEAN $^{2*}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,218,795,231]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"<sup>1</sup>Johns Hopkins University, Laboratory for Computational Sensing and Robotics, Baltimore, MD, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,231,784,244]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{2}$ University of British Columbia, Dept. of Electrical and Computer Engineering, Vancouver, BC, CA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,244,759,258]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"<sup>3</sup>University of Texas at Austin, Walker Department of Mechanical Engineering, Austin, TX, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,258,645,271]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4Johns Hopkins University, Dept. of Computer Science, Baltimore, MD, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,271,380,284]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{\\dagger}$ Equal Authorship Contribution ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,284,406,297]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"*tims@ece.ubc.ca; eboctor@jhu.edu ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,311,810,503]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: Real-time transrectal ultrasound (TRUS) image guidance during robot-assisted laparoscopic radical prostatectomy has the potential to enhance surgery outcomes. Whether conventional or photoacoustic TRUS is used, the robotic system and the TRUS must be registered to each other. Accurate registration can be performed using photoacoustic (PA markers). However, this requires a manual search by an assistant [19]. This paper introduces the first automatic search for PA markers using a transrectal ultrasound robot. This effectively reduces the challenges associated with the da Vinci-TRUS registration. This paper investigated the performance of three search algorithms in simulation and experiment: Weighted Average (WA), Golden Section Search (GSS), and Ternary Search (TS). For validation, a surgical prostate scenario was mimicked and various ex vivo tissues were tested. As a result, the WA algorithm can achieve $0.53^{\\circ} \\pm 0.30^{\\circ}$ average error after 9 data acquisitions, while the TS and GSS algorithm can achieve $0.29^{\\circ} \\pm 0.31^{\\circ}$ and $0.48^{\\circ} \\pm 0.32^{\\circ}$ average errors after 28 data acquisitions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,517,807,541]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2021 Optica Publishing Group under the terms of the Optica Publishing Group Open Access Publishing Agreement ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,556,316,569]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,571,808,773]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Prostate cancer (PCa) is one of the most common malignant tumors among men worldwide, with a high mortality rate [1]. According to [2], $11.6\\%$ of men will develop prostate cancer in their lifetime, with approximately a $20\\%$ death rate in the United States. Radical prostatectomy is a popular surgical approach to treat PCa by removing the entire prostate gland since 1905 [3,4]. In clinical practice, the traditional open radical prostatectomy (ORP) has almost been replaced by laparoscopic radical prostatectomy (RLP) [5]. As a minimally invasive surgical procedure for PCa, RLP significantly reduces blood loss, hospitalization duration, and postoperative complications [6]. However, the long learning curve associated with laparoscopic procedures limits the application of RLP [7]. Robot-assisted laparoscopic prostatectomy (RALP) has been demonstrated [5] to shorten this learning curve by leveraging the wristed instruments and the 3-D endoscopic camera of the telerobotic surgical system, usually the da Vinci surgical system, to achieve intuitive operation [8]. However, the endoscopic camera cannot localize the prostate lesions nor visualize the sub-surface anatomy of the prostate gland. Therefore, a complementary medical imaging modality is necessary to facilitate RALP. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,775,808,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Transrectal ultrasound (TRUS) facilitates the intraoperative identification of vital anatomic structures of the prostate gland and adjacent tissues, e.g., peripheral nerve and neurovascular bundles (NVBs), in a non-invasive and real-time manner [9]. TRUS provides precise ultrasound images of tissue pointed by the surgeon with the instrument. A robotic transrectal ultrasound system for prostatectomy was presented to alleviate the inconvenience of manipulating the TRUS and has been adopted in RALP studies [10-12]. The da Vinci and TRUS coordinate systems are registered by touching the tissue with the instrument tip at three or more different ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,117,810,146]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"locations. However, the search process for each location is manual, time-consuming, and requires an additional skilled operator in the operating room [11]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,147,810,349]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A very accurate alternative registration method between the TRUS and the da Vinci system involves the use of photoacoustic markers (PMs), which are generated by the so-called photoacoustic effect, i.e., the formation of acoustic waves when a pulsed laser source is absorbed by optical materials. Robot assisted photoacoustic imaging using the da Vinci surgical system was investigated in [13-16]. In [17], authors demonstrated that photoacoustic markers generated by a pulsed laser could be reconstructed as images representing the local optical absorption of tissue constituents. Cheng et al. [18]'s research proved the feasibility and advantages of PM in surgical guidance. Instead of physically touching the tissue, a photoacoustic (PA) approach using focused laser illumination as the PM was introduced in [19], in which the registration between the endoscopic stereo camera frame and the TRUS frame was performed using Horn's method [33]. While accurate, this registration is still time-consuming (as much as $7\\mathrm{min}$ ), because the TRUS is manually rotated to align its imaging plane to the laser spots. Driven by this limitation, an automatic image-based search for the photoacoustic markers is proposed in this paper. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,349,810,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The directivity pattern of clinical transducer was investigated in [20]. The PA image intensity is proportional to the distance between the PM and the TRUS imaging plane. When the PM is coplanar with the imaging plane of the TRUS transducer, the detected PA image intensity of the PM is maximum [21]. Therefore, we have a PA image intensity function, which should be unimodal and symmetric. Based on this, the key component of our work is to conduct a one-dimensional search in the presence of PA imaging to find the position corresponding to the maximum PA intensity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,452,810,537]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The numerical optimization of unimodal functions in one-dimensional (1-D) search space is a common topic in many engineering fields [22-24]. Introducing an efficient algorithm to replace the exhaustive search will significantly shorten the duration of the registration. The Golden Section Search (GSS) algorithm [25] is a classic approach to solve this maximization problem. Similarly, Ternary Search (TS) algorithm is a widely used divide-and-conquer algorithm for searching the maximum of a unimodal function [26,27]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,539,810,597]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this paper, we propose a novel automatic search module to localize the PMs using the robotized transrectal ultrasound actuator in robot-assisted radical laparoscopic prostatectomy. We simulate and experimentally evaluate several optimization algorithms. The proposed framework outperforms the manual search in terms of time and required technical staff. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,604,282,618]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Method ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[186,626,354,638]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1 Problem Definition ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,640,810,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In our RALP system depicted in Fig. 1. (a), a laser source generates a PM on the surface of the tissue. This PM can be detected by a TRUS beneath the tissue. This detected intensity of the PM achieves a maximum when the US imaging plane is coplanar with the PM, namely the TRUS is at the angle $\\theta_{p}$ , and attenuates when the imaging plane moving away from $\\theta_{p}$ . As described in Fig. 1. (b), there is a PA signal intensity function related to the rotation angle of the TRUS. Theoretically, this intensity function is unimodal and symmetric if noise is not considered [20], and we are searching for its peak. We can drive the motorized TRUS to rotate within $-35^{\\circ}$ to $35^{\\circ}$ , providing enough coverage for the prostate imaging, and synchronously calculate PA signal intensity at each location using the $\\mathrm{US + PA}$ imaging system. In this way, we will investigate efficient algorithms to solve this problem compared to the manual scanning. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[264,119,509,292]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0516/07de968d79f3142ba0148e3c71158134bf8c384091d782c92c845cbe63cec7f9.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[545,119,769,292]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. (a) The laser illuminates a small spot (PM). The motorized TRUS is located at $\\\\theta_{i}$ . The goal is to find $\\\\theta_{p}$ of the PA marker. (b) The TRUS also receives out-of-plane signals. Therefore, PA signals will be recorded at different angles. \"]","image_footnote":"[]","img_path":"images/0318/d1efbd1877dbc46e74c333d3b84e4af8816dd9d533cd943cce43c842b14f6fec.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,337,354,352]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2 Weighted Average ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,352,808,444]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The laser illuminates a small spot as shown in Fig. 1. (a). The motorized TRUS rotates from $-35^{\\circ}$ to $35^{\\circ}$ in equal increments of $\\theta_{d}$ at $\\theta_{i}$ s where $i = 1, \\dots, N$ for a full scan. The goal is to find $\\theta_{p}$ in the TRUS coordinate system. The TRUS also receives out-of-plane signals. The maximum PA signal intensity, $S(\\theta_{i})$ , is recorded for each $\\theta_{i}$ , described in Fig. 1. (b). As the directivity pattern of the TRUS transducer with respect to the incoming waves is symmetric, a simple weighted average can be used to localize the PA marker, $\\theta_{p}$ : ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[346,444,648,470]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\theta_ {p} = \\sum \\theta_ {i} S (\\theta_ {i}) / \\sum S (\\theta_ {i}), i = 1, \\dots , N \\# (1.)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[184,477,808,507]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Note that we need to set a threshold to filter out the samples with very low or no PA signal intensity. This helps to reduce noise and improve localization accuracy. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,513,537,529]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.3 Golden Section Search and Ternary Search ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,536,808,657]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Golden Section Search (GSS) is an efficient algorithm for finding the extremum (maximum or minimum) of a unimodal function. The GSS has been widely used in many applications because of its rapid convergence, without requiring that the objective function be continuous. In the GSS algorithm, we compare a pair of observation at two interior points $\\theta_{m,1},\\theta_{m,2}\\in R$ satisfying $\\theta_l < \\theta_{m,1} < \\theta_{m,2} < \\theta_r$ for each iteration. The two interior points partition the search interval in terms of the golden section ratio $r$ . Here, we set the initial value of $\\theta_l$ and $\\theta_r$ as $-35^{\\circ}$ and $35^{\\circ}$ . They are updated at each iteration and eventually convergence towards $\\theta_p$ . The interior points $\\theta_{m,1}$ and $\\theta_{m,2}$ are computed as follows: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[410,657,584,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nr = \\frac {\\sqrt {5} - 1}{2} \\approx 0. 6 1 8 \\# (2.)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[390,686,604,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\theta_ {m, 1} = r \\theta_ {l} + (1 - r) \\theta_ {r} \\# (3.)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[390,702,604,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\theta_ {m, 2} = (1 - r) \\theta_ {l} + r \\theta_ {r} \\# (4.)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[184,717,808,857]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The strategy of GSS can be stated as follows: if $S(\\theta_{m,1}) \\geq S(\\theta_{m,2})$ , the maxima must be in the interval $[\\theta_l, \\theta_{m,2}]$ . Likewise, if $S(\\theta_{m,1}) < S(\\theta_{m,2})$ , the maxima must be in the interval $[\\theta_{m,1}, \\theta_r]$ . Subsequently, we compute two new interior points in the interval mentioned above for the next iteration. At every iteration, we calculate the interior points in this manner and keep narrowing the search interval until meeting the termination condition. Theoretically, the iteration would terminate when $\\theta_l \\geq \\theta_r$ is met. In practice, however, we can set a termination condition to boost the speed of convergence. Once the search interval is less than this termination condition, we stop the iteration and take $\\theta_p = (\\theta_l + \\theta_r) / 2$ as the output location. If we set $r = 1/3$ instead of the golden section ratio of 0.618, the algorithm turns into the Ternary ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,117,810,147]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Search (TS). Except for the scalar $r$ used for interior points calculation, the other parts of the TS are the same as the GSS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,154,372,167]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.4 Simulation Validation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,167,810,286]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the simulation, the experimental directivity pattern and PA model developed in [20] was used. The PA signals were generated by MATLAB k-Wave toolbox and White Gaussian noise was added to them. The intensity of PA signals was normalized. The reference angles of PA markers were located at 1000 random locations within $-35^{\\circ}$ to $35^{\\circ}$ , and PA signal was recorded at the desired positions based on the proposed search algorithms. Here, we compared the performance of all three search algorithms with different numbers of data acquisitions. With the WA algorithm, laser spots were located at a random position and PA signals were detected at several $\\theta_{i}$ s spaced at certain $\\theta_{d}$ , determined by the number of acquisitions $N$ : ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[415,287,583,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\theta_ {d} = 7 0 ^ {o} / (N - 1) \\# (5.)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[184,301,810,376]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"So, as the number of acquisitions increases, $\\theta_d$ decreases. Note that the number of acquisitions cannot be too small because there may be no PA signals generated. In the GSS and TS algorithms, the angle of the TRUS is determined by the policy introduced in 2.3 and the iteration/acquisition can be continued until the desired accuracy is met. We tested the performance of these two algorithms when acquiring data 2-28 times. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,382,380,396]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.5 Experiment Validation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,397,810,571]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to the simulation validation, we conducted experimental studies to illustrate the advantages of our proposed method. In our experiment, a pulsed laser diode illuminated random locations on the tissue surface. To validate our approach, we conducted two types of analysis: offline and online. For the offline analysis, we conducted experiments to collect data by scanning the entire rotation interval with a very small step size $(\\sim 0.5^{\\circ})$ , enabling us to have a bank of PA data for our investigation. We simulated the online search based on this collected data. The numerical precision of the motor rotation angle was made consistent with the online analysis by interpolating the original offline data. For the online analysis, the algorithms were investigated in a real-time implementation where each of the search algorithms were integrated into the robotic and imaging systems. As a result, PA data were acquired at the locations that the algorithm asked for, and the output was compared with the reference acquired from a manual search. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[290,575,699,805]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2. Schematic diagram of the overall system composition. It also describes the TRUS coordinate system (TR). The $y$ -axis is parallel with the axis of rotation of the TRUS. \"]","image_footnote":"[]","img_path":"images/0680/feb0d2a24d9822daa59209c73df89020ba7b5443bf312dcc3922242af6e7a1f6.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,843,344,857]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. System Architecture ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,117,813,294]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The overall system depicted in Fig. 2. comprises of several modules including the main host computer, pulsed laser system, TRUS actuator control module, and PA+US imaging system. The imaging system was described in [19]. Here, we emphasize the modules related to the automatic implementation of the search algorithms. In the pulse laser system, the $785\\mathrm{nm}$ pulse laser diode (QSP-785-4, QPhotonics LLC, Ann Arbor, MI, USA) is excited by a laser driver (LDP-V, PicoLAS GmbH, Germany) to generate a $2\\mu \\mathrm{J}$ /pulse laser beam. The PA+US imaging module synchronously acquires PA signals. The generated PA signals can be detected by a TRUS transducer (BPL 9-5/55, BK Medical, Peabody, MA, USA) and a SonixDAQ (Ultrasonix Medical Corp., Canada). The actuator control module can drive the TRUS transducer to rotate through an actuator (rotation stage, PRM1Z8, Thorlabs, Newton, NJ, USA) rigidly attached to it. Real-time communication between each component in the system is based on the Robot Operating System (ROS). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,299,339,314]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. Experimental Setup ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,314,810,488]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The experimental set-up is shown in Fig. 3(a). An ex vivo bovine liver tissue was supported by two pieces of ultrasound gel pad (Parker Laboratories, Fairfield, NJ, USA) with a total thickness of $5\\mathrm{cm}$ to mimic the prostate gland. A laser diode held by a clip was placed close to the surface of the ex vivo tissue. The laser's location and its surrounding region ( $5\\mathrm{mm} \\times 5\\mathrm{mm}$ area) were stained with India ink (Dr. Ph. Martin, Oceanside, CA, USA) to increase laser absorption. A TRUS transducer motorized by an actuator was placed beneath the ex vivo tissue and ultrasound pads to detect the PM. Here, we tested the proposed approach on a homogenous black plastisol phantom, and three types of ex vivo tissue, bovine liver, muscle, and chicken breast, to demonstrate its feasibility. In one case, in accordance with the prostate nerve sensing [28], the ex vivo bovine muscle was stained by indocyanine green (ICG) dye (TCI, Tokyo, Japan). As illustrated in Fig. 3. (b), the PA signals arranged on a $3 \\times 3$ grid were collected on each type of material. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,489,575,728]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0889/58acf201bc8350799ce062d70e2374b71e2ffe96bf5e1da21d35f01dbf52d307.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[598,498,805,714]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3. (a) The offline analysis experimental set-up with bovine liver ex vivo tissue stained with India ink. (b) The conceptual illustration of the laser spot location on ex vivo chicken breast tissue from the top view of the $x-y$ plane. The red dots indicate the laser spot, and a $3 \\\\times 3$ grid roughly spaced at $20\\\\mathrm{mm}$ in the $x$ -axis and $y$ -axis directions, respectively, of the $x-y$ plane of the TRUS coordinate system. For other ex vivo tissues and plastisol phantom, the laser spot location is arranged in the same way. \"]","image_footnote":"[]","img_path":"images/0971/41a6c3413fb4d60c66bbba762fc795b7e6d7c824ca6616347cec1f2a89375609.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,805,413,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Online Search implementation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,819,812,869]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We integrated the automatic search module into the overall TRUS-da Vinci robotic system using ROS and used a LabVIEW script [19] to control the rotation stage. To integrate this TRUS controller into our ROS communication system, we used the ROS for LabVIEW toolkit ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,117,813,268]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"software [29] developed by the Tufts University Center for Engineering Education and Outreach. We created a node for the TRUS controller, as well as a publisher and a subscriber to receive the angle that the TRUS should rotate to and return the actual rotated angle. For online analysis, there was no need to exhaustively scan the entire rotation range with a small step size to collect data as in our offline analysis. The TRUS only rotated to specified locations that the algorithm asked for and acquired PA signals from the data acquisition system at these locations. Here, we tested the proposed online automatic search module on a black plastisol phantom. Like in the offline analysis case, we tested each search algorithm on the $3 \\times 3$ grid of locations and the results were compared with manually found reference locations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,276,454,290]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"D. Tool Tip Detection - Sensitive Range ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,291,810,406]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When using the da Vinci instrument tool tip for registration, a key stage in this procedure is the da Vinci surgical instrument tip detection [30]. Similar to the PM intensity, the tip intensity is the highest when the US imaging plane is coplanar with the surgical instrument tip. It decreases and eventually disappears as the US imaging plane deviates from the coplanar position. Consequently, we only need to make sure the surgical instrument tip is within the range (termed sensitive range) that can be detected by the US, not necessarily to be exactly coplanar with the US imaging plane. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,407,812,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We experimentally investigated the sensitive range when detecting the da Vinci surgical instrument tip. As shown in Fig. 4., the da Vinci instrument tip held on a robotic arm was pressed against the surface of a piece of ex vivo chicken breast. We rotated the TRUS clockwise with a step size of $1^{\\circ}$ starting with the reference location and recorded the corresponding B-mode image at each location. The range from the reference location to the location where the tip disappeared (shown in Fig. 9. (b) and (c)) was half of the sensitive range. Assuming that the function of detected tip intensity versus TRUS rotation location is symmetric, the other half sensitive range was inferred by flipping along the reference location. Here, we roughly calculated the entire sensitive range by adding these two half sensitive ranges. Three locations of the da Vinci surgical instrument tip spaced at about $2\\mathrm{cm}$ in $x$ -axis were tested in this experiment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,592,812,696]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the B-mode image processing, we first segmented the da Vinci instrument tip by leveraging GrabCut [31], following to find the centroid of this connected instrument tip area, and finally taking the pixel value of this centroid as the instrument tip intensity. Let $\\theta_{high}$ denote the location with the highest tip intensity, and $\\theta_{low}$ denote the location with the lowest tip intensity that can be detected. Thus, half of the sensitive range can be defined as the absolute value of these two locations, namely $|\\theta_{high} - \\theta_{low}|$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,704,272,718]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Result ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,719,813,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The proposed automatic search module was validated by both simulation and experiment (including offline analysis and online analysis). The performance of various search algorithms was evaluated in terms of localization accuracy and time efficiency. For the evaluation of localization accuracy, we measured the localization error which was defined as the absolute value of the difference between the reference location and optimal output location. To assess time efficiency, we adopt the number of data acquisitions as the metric due to most of the time in the proposed search procedure being used to acquire data. In the following sections, we will illustrate and discuss the results of each in detail. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[357,114,630,362]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4. The experimental setup for investigating the sensitive range of da Vinci surgical instrument tip detection. \"]","image_footnote":"[]","img_path":"images/0509/253199986304ef659c75756e982b919cea4351d182e4cda1096df27b12275f0c.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,385,357,398]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1 Simulation Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,407,813,554]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the TS and GSS algorithm, we tested a set of number of acquisitions from 2 to 28 in increments of 2. Likewise, we tested a set of number of acquisitions from 8 to 28 for the WA algorithm to ensure that at least one valid PA signal can be acquired at the proposed equal intervals. We set a fixed threshold of 0.2 for all experiments in the WA algorithm. The average error after 1000 trials changed with the number of acquisitions as shown in Fig. 5. The error of TS and GSS algorithms rapidly dropped at the beginning and converged to a small value, while the error of WA did not change much with the number of acquisitions. When conducting 28 acquisitions, the average errors of the TS and GSS algorithm were $0.06^{\\circ}$ and $0.01^{\\circ}$ , respectively. In the WA algorithm, the average error when acquiring different numbers of PA signals was $0.47^{\\circ} \\pm 0.11^{\\circ}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[346,559,643,691]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5. The average error of 1000 experiments using various algorithms in the simulation study. Red dots, blue dots, and green dots represent the error of TS, GSS, and WA algorithm. \"]","image_footnote":"[]","img_path":"images/0323/52a50824e140129850628efe5aaf94af3796f4876b2d9405a7d5994f919fd4ae.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,729,393,744]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2 Offline Analysis Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,746,802,818]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In our offline analysis, we interpolated each set of data to achieve the same resolution as the simulated data. Fig. 6 depicts the average error versus the number of acquisitions on various materials resulting from the offline analysis. Table 1 summarizes the error of each algorithm when acquiring the PA signal 16 times. Note that we only obtained one set of data on bovine muscle stained by ICG, so the results of this test did not have a standard deviation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[196,119,411,215]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0669/8ee9340d290bceeace583b584728f18bcc4f4ba94a36a547bffa99543cfb6a04.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[416,119,612,214]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0958/f1efaf94a7209b9c859c11826518a66d865e32efd7e58ea611402a1258c9148f.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[616,119,812,213]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0891/2c054719a9ff1ce2b2d438033588e5155b3c856b1240c21ac4b41f9927538a54.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[194,217,411,309]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0684/91c4b3f4ab3dc107993e3f05a2af4840d468428d0e3af2d20715d6cc0c68efa7.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[413,218,614,309]","code_body":null,"code_caption":null,"image_caption":"[\"Number of acquisitions \",\"Fig. 6. The average error of offline analysis versus the number of acquisitions. The sub-figures (a) - (e) indicate the offline analysis results on bovine liver, muscle, chicken breast, phantom and bovine muscle stained with ICG, respectively. \"]","image_footnote":"[]","img_path":"images/0866/324278aa48cb9c151d2a6afbc9417131dabdc4c5fd39bd505b7721a04ae7289f.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[212,401,784,520]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0104/b984b8c67c228714134484a9b4f2663335fe6075bb2deb242f2eb971f52747fa.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Algorithms</td><td colspan=\"5\">Average Error (Degree)</td></tr><tr><td>Bovine Liver</td><td>Bovine Muscle</td><td>Chicken Breast</td><td>Plastisol Phantom</td><td>Bovine Muscle +ICG</td></tr><tr><td>WA</td><td>0.51 ± 0.36</td><td>0.93 ± 0.83</td><td>0.35 ± 0.23</td><td>0.54 ± 0.41</td><td>1.28</td></tr><tr><td>TS</td><td>0.34 ± 0.27</td><td>0.29 ± 0.22</td><td>0.34 ± 0.20</td><td>0.32 ± 0.22</td><td>0.32</td></tr><tr><td>GSS</td><td>0.20 ± 0.19</td><td>0.52 ± 0.61</td><td>0.30 ± 0.24</td><td>0.45 ± 0.40</td><td>1.12</td></tr></table>","table_caption":"[\"Table 1. Average Error of Various Algorithms in Offline Analysis Terminating After 16 Times of Acquisitions \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[187,525,392,540]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3 Online Analysis Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,541,813,779]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In online analysis, each algorithm described earlier was integrated into the TRUS-da Vinci robotic system. When conducting the online analysis, the TRUS automatically rotated to the position specified by the algorithm, and finally stopped at $\\theta_{p}$ calculated by this algorithm. Fig. 7. illustrates the comparison of the average errors of TS and GSS algorithms with varying numbers of acquisitions. The average errors of these two algorithms decrease with an increase in the number of acquisitions. For the TS and GSS algorithms, the specific location of the TRUS at each number of acquisitions is illustrated in Fig. 8. The GSS and TS algorithm achieved minimum error, $0.48^{\\circ} \\pm 0.30^{\\circ}$ and $0.29^{\\circ} \\pm 0.30^{\\circ}$ , when acquiring 28 times data. When adopting WA, we took $5^{\\circ}$ as the step size, that is, acquiring 15 times PA signals to cover the entire space. However, in the online analysis, we can terminate the search as long as the entire peak of the intensity is recorded and passed. We can often complete the WA search by collecting data fewer than 15 times. The average error of WA was $0.53^{\\circ} \\pm 0.30^{\\circ}$ with 8.7 data acquisitions. Table 2 is the comparison of the average error of various algorithms when taking a similar number of acquisitions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[359,123,630,239]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 7. Average error of TS and GSS with a varying number of acquisitions in online analysis. The blue bar and orange bar indicate the TS and GSS algorithms respectively. \"]","image_footnote":"[]","img_path":"images/0747/4d98eefe1f00509724e8cc0074bfed3db4e23524df1e48cddfd8a5148ff10d28.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[328,305,669,383]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0799/22439efbc823fb6a99c5c5b4208b079885927393211be00a67bfebfb1ef56542.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td>Algorithms</td><td>Average Error</td><td>Number of Acquisitions</td></tr><tr><td>WA</td><td>0.53 ± 0.30</td><td>8.7</td></tr><tr><td>TS</td><td>1.05 ± 1.04</td><td>16</td></tr><tr><td>GSS</td><td>0.74 ± 0.58</td><td>16</td></tr></table>","table_caption":"[\"Table 2. Average Error of Various Algorithms in Online Analysis \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[236,400,759,631]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0389/578ed05d20a9b54488c415c8989ca03f78756bc249e86350b53cd14b09584636.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[235,636,759,869]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0458/7776dee390f3c84599c2cbb4894494004a71f2a2cfba01cbf0601ce7e7336891.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[233,118,764,354]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 8. TRUS location during the TS and GSS algorithms. The blue dots, red dots, and orange dashed line refer to the locations in TS and GSS as well as the reference location $\\\\theta_{gt}$ . The position 1 to 9 were located on a $3 \\\\times 3$ grid as described in Fig. 3. (b). \"]","image_footnote":"[]","img_path":"images/0673/8ac778439ae3217e8e88e923693e41a929464c9dcc03f34400f5650cb5c2f9a5.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,409,398,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.4 Sensitive Range Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,424,813,541]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We pressed the da Vinci surgical instrument tip against the ex vivo chicken breast tissue surface at three locations. For each tip location, a set of B-mode images were recorded with the TRUS rotated in steps of $1^{\\circ}$ (Fig. 9. (a) and (d) show one of the B-mode images sets and the corresponding tip intensity curve). We took the position corresponding to the strongest and weakest tip intensity that can be detected as half of the sensitive range. In our experiment, half of the sensitive range of the three locations were $5^{\\circ}, 4^{\\circ}$ , and $4^{\\circ}$ respectively, and the average value was $4.33^{\\circ} \\pm 0.58^{\\circ}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[189,560,313,638]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \",\"(b) \"]","image_footnote":"[]","img_path":"images/0272/09ad17bd34224003a77a4c936d5c4720c238cdf07f1d0681c0ac89a44ac3ed98.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[315,560,437,638]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0850/0d73899a6b98a476d8218824ad73e321c4747619db2d35be3d98ac4a378e87c7.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[439,560,560,638]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0430/cd240ec5d3c023e7cda44736d95330e2622fccf883f2d26702a43338d7751a1b.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[562,560,684,638]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0218/13c5fdcbe824dfdff209edc5d298abe2c99453cc7b3a12d8acfe7d5b79ab8c34.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[686,560,810,638]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0171/d94d6007541ef7bca8e8e9d36e935b687d86830b23c27d64a3b2d6163926c9b8.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[187,655,380,776]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0492/6892a7ddfebbb55f1a3d89d0f49ea3c790bfa01d9c2d5cc170040af36340b875.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[383,654,576,775]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0866/59e02f0b645cad330c89f173b8445c076cd914397c2e9d3bae5b27f72db99a64.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[584,655,816,775]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 9. (a) A set of B-mode images with varying tip intensity. The da Vinci surgical instrument tip is within the red dashed circle. The reference location is $0^{\\\\circ}$ . (b) The B-mode image at the reference location. It can be partitioned into 3 layers: from top to bottom are air, ex vivo tissue and ultrasound pad. (c) The B-mode image at a location transcending the sensitive range. (d) The tip intensity versus TRUS location. As the TRUS location moves away from the reference location $0^{\\\\circ}$ , the corresponding tip intensity keeps reducing. \"]","image_footnote":"[]","img_path":"images/0048/05cb001b443a7c0ea651cdef4d59666d2cc0eb030b937edb1e0d0e0bfcdb6ec6.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[186,859,308,872]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,117,810,217]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of the experimental results described in 3.4, the sensitive range for the da Vinci surgical instrument tip detection is about $8.66^{\\circ}$ . In fact, we can obtain a much lower error $(0.53^{\\circ} \\pm 0.30^{\\circ})$ using the WA algorithm in our study just acquiring PA signals eight times. Consequently, the accuracy of all three algorithms should be considered precise and sufficient compared to the sensitive range of tip detection. Regarding the three algorithms adopted in this paper, TS and GSS output the most precise PM location on ex vivo tissues when acquiring data 28 times. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,218,808,369]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The proposed search algorithms have the potential to be used as a part of the control platform for the surgical tool tracking and TRUS servoing tasks. In online analysis, and with only acquiring two PA signals, the average error was $4.20^{\\circ}$ and $5.89^{\\circ}$ when adopting the TS and GSS algorithm starting at the far left $(-35^{\\circ})$ and right $(+35^{\\circ})$ of the boundary which is reasonable when compared to the required $8.66^{\\circ}$ . However, this accuracy will significantly improve with more data acquisitions as illustrated in this paper. Besides, the TS and GSS tend to converge toward and settle at the target location $\\theta_{p}$ . This property makes these two algorithms potentially applicable in tool tracking procedures and will be further investigated in our future studies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,372,808,571]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From the perspective of time, the primary limitation of the proposed technique is the relatively long time of acquiring PA signals from SonixDAQ. In this work, we utilized the API of SonixDAQ to read raw PA signals from the device and read these raw data files to do beamforming and reconstruction. This manner typically takes about 10 seconds. Driven by this limitation, our group is developing a real-time PA imaging based on SPARE (Synthetic-aperture Based Photoacoustic Re-beamforming [32]). This can essentially benefit the time efficiency of the PM-based RAPL system. Future work will integrate SPARE into the system to ameliorate the time-consuming PA signals acquisition and improve the system's efficiency. In that case, the only time we need to consider is the time of TRUS rotation. When acquiring data for 16 times, the total rotation travel in TS and GSS are about $36^{\\circ}$ and $24^{\\circ}$ , respectively. Thus, the estimated time of rotation is within 1-2 seconds, which is much less than the 2-3 minutes of manual search reported in [30] and close to a real-time search approach. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,580,310,595]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5. Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[184,603,810,780]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this study, we presented an automatic search method for PM to deal with the drawbacks of manual search procedures. We cast the PM search procedure as an optimization problem of a 1-D unimodal function and investigated three algorithms to address this problem. Simulation studies and experiments on various ex vivo tissues and phantom validated the validity of our proposed method. In simulation studies, all three algorithms perform well. In offline analysis, the average error of the TS and GSS algorithm on all materials was below $0.5^{\\circ}$ when acquiring 28 PA acquisitions. In online analysis, the average error of the TS and GSS algorithm achieved $0.29^{\\circ} \\pm 0.31^{\\circ}$ and $0.48^{\\circ} \\pm 0.32^{\\circ}$ after 28 acquisitions, while the WA achieved $0.53^{\\circ} \\pm 0.30^{\\circ}$ using only 8.7 times acquisitions. In summary, the proposed technique significantly improved the system's degree of automation and alleviated the labor required, while achieving good search accuracy. In future work, the proposed search method will be combined with real-time photoacoustic imaging to significantly improve the time efficiency of the PM-based RAPL. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,786,808,845]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding. This work was supported in part by NSF Career Award 1653322, NIH R01-CA134675, the Johns Hopkins University internal funds, Canadian Institutes of Health Research (CIHR), CA Laszlo Chair in Biomedical Engineering held by Professor Salcudean, and an equipment loan from Intuitive Surgical, Inc. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,117,810,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments. We would like to acknowledge to our sponsors and funding agencies: Funding from the National Science Foundation Career Award 1653322, National Institute of Health R01-CA134675, the Johns Hopkins University internal funds, Canadian Institutes of Health Research, CA Laszlo Chair in Biomedical Engineering held by Professor Salcudean, and Intuitive Surgical for the equipment support. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,198,576,212]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclosures. The authors declare no conflicts of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[184,219,807,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data availability. Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,256,279,270]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[187,277,807,871]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. H. Sung, J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, and F. Bray, \\\"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,\\\" CA Cancer J Clin 71(3), (2021). \",\"2. R. L. Siegel, K. D. Miller, and A. Jemal, \\\"Cancer statistics, 2020,\\\" CA Cancer J Clin 70(1), (2020). \",\"3. A. J. Costello, \\\"Considering the role of radical prostatectomy in 21st century prostate cancer care,\\\" Nat Rev Urol 17, 177-188 (2020). \",\"4. H. H. Young, \\\"conservative perineal prostatectomy: the results of two years' experience and report of seventy-five cases,\\\" Ann. Surg. 41, 549-557 (1905). \",\"5. M. Lein, I. Stibane, R. Mansour, C. Hege, J. Roigas, A. Wille, K. Jung, G. Kristiansen, D. Schnorr, S. A. Loening, and S. Deger, \\\"Complications, Urinary Continence, and Oncologic Outcome of 1000 Laparoscopic Transperitoneal Radical Prostatectomies—Experience at the Charité Hospital Berlin, Campus Mitte,\\\" Eur Urol 50(6), 1278-1284 (2006). \",\"6. V. Ficarra, S. Cavalleri, G. Novara, M. Aragona, and W. Artibani, \\\"Evidence from Robot-Assisted Laparoscopic Radical Prostatectomy: A Systematic Review,\\\" Eur Urol 51(1), 45-56 (2007). \",\"7. N. Grivas, I. Zachos, G. Georgiadis, M. Karavitakis, V. Tzortzis, and C. Mamoulakis, \\\"Learning curves in laparoscopic and robot-assisted prostate surgery: a systematic search and review,\\\" World J Urol 40(4), 929-949 (2022). \",\"8. J. Binder and W. Kramer, \\\"Robotically-assisted laparoscopic radical prostatectomy,\\\" BJU International 87(4), 408-410 (2001). \",\"9. C. R. Mitchell and S. D. Herrell, \\\"Image-Guided Surgery and Emerging Molecular Imaging: Advances to Complement Minimally Invasive Surgery,\\\" Urologic Clinics of North America 41(4), 567-580 (2014). \",\"10. J. A. Long, B. H. Lee, J. Guillotreau, R. Autorino, H. Laydner, R. Yakoubi, E. Rizkala, R. J. Stein, J. H. Kaouk, and G. P. Haber, \\\"Real-Time Robotic Transrectal Ultrasound Navigation During Robotic Radical Prostatectomy: Initial Clinical Experience,\\\" Urology 80(3), 608-613 (2012). \",\"11. O. Mohareri, J. Ischia, P. C. Black, C. Schneider, J. Lobo, L. Goldenberg, and S. E. Salcudean, \\\"Intraoperative Registered Transrectal Ultrasound Guidance for Robot-Assisted Laparoscopic Radical Prostatectomy,\\\" J Urol 193(1), 302-312 (2015). \",\"12. T. Adebar, S. Salcudean, S. Mahdavi, M. Moradi, C. Nguan, and L. Goldenberg, \\\"A robotic system for intra-operative trans-rectal ultrasound and ultrasound elastography in radical prostatectomy,\\\" Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 6689 LNCS, 79-89 (2011). \",\"13. H. Moradi, E. M. Boctor, and S. E. Salcudean, \\\"Robot-assisted image guidance for prostate nerve-sparing surgery,\\\" IEEE International Ultrasonics Symposium, IUS 2020-September, (2020). \",\"14. H. Moradi, S. Tang, and S. E. Salcudean, \\\"Toward robot-assisted photoacoustic imaging: Implementation using the da Vinci research kit and virtual fixtures,\\\" IEEE Robot Autom Lett 4(2), 1807-1814 (2019). \",\"15. H. Moradi, S. Tang, and S. E. Salcudean, \\\"Toward intra-operative prostate photoacoustic imaging: Configuration evaluation and implementation using the da Vinci research kit,\\\" IEEE Trans Med Imaging 38(1), 57-68 (2019). \",\"16. N. Gandhi, M. Allard, S. Kim, P. Kazanzides, and M. A. L. Bell, \\\"Photoacoustic-based approach to surgical guidance performed with and without a da Vinci robot,\\\" J Biomed Opt 22(12), 121606 (2017). \",\"17. J. L. Su, R. R. Bouchard, A. B. Karpiouk, J. D. Hazle, and S. Y. Emelianov, \\\"Photoacoustic imaging of prostate brachytherapy seeds,\\\" Biomed Opt Express 2(8), 2243 (2011). \",\"18. A. Cheng, X. Guo, H. J. Kang, M. Choti, J. Kang, A. A. Cheng, M. A. Choti, J. U. Kang, R. H. Taylor, and E. M. Boctor, \\\"Direct ultrasound to video registration using photoacoustic markers from a single image pose,\\\" Advanced Biomedical and Clinical Diagnostic and Surgical Guidance Systems XIII 9313, 83-90 (2015). \",\"19. H. Song, H. Moradi, B. Jiang, K. Xu, Y. Wu, R. H. Taylor, A. Deguet, J. U. Kang, S. E. Salcudean, and E. M. Boctor, \\\"Real-time intraoperative surgical guidance system in the da Vinci surgical robot based on \"]","page_idx":"11","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[187,118,807,561]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"transrectal ultrasound/photoacoustic imaging with photoacoustic markers: an ex vivo demonstration,\\\" IEEE Robot Autom Lett 8(3), 1287-1294 (2023). \",\"20. H. Moradi, S. Tang, and S. E. Salcudean, \\\"Deconvolution based photoacoustic reconstruction with sparsity regularization,\\\" Opt Express 25(3), 2771-2789 (2017). \",\"21. S. Rastegar, S. L. Jacques, M. Motamedi, and B.-M. Kim, \\\"Theoretical analysis of equivalency of high-power diode laser (810 nm) and Nd:YAG laser (1064 nm) for coagulation of tissue: predictions for prostate coagulation,\\\" Laser-Tissue Interaction III 1646, 150-160 (1992). \",\"22. C. Balakishan, N. Sandeep, and M. V Aware, \\\"Design and Implementation of Three-Level DC-DC Converter with Golden Section Search Based MPPT for the Photovoltaic Applications,\\\" Advances in Power Electronics 2015, 587197 (2015). \",\"23. R. Das and B. Kundu, \\\"Estimation of Internal Heat Generation in a Fin Involving All Modes of Heat Transfer Using Golden Section Search Method,\\\" Heat Transfer Engineering, 39(1), 58-71 (2017). \",\"24. C. H. Tsai, J. Kolibal, and M. Li, \\\"The golden section search algorithm for finding a good shape parameter for meshless collocation methods,\\\" Eng Anal Bound Elem 34(8), 738-746 (2010). \",\"25. J. Kiefer, \\\"Sequential minimax search for a maximum,\\\" Proceedings of the American Mathematical Society 4(3), (1953). \",\"26. K. M. Salehin and R. Rojas-Cessa, \\\"Ternary-search-based scheme to measure link available-bandwidth in wired networks,\\\" GLOBECOM - IEEE Global Telecommunications Conference (2010). \",\"27. M. S. Bajwa, A. P. Agarwal, and S. Manchanda, \\\"Ternary search algorithm: Improvement of binary search,\\\" 2015 2nd International Conference on Computing for Sustainable Global Development, INDIACom, 1723-1725 (2015). \",\"28. H. Moradi, K. Xu, H. Song, S. E. Salcudean, and E. M. Boctor, \\\"Towards photoacoustic prostate imaging using continuous wave laser excitation,\\\" Photon's Plus Ultrasound: Imaging and Sensing 2023 12379, 363-369 (2023). \",\"29. \\\"ROS for Labview Preview from Tufts CEEO - ROS robotics news,\\\" https://www.ros.org/news/2013/10/ros-for-labview-preview-from-tuf \",\"30. O. Mohareri, M. Ramezani, T. K. Adebar, P. Abolmaesumi, and S. E. Salcudean, \\\"Automatic localization of the da Vinci surgical instrument tips in 3-D transrectal ultrasound,\\\" IEEE Trans Biomed Eng 60(9), 2663-2672 (2013). \",\"31. C. Rother, V. Kolmogorov, and A. Blake, \\\"GrabCut\\\" interactive foreground extraction using iterated graph cuts,\\\" ACM Trans Graph (TOG) 23(3), 309-314 (2004). \",\"32. H. J. Kang, M. A. L. Bell, H. K. Zhang, X. Guo, and E. M. Boctor, \\\"Synthetic-aperture based photoacoustic re-beamforming (SPARE) approach using beamformed ultrasound data,\\\" Biomed Opt Express 7(8), 3056-3068 (2016). \",\"33. Berthold K. P. Horn, \\\"Closed-form solution of absolute orientation using unit quaternions,\\\" J. Opt. Soc. Am. A 4, 629-642 (1987) \"]","page_idx":"12","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"}],"string":"[\n {\n \"bbox\": \"[187,117,769,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Automatic Search for Photoacoustic Marker Using Automated Transrectal Ultrasound \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,178,759,213]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ZIJIAN WU $^{1\\\\dagger}$ , HAMID MORADI $^{2\\\\dagger}$ , SHUOJUE YANG $^{3}$ , HYUNWOO SONG $^{1,4}$ , EMAD M. BOCTOR $^{1,4*}$ , AND SEPTIMIU E. SALCUBEAN $^{2*}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,218,795,231]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"<sup>1</sup>Johns Hopkins University, Laboratory for Computational Sensing and Robotics, Baltimore, MD, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,231,784,244]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{2}$ University of British Columbia, Dept. of Electrical and Computer Engineering, Vancouver, BC, CA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,244,759,258]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"<sup>3</sup>University of Texas at Austin, Walker Department of Mechanical Engineering, Austin, TX, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,258,645,271]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4Johns Hopkins University, Dept. of Computer Science, Baltimore, MD, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,271,380,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{\\\\dagger}$ Equal Authorship Contribution \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,284,406,297]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"*tims@ece.ubc.ca; eboctor@jhu.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,311,810,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: Real-time transrectal ultrasound (TRUS) image guidance during robot-assisted laparoscopic radical prostatectomy has the potential to enhance surgery outcomes. Whether conventional or photoacoustic TRUS is used, the robotic system and the TRUS must be registered to each other. Accurate registration can be performed using photoacoustic (PA markers). However, this requires a manual search by an assistant [19]. This paper introduces the first automatic search for PA markers using a transrectal ultrasound robot. This effectively reduces the challenges associated with the da Vinci-TRUS registration. This paper investigated the performance of three search algorithms in simulation and experiment: Weighted Average (WA), Golden Section Search (GSS), and Ternary Search (TS). For validation, a surgical prostate scenario was mimicked and various ex vivo tissues were tested. As a result, the WA algorithm can achieve $0.53^{\\\\circ} \\\\pm 0.30^{\\\\circ}$ average error after 9 data acquisitions, while the TS and GSS algorithm can achieve $0.29^{\\\\circ} \\\\pm 0.31^{\\\\circ}$ and $0.48^{\\\\circ} \\\\pm 0.32^{\\\\circ}$ average errors after 28 data acquisitions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,517,807,541]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2021 Optica Publishing Group under the terms of the Optica Publishing Group Open Access Publishing Agreement \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,556,316,569]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,571,808,773]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Prostate cancer (PCa) is one of the most common malignant tumors among men worldwide, with a high mortality rate [1]. According to [2], $11.6\\\\%$ of men will develop prostate cancer in their lifetime, with approximately a $20\\\\%$ death rate in the United States. Radical prostatectomy is a popular surgical approach to treat PCa by removing the entire prostate gland since 1905 [3,4]. In clinical practice, the traditional open radical prostatectomy (ORP) has almost been replaced by laparoscopic radical prostatectomy (RLP) [5]. As a minimally invasive surgical procedure for PCa, RLP significantly reduces blood loss, hospitalization duration, and postoperative complications [6]. However, the long learning curve associated with laparoscopic procedures limits the application of RLP [7]. Robot-assisted laparoscopic prostatectomy (RALP) has been demonstrated [5] to shorten this learning curve by leveraging the wristed instruments and the 3-D endoscopic camera of the telerobotic surgical system, usually the da Vinci surgical system, to achieve intuitive operation [8]. However, the endoscopic camera cannot localize the prostate lesions nor visualize the sub-surface anatomy of the prostate gland. Therefore, a complementary medical imaging modality is necessary to facilitate RALP. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,775,808,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Transrectal ultrasound (TRUS) facilitates the intraoperative identification of vital anatomic structures of the prostate gland and adjacent tissues, e.g., peripheral nerve and neurovascular bundles (NVBs), in a non-invasive and real-time manner [9]. TRUS provides precise ultrasound images of tissue pointed by the surgeon with the instrument. A robotic transrectal ultrasound system for prostatectomy was presented to alleviate the inconvenience of manipulating the TRUS and has been adopted in RALP studies [10-12]. The da Vinci and TRUS coordinate systems are registered by touching the tissue with the instrument tip at three or more different \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,117,810,146]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"locations. However, the search process for each location is manual, time-consuming, and requires an additional skilled operator in the operating room [11]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,147,810,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A very accurate alternative registration method between the TRUS and the da Vinci system involves the use of photoacoustic markers (PMs), which are generated by the so-called photoacoustic effect, i.e., the formation of acoustic waves when a pulsed laser source is absorbed by optical materials. Robot assisted photoacoustic imaging using the da Vinci surgical system was investigated in [13-16]. In [17], authors demonstrated that photoacoustic markers generated by a pulsed laser could be reconstructed as images representing the local optical absorption of tissue constituents. Cheng et al. [18]'s research proved the feasibility and advantages of PM in surgical guidance. Instead of physically touching the tissue, a photoacoustic (PA) approach using focused laser illumination as the PM was introduced in [19], in which the registration between the endoscopic stereo camera frame and the TRUS frame was performed using Horn's method [33]. While accurate, this registration is still time-consuming (as much as $7\\\\mathrm{min}$ ), because the TRUS is manually rotated to align its imaging plane to the laser spots. Driven by this limitation, an automatic image-based search for the photoacoustic markers is proposed in this paper. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,349,810,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The directivity pattern of clinical transducer was investigated in [20]. The PA image intensity is proportional to the distance between the PM and the TRUS imaging plane. When the PM is coplanar with the imaging plane of the TRUS transducer, the detected PA image intensity of the PM is maximum [21]. Therefore, we have a PA image intensity function, which should be unimodal and symmetric. Based on this, the key component of our work is to conduct a one-dimensional search in the presence of PA imaging to find the position corresponding to the maximum PA intensity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,452,810,537]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The numerical optimization of unimodal functions in one-dimensional (1-D) search space is a common topic in many engineering fields [22-24]. Introducing an efficient algorithm to replace the exhaustive search will significantly shorten the duration of the registration. The Golden Section Search (GSS) algorithm [25] is a classic approach to solve this maximization problem. Similarly, Ternary Search (TS) algorithm is a widely used divide-and-conquer algorithm for searching the maximum of a unimodal function [26,27]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,539,810,597]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this paper, we propose a novel automatic search module to localize the PMs using the robotized transrectal ultrasound actuator in robot-assisted radical laparoscopic prostatectomy. We simulate and experimentally evaluate several optimization algorithms. The proposed framework outperforms the manual search in terms of time and required technical staff. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,604,282,618]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Method \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,626,354,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1 Problem Definition \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,640,810,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In our RALP system depicted in Fig. 1. (a), a laser source generates a PM on the surface of the tissue. This PM can be detected by a TRUS beneath the tissue. This detected intensity of the PM achieves a maximum when the US imaging plane is coplanar with the PM, namely the TRUS is at the angle $\\\\theta_{p}$ , and attenuates when the imaging plane moving away from $\\\\theta_{p}$ . As described in Fig. 1. (b), there is a PA signal intensity function related to the rotation angle of the TRUS. Theoretically, this intensity function is unimodal and symmetric if noise is not considered [20], and we are searching for its peak. We can drive the motorized TRUS to rotate within $-35^{\\\\circ}$ to $35^{\\\\circ}$ , providing enough coverage for the prostate imaging, and synchronously calculate PA signal intensity at each location using the $\\\\mathrm{US + PA}$ imaging system. In this way, we will investigate efficient algorithms to solve this problem compared to the manual scanning. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[264,119,509,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0516/07de968d79f3142ba0148e3c71158134bf8c384091d782c92c845cbe63cec7f9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[545,119,769,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. (a) The laser illuminates a small spot (PM). The motorized TRUS is located at $\\\\\\\\theta_{i}$ . The goal is to find $\\\\\\\\theta_{p}$ of the PA marker. (b) The TRUS also receives out-of-plane signals. Therefore, PA signals will be recorded at different angles. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0318/d1efbd1877dbc46e74c333d3b84e4af8816dd9d533cd943cce43c842b14f6fec.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,337,354,352]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2 Weighted Average \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,352,808,444]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The laser illuminates a small spot as shown in Fig. 1. (a). The motorized TRUS rotates from $-35^{\\\\circ}$ to $35^{\\\\circ}$ in equal increments of $\\\\theta_{d}$ at $\\\\theta_{i}$ s where $i = 1, \\\\dots, N$ for a full scan. The goal is to find $\\\\theta_{p}$ in the TRUS coordinate system. The TRUS also receives out-of-plane signals. The maximum PA signal intensity, $S(\\\\theta_{i})$ , is recorded for each $\\\\theta_{i}$ , described in Fig. 1. (b). As the directivity pattern of the TRUS transducer with respect to the incoming waves is symmetric, a simple weighted average can be used to localize the PA marker, $\\\\theta_{p}$ : \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[346,444,648,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\theta_ {p} = \\\\sum \\\\theta_ {i} S (\\\\theta_ {i}) / \\\\sum S (\\\\theta_ {i}), i = 1, \\\\dots , N \\\\# (1.)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[184,477,808,507]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Note that we need to set a threshold to filter out the samples with very low or no PA signal intensity. This helps to reduce noise and improve localization accuracy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,513,537,529]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.3 Golden Section Search and Ternary Search \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,536,808,657]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Golden Section Search (GSS) is an efficient algorithm for finding the extremum (maximum or minimum) of a unimodal function. The GSS has been widely used in many applications because of its rapid convergence, without requiring that the objective function be continuous. In the GSS algorithm, we compare a pair of observation at two interior points $\\\\theta_{m,1},\\\\theta_{m,2}\\\\in R$ satisfying $\\\\theta_l < \\\\theta_{m,1} < \\\\theta_{m,2} < \\\\theta_r$ for each iteration. The two interior points partition the search interval in terms of the golden section ratio $r$ . Here, we set the initial value of $\\\\theta_l$ and $\\\\theta_r$ as $-35^{\\\\circ}$ and $35^{\\\\circ}$ . They are updated at each iteration and eventually convergence towards $\\\\theta_p$ . The interior points $\\\\theta_{m,1}$ and $\\\\theta_{m,2}$ are computed as follows: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[410,657,584,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nr = \\\\frac {\\\\sqrt {5} - 1}{2} \\\\approx 0. 6 1 8 \\\\# (2.)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[390,686,604,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\theta_ {m, 1} = r \\\\theta_ {l} + (1 - r) \\\\theta_ {r} \\\\# (3.)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[390,702,604,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\theta_ {m, 2} = (1 - r) \\\\theta_ {l} + r \\\\theta_ {r} \\\\# (4.)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[184,717,808,857]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The strategy of GSS can be stated as follows: if $S(\\\\theta_{m,1}) \\\\geq S(\\\\theta_{m,2})$ , the maxima must be in the interval $[\\\\theta_l, \\\\theta_{m,2}]$ . Likewise, if $S(\\\\theta_{m,1}) < S(\\\\theta_{m,2})$ , the maxima must be in the interval $[\\\\theta_{m,1}, \\\\theta_r]$ . Subsequently, we compute two new interior points in the interval mentioned above for the next iteration. At every iteration, we calculate the interior points in this manner and keep narrowing the search interval until meeting the termination condition. Theoretically, the iteration would terminate when $\\\\theta_l \\\\geq \\\\theta_r$ is met. In practice, however, we can set a termination condition to boost the speed of convergence. Once the search interval is less than this termination condition, we stop the iteration and take $\\\\theta_p = (\\\\theta_l + \\\\theta_r) / 2$ as the output location. If we set $r = 1/3$ instead of the golden section ratio of 0.618, the algorithm turns into the Ternary \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,117,810,147]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Search (TS). Except for the scalar $r$ used for interior points calculation, the other parts of the TS are the same as the GSS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,154,372,167]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.4 Simulation Validation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,167,810,286]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the simulation, the experimental directivity pattern and PA model developed in [20] was used. The PA signals were generated by MATLAB k-Wave toolbox and White Gaussian noise was added to them. The intensity of PA signals was normalized. The reference angles of PA markers were located at 1000 random locations within $-35^{\\\\circ}$ to $35^{\\\\circ}$ , and PA signal was recorded at the desired positions based on the proposed search algorithms. Here, we compared the performance of all three search algorithms with different numbers of data acquisitions. With the WA algorithm, laser spots were located at a random position and PA signals were detected at several $\\\\theta_{i}$ s spaced at certain $\\\\theta_{d}$ , determined by the number of acquisitions $N$ : \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[415,287,583,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\theta_ {d} = 7 0 ^ {o} / (N - 1) \\\\# (5.)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[184,301,810,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"So, as the number of acquisitions increases, $\\\\theta_d$ decreases. Note that the number of acquisitions cannot be too small because there may be no PA signals generated. In the GSS and TS algorithms, the angle of the TRUS is determined by the policy introduced in 2.3 and the iteration/acquisition can be continued until the desired accuracy is met. We tested the performance of these two algorithms when acquiring data 2-28 times. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,382,380,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.5 Experiment Validation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,397,810,571]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to the simulation validation, we conducted experimental studies to illustrate the advantages of our proposed method. In our experiment, a pulsed laser diode illuminated random locations on the tissue surface. To validate our approach, we conducted two types of analysis: offline and online. For the offline analysis, we conducted experiments to collect data by scanning the entire rotation interval with a very small step size $(\\\\sim 0.5^{\\\\circ})$ , enabling us to have a bank of PA data for our investigation. We simulated the online search based on this collected data. The numerical precision of the motor rotation angle was made consistent with the online analysis by interpolating the original offline data. For the online analysis, the algorithms were investigated in a real-time implementation where each of the search algorithms were integrated into the robotic and imaging systems. As a result, PA data were acquired at the locations that the algorithm asked for, and the output was compared with the reference acquired from a manual search. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[290,575,699,805]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2. Schematic diagram of the overall system composition. It also describes the TRUS coordinate system (TR). The $y$ -axis is parallel with the axis of rotation of the TRUS. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0680/feb0d2a24d9822daa59209c73df89020ba7b5443bf312dcc3922242af6e7a1f6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,843,344,857]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. System Architecture \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,117,813,294]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The overall system depicted in Fig. 2. comprises of several modules including the main host computer, pulsed laser system, TRUS actuator control module, and PA+US imaging system. The imaging system was described in [19]. Here, we emphasize the modules related to the automatic implementation of the search algorithms. In the pulse laser system, the $785\\\\mathrm{nm}$ pulse laser diode (QSP-785-4, QPhotonics LLC, Ann Arbor, MI, USA) is excited by a laser driver (LDP-V, PicoLAS GmbH, Germany) to generate a $2\\\\mu \\\\mathrm{J}$ /pulse laser beam. The PA+US imaging module synchronously acquires PA signals. The generated PA signals can be detected by a TRUS transducer (BPL 9-5/55, BK Medical, Peabody, MA, USA) and a SonixDAQ (Ultrasonix Medical Corp., Canada). The actuator control module can drive the TRUS transducer to rotate through an actuator (rotation stage, PRM1Z8, Thorlabs, Newton, NJ, USA) rigidly attached to it. Real-time communication between each component in the system is based on the Robot Operating System (ROS). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,299,339,314]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. Experimental Setup \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,314,810,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The experimental set-up is shown in Fig. 3(a). An ex vivo bovine liver tissue was supported by two pieces of ultrasound gel pad (Parker Laboratories, Fairfield, NJ, USA) with a total thickness of $5\\\\mathrm{cm}$ to mimic the prostate gland. A laser diode held by a clip was placed close to the surface of the ex vivo tissue. The laser's location and its surrounding region ( $5\\\\mathrm{mm} \\\\times 5\\\\mathrm{mm}$ area) were stained with India ink (Dr. Ph. Martin, Oceanside, CA, USA) to increase laser absorption. A TRUS transducer motorized by an actuator was placed beneath the ex vivo tissue and ultrasound pads to detect the PM. Here, we tested the proposed approach on a homogenous black plastisol phantom, and three types of ex vivo tissue, bovine liver, muscle, and chicken breast, to demonstrate its feasibility. In one case, in accordance with the prostate nerve sensing [28], the ex vivo bovine muscle was stained by indocyanine green (ICG) dye (TCI, Tokyo, Japan). As illustrated in Fig. 3. (b), the PA signals arranged on a $3 \\\\times 3$ grid were collected on each type of material. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,489,575,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0889/58acf201bc8350799ce062d70e2374b71e2ffe96bf5e1da21d35f01dbf52d307.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[598,498,805,714]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3. (a) The offline analysis experimental set-up with bovine liver ex vivo tissue stained with India ink. (b) The conceptual illustration of the laser spot location on ex vivo chicken breast tissue from the top view of the $x-y$ plane. The red dots indicate the laser spot, and a $3 \\\\\\\\times 3$ grid roughly spaced at $20\\\\\\\\mathrm{mm}$ in the $x$ -axis and $y$ -axis directions, respectively, of the $x-y$ plane of the TRUS coordinate system. For other ex vivo tissues and plastisol phantom, the laser spot location is arranged in the same way. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0971/41a6c3413fb4d60c66bbba762fc795b7e6d7c824ca6616347cec1f2a89375609.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,805,413,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Online Search implementation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,819,812,869]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We integrated the automatic search module into the overall TRUS-da Vinci robotic system using ROS and used a LabVIEW script [19] to control the rotation stage. To integrate this TRUS controller into our ROS communication system, we used the ROS for LabVIEW toolkit \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,117,813,268]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"software [29] developed by the Tufts University Center for Engineering Education and Outreach. We created a node for the TRUS controller, as well as a publisher and a subscriber to receive the angle that the TRUS should rotate to and return the actual rotated angle. For online analysis, there was no need to exhaustively scan the entire rotation range with a small step size to collect data as in our offline analysis. The TRUS only rotated to specified locations that the algorithm asked for and acquired PA signals from the data acquisition system at these locations. Here, we tested the proposed online automatic search module on a black plastisol phantom. Like in the offline analysis case, we tested each search algorithm on the $3 \\\\times 3$ grid of locations and the results were compared with manually found reference locations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,276,454,290]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"D. Tool Tip Detection - Sensitive Range \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,291,810,406]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When using the da Vinci instrument tool tip for registration, a key stage in this procedure is the da Vinci surgical instrument tip detection [30]. Similar to the PM intensity, the tip intensity is the highest when the US imaging plane is coplanar with the surgical instrument tip. It decreases and eventually disappears as the US imaging plane deviates from the coplanar position. Consequently, we only need to make sure the surgical instrument tip is within the range (termed sensitive range) that can be detected by the US, not necessarily to be exactly coplanar with the US imaging plane. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,407,812,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We experimentally investigated the sensitive range when detecting the da Vinci surgical instrument tip. As shown in Fig. 4., the da Vinci instrument tip held on a robotic arm was pressed against the surface of a piece of ex vivo chicken breast. We rotated the TRUS clockwise with a step size of $1^{\\\\circ}$ starting with the reference location and recorded the corresponding B-mode image at each location. The range from the reference location to the location where the tip disappeared (shown in Fig. 9. (b) and (c)) was half of the sensitive range. Assuming that the function of detected tip intensity versus TRUS rotation location is symmetric, the other half sensitive range was inferred by flipping along the reference location. Here, we roughly calculated the entire sensitive range by adding these two half sensitive ranges. Three locations of the da Vinci surgical instrument tip spaced at about $2\\\\mathrm{cm}$ in $x$ -axis were tested in this experiment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,592,812,696]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the B-mode image processing, we first segmented the da Vinci instrument tip by leveraging GrabCut [31], following to find the centroid of this connected instrument tip area, and finally taking the pixel value of this centroid as the instrument tip intensity. Let $\\\\theta_{high}$ denote the location with the highest tip intensity, and $\\\\theta_{low}$ denote the location with the lowest tip intensity that can be detected. Thus, half of the sensitive range can be defined as the absolute value of these two locations, namely $|\\\\theta_{high} - \\\\theta_{low}|$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,704,272,718]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Result \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,719,813,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The proposed automatic search module was validated by both simulation and experiment (including offline analysis and online analysis). The performance of various search algorithms was evaluated in terms of localization accuracy and time efficiency. For the evaluation of localization accuracy, we measured the localization error which was defined as the absolute value of the difference between the reference location and optimal output location. To assess time efficiency, we adopt the number of data acquisitions as the metric due to most of the time in the proposed search procedure being used to acquire data. In the following sections, we will illustrate and discuss the results of each in detail. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[357,114,630,362]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4. The experimental setup for investigating the sensitive range of da Vinci surgical instrument tip detection. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0509/253199986304ef659c75756e982b919cea4351d182e4cda1096df27b12275f0c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,385,357,398]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1 Simulation Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,407,813,554]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the TS and GSS algorithm, we tested a set of number of acquisitions from 2 to 28 in increments of 2. Likewise, we tested a set of number of acquisitions from 8 to 28 for the WA algorithm to ensure that at least one valid PA signal can be acquired at the proposed equal intervals. We set a fixed threshold of 0.2 for all experiments in the WA algorithm. The average error after 1000 trials changed with the number of acquisitions as shown in Fig. 5. The error of TS and GSS algorithms rapidly dropped at the beginning and converged to a small value, while the error of WA did not change much with the number of acquisitions. When conducting 28 acquisitions, the average errors of the TS and GSS algorithm were $0.06^{\\\\circ}$ and $0.01^{\\\\circ}$ , respectively. In the WA algorithm, the average error when acquiring different numbers of PA signals was $0.47^{\\\\circ} \\\\pm 0.11^{\\\\circ}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[346,559,643,691]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5. The average error of 1000 experiments using various algorithms in the simulation study. Red dots, blue dots, and green dots represent the error of TS, GSS, and WA algorithm. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0323/52a50824e140129850628efe5aaf94af3796f4876b2d9405a7d5994f919fd4ae.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,729,393,744]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2 Offline Analysis Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,746,802,818]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In our offline analysis, we interpolated each set of data to achieve the same resolution as the simulated data. Fig. 6 depicts the average error versus the number of acquisitions on various materials resulting from the offline analysis. Table 1 summarizes the error of each algorithm when acquiring the PA signal 16 times. Note that we only obtained one set of data on bovine muscle stained by ICG, so the results of this test did not have a standard deviation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[196,119,411,215]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0669/8ee9340d290bceeace583b584728f18bcc4f4ba94a36a547bffa99543cfb6a04.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[416,119,612,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0958/f1efaf94a7209b9c859c11826518a66d865e32efd7e58ea611402a1258c9148f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[616,119,812,213]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0891/2c054719a9ff1ce2b2d438033588e5155b3c856b1240c21ac4b41f9927538a54.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[194,217,411,309]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0684/91c4b3f4ab3dc107993e3f05a2af4840d468428d0e3af2d20715d6cc0c68efa7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[413,218,614,309]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Number of acquisitions \\\",\\\"Fig. 6. The average error of offline analysis versus the number of acquisitions. The sub-figures (a) - (e) indicate the offline analysis results on bovine liver, muscle, chicken breast, phantom and bovine muscle stained with ICG, respectively. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0866/324278aa48cb9c151d2a6afbc9417131dabdc4c5fd39bd505b7721a04ae7289f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[212,401,784,520]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0104/b984b8c67c228714134484a9b4f2663335fe6075bb2deb242f2eb971f52747fa.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Algorithms</td><td colspan=\\\"5\\\">Average Error (Degree)</td></tr><tr><td>Bovine Liver</td><td>Bovine Muscle</td><td>Chicken Breast</td><td>Plastisol Phantom</td><td>Bovine Muscle +ICG</td></tr><tr><td>WA</td><td>0.51 ± 0.36</td><td>0.93 ± 0.83</td><td>0.35 ± 0.23</td><td>0.54 ± 0.41</td><td>1.28</td></tr><tr><td>TS</td><td>0.34 ± 0.27</td><td>0.29 ± 0.22</td><td>0.34 ± 0.20</td><td>0.32 ± 0.22</td><td>0.32</td></tr><tr><td>GSS</td><td>0.20 ± 0.19</td><td>0.52 ± 0.61</td><td>0.30 ± 0.24</td><td>0.45 ± 0.40</td><td>1.12</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Average Error of Various Algorithms in Offline Analysis Terminating After 16 Times of Acquisitions \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[187,525,392,540]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3 Online Analysis Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,541,813,779]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In online analysis, each algorithm described earlier was integrated into the TRUS-da Vinci robotic system. When conducting the online analysis, the TRUS automatically rotated to the position specified by the algorithm, and finally stopped at $\\\\theta_{p}$ calculated by this algorithm. Fig. 7. illustrates the comparison of the average errors of TS and GSS algorithms with varying numbers of acquisitions. The average errors of these two algorithms decrease with an increase in the number of acquisitions. For the TS and GSS algorithms, the specific location of the TRUS at each number of acquisitions is illustrated in Fig. 8. The GSS and TS algorithm achieved minimum error, $0.48^{\\\\circ} \\\\pm 0.30^{\\\\circ}$ and $0.29^{\\\\circ} \\\\pm 0.30^{\\\\circ}$ , when acquiring 28 times data. When adopting WA, we took $5^{\\\\circ}$ as the step size, that is, acquiring 15 times PA signals to cover the entire space. However, in the online analysis, we can terminate the search as long as the entire peak of the intensity is recorded and passed. We can often complete the WA search by collecting data fewer than 15 times. The average error of WA was $0.53^{\\\\circ} \\\\pm 0.30^{\\\\circ}$ with 8.7 data acquisitions. Table 2 is the comparison of the average error of various algorithms when taking a similar number of acquisitions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[359,123,630,239]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 7. Average error of TS and GSS with a varying number of acquisitions in online analysis. The blue bar and orange bar indicate the TS and GSS algorithms respectively. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0747/4d98eefe1f00509724e8cc0074bfed3db4e23524df1e48cddfd8a5148ff10d28.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[328,305,669,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0799/22439efbc823fb6a99c5c5b4208b079885927393211be00a67bfebfb1ef56542.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Algorithms</td><td>Average Error</td><td>Number of Acquisitions</td></tr><tr><td>WA</td><td>0.53 ± 0.30</td><td>8.7</td></tr><tr><td>TS</td><td>1.05 ± 1.04</td><td>16</td></tr><tr><td>GSS</td><td>0.74 ± 0.58</td><td>16</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Average Error of Various Algorithms in Online Analysis \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[236,400,759,631]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0389/578ed05d20a9b54488c415c8989ca03f78756bc249e86350b53cd14b09584636.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[235,636,759,869]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0458/7776dee390f3c84599c2cbb4894494004a71f2a2cfba01cbf0601ce7e7336891.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[233,118,764,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 8. TRUS location during the TS and GSS algorithms. The blue dots, red dots, and orange dashed line refer to the locations in TS and GSS as well as the reference location $\\\\\\\\theta_{gt}$ . The position 1 to 9 were located on a $3 \\\\\\\\times 3$ grid as described in Fig. 3. (b). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0673/8ac778439ae3217e8e88e923693e41a929464c9dcc03f34400f5650cb5c2f9a5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,409,398,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.4 Sensitive Range Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,424,813,541]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We pressed the da Vinci surgical instrument tip against the ex vivo chicken breast tissue surface at three locations. For each tip location, a set of B-mode images were recorded with the TRUS rotated in steps of $1^{\\\\circ}$ (Fig. 9. (a) and (d) show one of the B-mode images sets and the corresponding tip intensity curve). We took the position corresponding to the strongest and weakest tip intensity that can be detected as half of the sensitive range. In our experiment, half of the sensitive range of the three locations were $5^{\\\\circ}, 4^{\\\\circ}$ , and $4^{\\\\circ}$ respectively, and the average value was $4.33^{\\\\circ} \\\\pm 0.58^{\\\\circ}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[189,560,313,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\",\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0272/09ad17bd34224003a77a4c936d5c4720c238cdf07f1d0681c0ac89a44ac3ed98.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[315,560,437,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0850/0d73899a6b98a476d8218824ad73e321c4747619db2d35be3d98ac4a378e87c7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[439,560,560,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0430/cd240ec5d3c023e7cda44736d95330e2622fccf883f2d26702a43338d7751a1b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[562,560,684,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0218/13c5fdcbe824dfdff209edc5d298abe2c99453cc7b3a12d8acfe7d5b79ab8c34.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[686,560,810,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0171/d94d6007541ef7bca8e8e9d36e935b687d86830b23c27d64a3b2d6163926c9b8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[187,655,380,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0492/6892a7ddfebbb55f1a3d89d0f49ea3c790bfa01d9c2d5cc170040af36340b875.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[383,654,576,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0866/59e02f0b645cad330c89f173b8445c076cd914397c2e9d3bae5b27f72db99a64.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[584,655,816,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 9. (a) A set of B-mode images with varying tip intensity. The da Vinci surgical instrument tip is within the red dashed circle. The reference location is $0^{\\\\\\\\circ}$ . (b) The B-mode image at the reference location. It can be partitioned into 3 layers: from top to bottom are air, ex vivo tissue and ultrasound pad. (c) The B-mode image at a location transcending the sensitive range. (d) The tip intensity versus TRUS location. As the TRUS location moves away from the reference location $0^{\\\\\\\\circ}$ , the corresponding tip intensity keeps reducing. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0048/05cb001b443a7c0ea651cdef4d59666d2cc0eb030b937edb1e0d0e0bfcdb6ec6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[186,859,308,872]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,117,810,217]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of the experimental results described in 3.4, the sensitive range for the da Vinci surgical instrument tip detection is about $8.66^{\\\\circ}$ . In fact, we can obtain a much lower error $(0.53^{\\\\circ} \\\\pm 0.30^{\\\\circ})$ using the WA algorithm in our study just acquiring PA signals eight times. Consequently, the accuracy of all three algorithms should be considered precise and sufficient compared to the sensitive range of tip detection. Regarding the three algorithms adopted in this paper, TS and GSS output the most precise PM location on ex vivo tissues when acquiring data 28 times. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,218,808,369]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The proposed search algorithms have the potential to be used as a part of the control platform for the surgical tool tracking and TRUS servoing tasks. In online analysis, and with only acquiring two PA signals, the average error was $4.20^{\\\\circ}$ and $5.89^{\\\\circ}$ when adopting the TS and GSS algorithm starting at the far left $(-35^{\\\\circ})$ and right $(+35^{\\\\circ})$ of the boundary which is reasonable when compared to the required $8.66^{\\\\circ}$ . However, this accuracy will significantly improve with more data acquisitions as illustrated in this paper. Besides, the TS and GSS tend to converge toward and settle at the target location $\\\\theta_{p}$ . This property makes these two algorithms potentially applicable in tool tracking procedures and will be further investigated in our future studies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,372,808,571]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From the perspective of time, the primary limitation of the proposed technique is the relatively long time of acquiring PA signals from SonixDAQ. In this work, we utilized the API of SonixDAQ to read raw PA signals from the device and read these raw data files to do beamforming and reconstruction. This manner typically takes about 10 seconds. Driven by this limitation, our group is developing a real-time PA imaging based on SPARE (Synthetic-aperture Based Photoacoustic Re-beamforming [32]). This can essentially benefit the time efficiency of the PM-based RAPL system. Future work will integrate SPARE into the system to ameliorate the time-consuming PA signals acquisition and improve the system's efficiency. In that case, the only time we need to consider is the time of TRUS rotation. When acquiring data for 16 times, the total rotation travel in TS and GSS are about $36^{\\\\circ}$ and $24^{\\\\circ}$ , respectively. Thus, the estimated time of rotation is within 1-2 seconds, which is much less than the 2-3 minutes of manual search reported in [30] and close to a real-time search approach. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,580,310,595]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5. Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,603,810,780]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this study, we presented an automatic search method for PM to deal with the drawbacks of manual search procedures. We cast the PM search procedure as an optimization problem of a 1-D unimodal function and investigated three algorithms to address this problem. Simulation studies and experiments on various ex vivo tissues and phantom validated the validity of our proposed method. In simulation studies, all three algorithms perform well. In offline analysis, the average error of the TS and GSS algorithm on all materials was below $0.5^{\\\\circ}$ when acquiring 28 PA acquisitions. In online analysis, the average error of the TS and GSS algorithm achieved $0.29^{\\\\circ} \\\\pm 0.31^{\\\\circ}$ and $0.48^{\\\\circ} \\\\pm 0.32^{\\\\circ}$ after 28 acquisitions, while the WA achieved $0.53^{\\\\circ} \\\\pm 0.30^{\\\\circ}$ using only 8.7 times acquisitions. In summary, the proposed technique significantly improved the system's degree of automation and alleviated the labor required, while achieving good search accuracy. In future work, the proposed search method will be combined with real-time photoacoustic imaging to significantly improve the time efficiency of the PM-based RAPL. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,786,808,845]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding. This work was supported in part by NSF Career Award 1653322, NIH R01-CA134675, the Johns Hopkins University internal funds, Canadian Institutes of Health Research (CIHR), CA Laszlo Chair in Biomedical Engineering held by Professor Salcudean, and an equipment loan from Intuitive Surgical, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,117,810,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments. We would like to acknowledge to our sponsors and funding agencies: Funding from the National Science Foundation Career Award 1653322, National Institute of Health R01-CA134675, the Johns Hopkins University internal funds, Canadian Institutes of Health Research, CA Laszlo Chair in Biomedical Engineering held by Professor Salcudean, and Intuitive Surgical for the equipment support. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,198,576,212]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disclosures. The authors declare no conflicts of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[184,219,807,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data availability. Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,256,279,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,277,807,871]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. H. Sung, J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, and F. 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A 4, 629-642 (1987) \\\"]\",\n \"page_idx\": \"12\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.48550/arxiv.2307.10546"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences/Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"2ea6ea59a17f8e187b4110f3ef9cb16f7ec9cb0d249382b01d2272e75d61cc65"},"title":{"kind":"string","value":"Automatic Search for Photoacoustic Marker Using Automated Transrectal Ultrasound"}}},{"rowIdx":156,"cells":{"abstract":{"kind":"string","value":"Tomato peels are used as a valuable material to extract lycopene-rich oleoresins by supercritical CO2 extraction. The extraction involves continuous circling of CO2 to the extractor after removing the solute in the separators, S40 and S45, where the solvent power of the CO2 is reduced by reducing pressure down to 20 MPa in S40 and 5 MPa in S45, respectively, leading to two extracts. Lycopene is found to be the major compound, representing 93% and 76% of the total carotenoids in S40 and S45 extracts, respectively. The two extracts are microencapsulated in whey protein concentrate and acacia gum by complex coacervation and freeze-drying, leading to corresponding P40 and P45 powders, with antioxidant activity of 8.57 ± 0.74 and 9.37 ± 0.48 mMol TEAC/g DW in P40 and P45, respectively. Different structural and morphological patterns are observed, with finer microparticles of 1-2 µm in P45. Both powders show dose and time-dependent antiproliferative activity. The half-maximal inhibitory concentration values are 100 µg/mL for P40 and 750 µg/mL for P45 sample, indicating a higher antiproliferative effect of P40 over P45 in HT-29 cell culture. The powders have an extended range of cytocompatibility, up to 1000 µg/mL, in L929 normal cells, stimulating the cell growth. Lycopene retention is tested, and values of 48% and 29% in P40 and P45 are found after 21 days at 25 °C, with the degradation rate in P45 significantly higher, due to the higher content of the surface lycopene, which favored its degradation."},"author":{"kind":"string","value":"Ionica Gheonea Dima|Gabriela Râpeanu|Anca Oancea|Oana Crăciunescu|Vasilica Barbu|Nicoleta Stănciuc|Gabriela Elena Bahrim|Liliana Mihalcea|Elena Enachi|Ana-Maria Prelipcean"},"content_list":{"kind":"list like","value":[{"bbox":"[57,118,107,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,133,927,203]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supercritical $\\mathrm{CO}_{2}$ Extraction and Microencapsulation of Lycopene-Enriched Oleoresins from Tomato Peels: Evidence on Antiproliferative and Cytocompatibility Activities ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,219,882,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Liliana Mihalcea $^{1}$ , Oana Crăciunescu $^{2}$ , Ionica Gheonea (Dima) $^{1}$ , Ana-Maria Prelipcean $^{2}$ , Elena Enachi $^{1}$ , Vasilica Barbu $^{1}$ , Gabriela Elena Bahrim $^{1}$ , Gabriela Râpeanu $^{1}$ , Anca Oancea $^{2}$ and Nicoleta Stanciuč $^{1,*}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,272,910,363]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"$^{1}$ Faculty of Food Science and Engineering, Dunărea de Jos University of Galati, 800201 Galati, Romania; Liliana.Mihalcea@ugal.ro (L.M.); Icona.Dima@ugal.ro (I.G.); Elena.Ionita@ugal.ro (E.E.); Vasilica.Barbu@ugal.ro (V.B.); Gabriela.Bahrim@ugal.ro (G.E.B.); Gabriela.Rapeanu@ugal.ro (G.R.) \",\"$^{2}$ Department of Cellular and Molecular Biology, National Institute of Research & Development for Biological Sciences, 060031 Bucharest, Romania; oana.craciunescu@incdsb.ro (O.C.); anamaria.prelipcean@incdsb.ro (A.-M.P.); anca.oancea@incdsb.ro (A.O.) \",\"* Correspondence: Nicoleta.Stanciuc@ugal.ro \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[57,403,87,423]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0814/8a6bedebc683f5d458f7b529c3e08d5bb52aca7869f3269b54d9c8d0929641df.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,405,144,424]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"check for updates ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,434,252,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Citation: Mihalcea, L.; Craciunescu, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,448,240,458]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"O.; Gheonea (Dima), I.; Prelipcean, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,462,247,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A.-M.; Enachi, E.; Barbu, V.; Bahrim,","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,476,218,487]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"G.E.; Râpeanu, G.; Oancea, A.;","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,489,216,502]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Stanciuic, N. Supercritical $\\mathrm{CO}_{2}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,504,255,516]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Extraction and Microencapsulation of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,519,247,529]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lycopene-Enriched Oleoresins from ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,533,200,543]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tomato Peels: Evidence on ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,546,169,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antiproliferative and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,561,210,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cytocompatibility Activities. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,575,245,587]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222. https:// ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,590,228,600]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"doi.org/10.3390/antiox10020222 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,618,149,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Academic Editor: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,632,181,644]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Soraya Rodriguez-Rojo ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,646,201,657]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 9 December 2020 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,659,196,671]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted: 26 January 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,675,200,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published: 2 February 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,703,258,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,778,154,804]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0253/c13a26d0dd7f61af69bd530c3ba2c74ef386bfd73559eba57a8233d8d3012a84.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,810,258,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,380,941,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: Tomato peels are used as a valuable material to extract lycopene-rich oleoresins by supercritical $\\mathrm{CO}_{2}$ extraction. The extraction involves continuous circling of $\\mathrm{CO}_{2}$ to the extractor after removing the solute in the separators, S40 and S45, where the solvent power of the $\\mathrm{CO}_{2}$ is reduced by reducing pressure down to $20\\mathrm{MPa}$ in S40 and $5\\mathrm{MPa}$ in S45, respectively, leading to two extracts. Lycopene is found to be the major compound, representing $93\\%$ and $76\\%$ of the total carotenoids in S40 and S45 extracts, respectively. The two extracts are microencapsulated in whey protein concentrate and acacia gum by complex coacervation and freeze-drying, leading to corresponding P40 and P45 powders, with antioxidant activity of $8.57\\pm 0.74$ and $9.37\\pm 0.48\\mathrm{mMol}$ TEAC/g DW in P40 and P45, respectively. Different structural and morphological patterns are observed, with finer microparticles of $1 - 2\\mu \\mathrm{m}$ in P45. Both powders show dose and time-dependent antiproliferative activity. The half-maximal inhibitory concentration values are $100~\\mu \\mathrm{g / mL}$ for P40 and $750~\\mu \\mathrm{g / mL}$ for P45 sample, indicating a higher antiproliferative effect of P40 over P45 in HT-29 cell culture. The powders have an extended range of cytocompatibility, up to $1000~\\mu \\mathrm{g / mL}$ , in L929 normal cells, stimulating the cell growth. Lycopene retention is tested, and values of $48\\%$ and $29\\%$ in P40 and P45 are found after 21 days at $25^{\\circ}C$ , with the degradation rate in P45 significantly higher, due to the higher content of the surface lycopene, which favored its degradation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,640,941,671]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: lycopene; supercritical $\\mathrm{CO}_{2}$ extraction; microencapsulation; antiproliferative activity; cytocompatibility ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,715,394,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,733,941,882]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is well known that tomato processing is one of the most developed within the vegetable processing industry at an international level, being responsible for important amounts of waste, thus causing a major disposal problem, both in terms of costs and impact on the environment [1]. Colle et al. [2] suggested that millions of tons of tomatoes are processed into products (saues, juices, soups, and dried tomatoes) or used as ingredients of ready-to-eat meals, resulting in large amounts of by-products, such as peel, pulp, and seeds, representing $10 - 40\\%$ of the total processed tomatoes. A significant part of these by-products is currently being disposed of in the environment or used as animal feed. However, the abundance of lycopene in the peels fraction suggests the possibility of utilizing it as a cheap source for lycopene extraction [3]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,883,941,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The main carotenoid in tomatoes is lycopene, representing approximately $80 - 90\\%$ of the total carotenoids. Due to its open-chain structure with 13 double bonds, with 11 of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,53,115,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[122,64,292,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"antioxidants ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,60,937,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MDPI ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[55,964,458,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222. https://doi.org/10.3390/antiox10020222 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[653,964,936,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://www.mdpi.com/journal/antioxidants ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[278,110,939,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"them conjugated, lycopene has the highest degree of unsaturation among all carotenoids. The presence of the 13 conjugated double bonds gives the characteristic deep red color of ripe tomato fruits and tomato products and the antioxidant activity [4]. Due to its structural particularities, growing demand has been observed for the natural form of lycopene, due to the specific properties to be effective in quenching the destructive free radicals (nitrogen dioxide— $\\mathrm{NO}_2\\bullet$ , sulfide— $\\mathrm{RS}\\bullet$ and singlet oxygen— $\\mathrm{O}_2\\bullet$ ) and in inhibiting DNA and cellular membrane damage [5]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,214,939,498]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Different benefits associated with the increased dietary consumption of tomatoes and derived products containing lycopene were reported—such as cardiovascular protection, and the decrease of prostate and breast cancer, and coronary heart disease incidence [6], inhibition of the oxidation of low-density lipoproteins, thus, helping to lower the level of blood cholesterol [7], and anti-inflammatory response, by inhibiting the activation of inducible nitric oxide synthase proteins [8]. From a marketing point of view, Scaglia et al. [9] suggested that lycopene is one of ten carotenoids that are currently marketed, with an estimated economic value in 2017 of 1.5 USD billion and an annual growth rate of $2.3\\%$ . Therefore, the extraction of the lycopene from tomato waste may bring significant benefits by further introducing the extracts in different foods, cosmeceuticals, and nutraceuticals. However, extractions of the bioactives from food matrices are limited by the requirement of non-toxic solvents that do not remain as residue in the product. Since the lycopene is stored in the tomato peels, it degrades easily during processing [10], supercritical carbon dioxide $(\\mathrm{SC - CO_2})$ extraction has been used as an emerging method to extract tomato oleoresin [11]. $\\mathrm{SC - CO_2}$ extraction is a greener alternative to organic solvent extraction, which operates above the solvent's critical pressure and temperature, enhancing the solvating power of the solvent. $\\mathrm{SC - CO_2}$ is a solvent frequently used, due to its main advantages as, low critical pressure and temperature, non-toxic, non-inflammable, high purity, low cost, and its availability. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,499,939,646]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Precisely due to the high content of unsaturated bonds, responsible for the specific biological properties, isolated lycopene is prone to degradation, being sensitive to oxidants, light, and heat during storage and processing [12], especially in the presence of oxygen [13]. In addition, the application of lycopene in the food industry as an added-value ingredient is drastically limited, due to its characteristics of low solubility in an aqueous environment and low bioaccessibility [14]. Therefore, design strategies are needed to produce lycopene in a stable form, with improved solubility and bioaccessibility. Recently, in order to improve the solubility and bioaccessibility of lycopene, several delivery systems have been developed, such as protein-based nanoparticles [15], emulsions [16], liposomes [17], and microcapsules [18]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,648,939,810]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Therefore, this study extends the possibility of using tomato peels as a valuable source of lycopene, by $\\mathrm{SC - CO_2}$ extraction and microencapsulation. In the first step, the valorization of fresh tomato peels by supercritical carbon dioxide extraction without modifiers at different extraction parameters, whereas the extracts were characterized in terms of total carotenoids, lycopene content, and antioxidant activity. Further, the extracts with the higher bioactives content were used to produce microcapsules, using whey protein isolates and acacia gum as microencapsulating agents, by complex coacervation and freeze-drying. The resulting powders were tested for microencapsulation efficiency, phytochemicals content and antioxidant activity, structural and morphological appearance, and antiproliferative and cytotoxic properties. In addition, the short-term storage stability of lycopene microcapsules was studied. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,824,475,835]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Materials and Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,840,379,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1. Chemicals ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,858,941,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Whey protein isolates (protein content of $95\\%$ ) was purchased from Fonterra (Auckland, New Zealand). The HPLC analytical-grade hexane, acetone, acetonitrile, ethyl acetate, methanol, and analytical grade [2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt] (ABTS), 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[273,112,939,231]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"acacia gum, lycopene, and $\\beta$ -carotene standards were obtained from Sigma-Aldrich (Steinheim, Germany). Carbon dioxide with a purity of $99.9\\%$ vol. was supplied by Messer Romania Gaz SRL (Bucharest, Romania). Dulbecco's Modified Eagle Medium (DMEM), Minimum Essential Medium (MEM), fetal calf serum (FCS), L-glutamine, a mixture of antibiotics (penicillin, streptomycin, neomycin) (PSN), and neutral red (NR) were purchased from Merck (Germany). HT-29 human colorectal adenocarcinoma cell line was purchased from ATCC, and NCTC clone L929 mouse fibroblast cell line came from ECACC (Sigma-Aldrich, Steinheim, Germany). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,243,408,256]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2. Tomato Fruits ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,262,941,367]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Red ripped tomatoes (Lycopersicon esculentum var. Buzău 1600) were purchased at commercial maturity from a local supermarket (Galati, Romania) in August 2019 and stored at $4^{\\circ}\\mathrm{C}$ until processing. The fruits were visually inspected for uniformity of color and selected based on similar characteristics. To obtain peels without any residual pulp, the tomatoes were first washed with distilled water, and the peels were removed manually, washed several times, and then blotted on paper towels to remove any residual pulp. The peels were stored at $-20^{\\circ}\\mathrm{C}$ until analyses. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,378,657,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.3. Tomato Peels Supercritical $\\mathrm{CO}_{2}$ Extraction Process ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,397,941,739]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The extractions with $\\mathrm{SC - CO_2}$ were performed with the pilot plant equipped with an extractor vessel with a total internal volume of $2\\mathrm{L}$ , and two separators S40 and S45, each with a volume of $1.5\\mathrm{L}$ (Natex Prozesstechnologie GesmbH, Ternitz, Austria). $\\mathrm{SC - CO_2}$ flow was monitored with a Coriolis mass flow meter. Several $\\mathrm{SC - CO_2}$ extraction batches have been tested without modifiers. The amount of $0.165\\mathrm{kg}$ of tomato peels, with a moisture content of $79.46\\pm 0.41\\%$ , was ground and placed in the extractor vessel, and liquid $\\mathrm{CO_2}$ from a cylinder tank with a siphon was passed through a chiller kept at $-3^{\\circ}\\mathrm{C}$ and compressed by a high-pressure membrane pump. The solvent was continuously cycled to the extractor after removing the solute in the separators, S40 and S45, where the solvent power of the $\\mathrm{CO_2}$ was reduced by reducing pressure down to $20\\mathrm{MPa}$ in S40 and 5 MPa in S45, respectively. The temperature was set at the same values as in the extractor for the S40 and at $25^{\\circ}\\mathrm{C}$ for the S45, respectively. The extraction parameters were automatically controlled and indicated by ABB software (ABB, Mannheim, Germany). The temperatures of the extractor and both separators were controlled by a surrounding heated jacket, whereas the pressure was controlled by the pressure control valves. Extracting conditions were set as follows: Pressure $40\\mathrm{MPa}$ , temperatures $70^{\\circ}\\mathrm{C}, 74^{\\circ}\\mathrm{C}$ and $80^{\\circ}\\mathrm{C}$ and time $155\\mathrm{min}$ according to previous studies [1]. The $\\mathrm{SC - CO_2}$ extracts (named S40 and S45) were collected in vials, then concentrated at $40^{\\circ}\\mathrm{C}$ using a vacuum rotary evaporator (AVC 2-18, Christ, UK), whereas all vials were protected from light and ambient oxygen with aluminum foil to minimize decomposition and oxidation. The obtained extracts were weighed to calculate the gravimetric yield and stored at $-20^{\\circ}\\mathrm{C}$ until further analyses. The gravimetric extraction yield was expressed as the ratio between the weight of extracted oleoresin and the weight of matrices loaded in the extractor vessel. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,751,813,766]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.4. Evaluation of Carotenoids and Lycopene Content in Extracts and Powders ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,770,941,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A spectrophotometric method was employed to determine the lycopene and total carotenoid contents in the extracts and powders. Therefore, about $5\\mathrm{mg}$ of dried extracts and $100\\mathrm{mg}$ of each microencapsulated powder were dissolved in $10\\mathrm{mL}$ of a mixture of $n$ -hexane:acetone (ratio of 3:1), in a volumetric flask. The absorbance was measured at $470\\mathrm{nm}$ and $503\\mathrm{nm}$ . The amount of lycopene and $\\beta$ -carotene was calculated according to the following equation [13]: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[442,870,939,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\operatorname {C a r o t e n o i d} \\left(\\frac {\\mathrm {g}}{\\mathrm {L}}\\right) = A \\times M _ {W} \\times D _ {f} / \\left(M _ {a} \\times L\\right) \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[55,60,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,112,939,173]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $A$ is absorbance of the hexane phase at 503 and $470\\mathrm{nm}$ ; $Mw$ is the molecular weight for lycopene, and $\\beta$ -carotene (536.873 and $536.87\\mathrm{g}\\cdot \\mathrm{mol}^{-1}$ , respectively), $D_{f}$ I sample dilution rate, $M_{a}$ I molar absorptivity in $n$ -hexane ( $3450\\mathrm{L mol}^{-1}\\mathrm{cm}^{-1}$ for lycopene and $2592\\mathrm{L mol}^{-1}\\mathrm{cm}^{-1}$ for $\\beta$ -carotene), and $L$ I cell diameter of the spectrophotometer ( $1\\mathrm{cm}$ ). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[314,174,907,187]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The amount of lycopene and $\\beta$ -carotene were expressed as mg/g DW of extract. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,200,910,215]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.5. High-Performance Liquid Chromatography (HPLC) Analysis of Lycopene in the Extracts ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,219,941,398]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the spectrophotometric profile, the extract with the higher content in lycopene and $\\beta$ -carotene was selected for HPLC analysis. A Thermo Finnigan Surveyor HPLC system coupled with a DAD UV-visible detector (Finnigan Surveyor LC, Thermo Scientific, USA) was used. The system was controlled by the Xcalibur software (Finnigan Surveyor LC, Thermo Scientific, Waltham, MA, USA), whereas the carotenoids compounds were assessed at $450~\\mathrm{nm}$ on a Lichrosorb RP-18 ( $5\\mu \\mathrm{m}$ ) Hibar RT 125-4 column. The mobile phase consisted of two solvents, namely, $90\\%$ acetonitrile (A) and $100\\%$ ethyl acetate (B). The injection volume was $10~\\mu \\mathrm{L}$ , while the flow rate was $1000~\\mathrm{mL / min}$ . The elution gradient was: $0 - 16\\mathrm{min}$ , $15\\%$ B; $16 - 54\\mathrm{min}$ , $15 - 62\\%$ B, $54 - 56\\mathrm{min}$ , $62\\%$ B; $56 - 60\\mathrm{min}$ , $62 - 15\\%$ B; $60 - 70\\mathrm{min}$ , $15\\%$ B. The quantification of lycopene (LOD $0.05\\mathrm{mgkg}^{-1}$ and LOQ $0.10\\mathrm{mgkg}^{-1}$ ) and $\\beta$ -carotene (LOD $0.05\\mathrm{mgkg}^{-1}$ and LOQ $0.10\\mathrm{mgkg}^{-1}$ ) was performed using the calibration curves for each compound. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,410,657,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.6. Determination of Free Radical Scavenging Activity ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,429,941,607]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The antioxidant activity of the extracts and powders was measured by using the TEAC (Trolox Equivalent Antioxidant Capacity) assay by evaluating the 2,2-azinobis-3-ethylbenzothialzoline-6-sulfonic acid $(\\mathrm{ABTS}^{+})$ radical cation decoloring reaction, as described by Scaglia et al. [9], with slight modifications. Briefly, the working $\\mathrm{ABTS}^{+}$ solution was obtained by mixing the $\\mathrm{ABTS}^{+}$ aqueous solution $(7\\mathrm{mM})$ with potassium persulfate (2.45 mM final concentration), followed by keeping the mixture to react in the dark at room temperature for $16\\mathrm{h}$ . An amount of $5\\mathrm{mg}$ of extracts and $100\\mathrm{mg}$ of powders, respectively, were previously dissolved in $10\\mathrm{mL}$ of a mixture of $n$ -hexane:acetone (ratio of 3:1), in a volumetric flask. A volume of $2.85\\mathrm{mL}$ of the $\\mathrm{ABTS}^{+}$ solution was mixed with $0.15\\mathrm{mL}$ of the extract or powders solution and allowed to react for $2\\mathrm{h}$ in a dark room, followed by an absorbance reading at $734\\mathrm{nm}$ . The $\\mathrm{ABTS}^{+}$ antioxidant activity of the samples was expressed as mM TEAC/g DW of extract based on the calibration curve using Trolox. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,619,855,634]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.7. Microencapsulation of the Extracts by Complex Coacervation and Freeze-Drying ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,638,941,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Two extracts were selected for microencapsulation, based on the highest lycopene content, namely, the two fractions corresponding to the two separators (S40 and S45), obtained in the following conditions: $40\\mathrm{MPa}$ , temperature $74^{\\circ}\\mathrm{C}$ , and an extraction time of $155\\mathrm{min}$ . The microencapsulation of the extracts was performed as described by Gheonea (Dima) et al. [18], with modifications. As microencapsulating materials, whey proteins isolate (WPI) and acacia gum were selected and dissolved in distilled water at a ratio of 5:1 $(w / w)$ . The solution was mixed on a magnetic stirrer until complete hydration at 450 rpm and $40^{\\circ}\\mathrm{C}$ . To obtain a coarse emulsion, an amount of $0.5\\mathrm{g}$ of each extract (S40 and S45) was first dissolved in $5\\mathrm{mL}$ of sunflower oil and dripped into the aqueous solution by stirring. The emulsion was then obtained by homogenization using an Ultra Turrax mixer (IKA T18 basic, Staufen, Germany) at $5000\\times g$ for $10\\mathrm{min}$ . To promote coacervation, the pH of the solutions was adjusted to 3.5 with $1\\mathrm{N}$ HCl solution at approximately $40^{\\circ}\\mathrm{C}$ , under constant mechanical stirring at $600\\mathrm{rpm}$ . The reaction mixtures were cooled in ice bath and stored at $4 - 6^{\\circ}\\mathrm{C}$ overnight to promote decantation. The coacervates were separated and freeze-dried (CHRIST Alpha 1-4 LD plus, Osterode am Harz, Germany) at $-42^{\\circ}\\mathrm{C}$ under a pressure of $10\\mathrm{Pa}$ for $48\\mathrm{h}$ . The resulting powders (coded P40 and P45) were collected and packed in metalized bags and kept in the refrigerator at $4^{\\circ}\\mathrm{C}$ until further analysis. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,112,517,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.8. Microencapsulation Efficiency ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,131,941,206]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The microencapsulation efficiency was calculated based on Equation (2), involving the measurement of total and free lycopene content. The total and free lycopene content were determined as described by Gheonea (Dima) et al. [18], with slight modifications. The method involved the quantification of total lycopene content $(Lyc_{total})$ in the powders and lycopene content on the surface of the microparticles $(Lyc_{surface})$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,206,941,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$Lyc_{total}$ were determined by weighing $100\\mathrm{mg}$ of the powders, which were dissolved in $6\\mathrm{mL}$ of $10\\%$ NaCl:methanol (ratio of 1:1, $v / v$ ). The solutions were sonicated for $30\\mathrm{min}$ to break the microcapsules, followed by addition of a volume of $30\\mathrm{mL}$ $n$ -hexane:acetone mixture (ratio of 1:1, $v / v$ ) and centrifugation at $6000\\times g$ for $10\\mathrm{min}$ . $Lyc_{surface}$ involved the use of $50\\mathrm{mg}$ of powders dissolved in $10\\mathrm{mL}$ of 1:1 $(v / v)$ $n$ -hexane:acetone mixture (ratio of 1:1, $v / v$ ). The solutions were agitated for maximum $2\\mathrm{min}$ using a vortex and centrifugated at $1500\\times g$ for $3\\mathrm{min}$ . In both cases, the optical density of the upper organic fraction was measured at $503\\mathrm{nm}$ . The lycopene content was calculated based on Equation (1). Microencapsulation efficiency was calculated using Equation (2): ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[369,351,939,384]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\text {Microencapsulation efficiency} (\\%) = \\frac {\\text {Lyc}_{\\text {total}} - \\text {Lyc}_{\\text {surface}}}{\\text {Lyc}_{\\text {total}}} \\times 100 \\tag{2}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[275,395,680,411]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.9. Structural and Morphological Analysis of the Powders ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,414,941,564]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The structure and the morphology of the obtained powders were determined using a confocal analysis performed on a Zeiss Axio Z1 Observer confocal inverted microscope (Carl Zeiss Microscopy GmbH, Köln, Germany). The LSM 710 microscope uses several laser scanning systems: Diode laser $(405\\mathrm{nm})$ , Ar laser $(458,488,$ and $514\\mathrm{nm})$ , DPSS $(561\\mathrm{nm}$ pumped solid-state diodes), and HeNe laser $(633\\mathrm{nm})$ . The distribution of bioactives into the complex biopolymer matrix was observed using the $20\\times$ apochromatic objective and the 0.6 magnification. The obtained powders were observed both in their native state and fluorescently labeled with Red Congo $(40~\\mu \\mathrm{M})$ , in a ratio of 3:1. The confocal images of the powders were captured and analyzed with the ZEN 2012 SP1 software (Black Edition, Carl Zeiss Microscopy GmbH, Jena, Germany). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,574,890,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.10. In Vitro Cytotoxicity of the Powders in HT-29 and L929 Cells by Neutral Red Assay ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,593,944,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell culture tests were performed according to SR EN ISO 10993-5 for medical device cytotoxicity using the direct contact method of cultivation and neutral red (NR) assay for quantitative assessment of cell viability, as previously described [19]. Briefly, HT-29 human colon cancer cells were cultured in DMEM supplemented with $20\\%$ $(v / v)$ FCS, $2\\mathrm{mM}$ L-glutamine and $1\\%$ $(v / v)$ PSN mixture in humidified atmosphere with $5\\%$ $\\mathrm{CO}_{2}$ , at $37^{\\circ}\\mathrm{C}$ , until subconfluence. Mouse fibroblasts from NCTC clone L929 cell line were cultured in MEM supplemented with $10\\%$ $(v / v)$ FCS, $2\\mathrm{mM}$ L-glutamine and $1\\%$ $(v / v)$ PSN mixture in humidified atmosphere with $5\\%$ $\\mathrm{CO}_{2}$ , at $37^{\\circ}\\mathrm{C}$ , until subconfluence. For the experiment, HT-29 cells and L929 cells were cultured in 24-well microplates, at a density of $4\\times 10^{4}$ cells/mL, in specific culture media, and the plates were incubated in a humidified atmosphere with $5\\%$ $\\mathrm{CO}_{2}$ , at $37^{\\circ}\\mathrm{C}$ for $24\\mathrm{h}$ , in order to allow cell adhesion to the plastic substrate. Then, the culture medium was replaced by a serially diluted stock solution of the microencapsulated powders, to give final concentrations between $1 - 1000~\\mu \\mathrm{g} / \\mathrm{mL}$ , and the incubation continued in standard conditions, for 24 and $48\\mathrm{h}$ , respectively. At the end of each incubation period, the conditioned medium was replaced with $50~\\mu \\mathrm{g} / \\mathrm{mL}$ NR solution, and the plate was incubated at $37^{\\circ}\\mathrm{C}$ , for $3\\mathrm{h}$ . After cell washing, the incorporated dye was released in $1\\%$ $(v / v)$ acetic acid solution in $50\\%$ $(v / v)$ ethanol by gentle shaking, for $15\\mathrm{min}$ . The amount of up taken dye was directly proportional to the number of viable cells. The optical density (OD) was recorded at $540\\mathrm{nm}$ in a Spectrostar nano microplate ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,60,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[273,112,939,143]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"reader (BMG Labtech, Germany). The results of cell viability were expressed as a percentage from untreated cells (control) using the following equation: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[436,155,939,171]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\text {Cell viability} (\\%) = \\mathrm {OD} _ {\\text {sample}} / \\mathrm {OD} _ {\\text {control}} \\times 100 \\tag{3}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[275,184,440,200]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.11. Light Microscopy ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,202,941,278]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell morphology of the control and powders-treated cultures was observed by light microscopy for the qualitative evaluation of the powders cytocompatibility. After $48\\mathrm{h}$ of cultivation in the presence of the microencapsulated powders, the cells were washed, fixed in methanol, and Giemsa stained. Micrographs were acquired at an Axio Observer D1 microscope equipped with a digital camera (Carl Zeiss, Germany). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,288,425,304]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.12. Stability Study ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,307,941,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For storage stability study, the powders were kept in light-resistant glass bottles at $25 \\pm 1^{\\circ}\\mathrm{C}$ for 21 days and observed for any change and percent residual content of lycopene. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,363,507,379]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.13. Statistical Analysis of Data ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,382,941,443]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All the experiments were performed in triplicates, with duplicate samples. The results were expressed in terms of average values. Statistical analysis of the data was performed by univariate analysis of variance (ANOVA) with a significance level of $95\\%$ $(p < 0.05)$ using the Tukey's test. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,454,356,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,469,863,483]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. The Phytochemical Content and Antioxidant Activity of the Tomato Peels Extract ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,488,941,563]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the first extraction batch, freshly grinded peels with value $(\\%)$ of the dry matter of $20.54 \\pm 0.41\\%$ were extracted using $\\mathrm{SC - CO_2}$ at the following parameters: Pressure $40\\mathrm{MPa}$ , different temperature of $70^{\\circ}\\mathrm{C}$ , $74^{\\circ}\\mathrm{C}$ , and $80^{\\circ}\\mathrm{C}$ , and the $\\mathrm{CO_2}$ masic flow of $0.32\\mathrm{kg / min}$ . The phytochemicals content of the extracts obtained in different separators is given in Table 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,612,942,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0127/bbf747bb780d9941ee8a75e62f17ce518a9a3a563d01bb1863f9ca4f40e515a8.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td rowspan=\"3\">Matrix</td><td colspan=\"6\">Phytochemicals</td></tr><tr><td colspan=\"2\">Lycopene (mg/g DW)</td><td colspan=\"2\">β-Carotene (mg/g DW)</td><td colspan=\"2\">Antioxidant Activity (mM TEAC/g DW)</td></tr><tr><td>S40</td><td>S45</td><td>S40</td><td>S45</td><td>S40</td><td>S45</td></tr><tr><td>SCE extract (70 °C)</td><td>6.06 ± 0.06b</td><td>9.48 ± 0.41c</td><td>10.88 ± 0.33b</td><td>18.93 ± 0.73c</td><td>48.52 ± 3.63b</td><td>24.35 ± 0.71c</td></tr><tr><td>SCE extract (74 °C)</td><td>5.28 ± 0.07b</td><td>39.11 ± 0.59a</td><td>12.57 ± 0.11a</td><td>68.24 ± 0.71a</td><td>77.61 ± 0.99a</td><td>62.74 ± 1.74a</td></tr><tr><td>SCE extract (80 °C)</td><td>8.11 ± 0.65a</td><td>30.59 ± 0.63b</td><td>11.85 ± 0.59ab</td><td>47.08 ± 1.05b</td><td>39.99 ± 1.02c</td><td>38.34 ± 2.13b</td></tr><tr><td>Microencapsulated powder (P40)</td><td colspan=\"2\">10.83 ± 0.09A</td><td colspan=\"2\">22.49 ± 1.00A</td><td colspan=\"2\">8.57 ± 0.74A</td></tr><tr><td>Microencapsulated powder (P45)</td><td colspan=\"2\">10.49 ± 0.23A</td><td colspan=\"2\">19.93 ± 0.42B</td><td colspan=\"2\">9.37 ± 0.48A</td></tr></table>","table_caption":"[\"Table 1. The phytochemicals content of the extracts, obtained in different separators (S40 and S45) and the corresponding microencapsulated powders. \"]","table_footnote":"[\"SCE—supercritical $\\\\mathrm{CO}_{2}$ fluids extraction. The results were expressed as mean $\\\\pm$ SD $(n = 3)$ . Means that do not share the same letter (a, b, c for the extracts and A and B for the powders) are significantly different $(p < 0.05)$ . \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[273,863,941,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The different phytochemical profiles, in terms of lycopene and $\\beta$ -carotene showed in Table 1, may be explained by temperature effect on the extraction rate of carotenoids. Therefore, for the extract separated at $20\\mathrm{MPa}$ in the first separator S40, it can be observed that the increase of the extraction temperature, from the $70^{\\circ}\\mathrm{C}$ to $80^{\\circ}\\mathrm{C}$ led to the increase ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,60,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[895,60,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,112,941,246]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of the lycopene content from $6.06 \\pm 0.06 \\, \\mathrm{mg/g}$ DW to $8.11 \\pm 0.65 \\, \\mathrm{mg/g}$ DW, respectively. This can be explained by the effect of the temperature on the improvement of the mass transfer and the solvent diffusion through the ground vegetable matrix. Likewise, the $\\beta$ -carotene concentrations were positively correlated with the increase of extraction temperature from $70^{\\circ}\\mathrm{C}$ to $74^{\\circ}\\mathrm{C}$ in both fractions. At the extraction temperatures of $70^{\\circ}\\mathrm{C}$ , the gravimetric yield was in the range of $3.39\\%$ for first separation S40 and $6.18\\%$ at the second separator S45, respectively. At the higher extraction temperature up to $80^{\\circ}\\mathrm{C}$ , the gravimetric yield was at $3.81\\%$ in the first separator S40 and $5.99\\%$ in the second one, S45, respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,247,941,485]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our results could be explained according to the separation conditions after the extraction process. Therefore, at the same extraction pressure of $40\\mathrm{MPa}$ , the fractionating of the oleoresins was performed using two consecutive separators with controlled temperature and pressure conditions. Our results indicate that at $5\\mathrm{MPa}$ in the second separator, S45, recovers the higher lycopene and $\\beta$ -carotene content. From Table 1 it can be seen that, overall, a higher content in lycopene and $\\beta$ -carotene was obtained when extracting at a temperature of $74^{\\circ}\\mathrm{C}$ , leading to an extract with a lycopene content of $39.11 \\pm 0.59\\mathrm{mg/g}$ DW and $\\beta$ -carotene of $68.24 \\pm 0.71\\mathrm{mg/g}$ DW in S45 separator. Machmudah et al. [20] reported a lycopene concentration of $459.20\\mathrm{mg/kg}$ at $40\\mathrm{MPa}$ at $90^{\\circ}\\mathrm{C}$ and a $\\mathrm{CO}_{2}$ flow rate of $4\\mathrm{mL/min}$ for $180\\mathrm{min}$ . The antioxidant activity was higher for the extract separated at $20\\mathrm{MPa}$ with $77.61 \\pm 0.99\\mathrm{mM}$ TEAC/g DW in S40 separator. Due to the highest concentration values of bioactive, it has been found that the extraction conditions of temperature $74^{\\circ}\\mathrm{C}$ , pressure $40\\mathrm{MPa}$ , $155\\mathrm{min}$ and $\\mathrm{SC - CO_2}$ flow rate $0.32\\mathrm{kg/min}$ allowed to obtain a gravimetric extraction yield of $2.12\\%$ in the first separator (pressure $20\\mathrm{MPa}$ and temperature $74^{\\circ}\\mathrm{C}$ ) and $8.06\\%$ for the second separator (pressure $5\\mathrm{MPa}$ and the temperature $25^{\\circ}\\mathrm{C}$ ), respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,485,939,529]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 1 shows the chromatographic profile of the two selected extracts, obtained at the best $\\mathrm{SC - CO_2}$ extraction condition of pressure $40\\mathrm{MPa}$ , temperature $74^{\\circ}\\mathrm{C}$ , and extraction time of $155\\mathrm{min}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[282,544,852,788]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. The chromatographic profile of the tomato peels supercritical $\\\\mathrm{CO}_{2}$ extracts at $450\\\\mathrm{nm}$ (S40—the extract fraction separated at $20\\\\mathrm{MPa}$ in the first separator, S45—the extract fraction separated at $5\\\\mathrm{MPa}$ in the second separator), the major identified compounds being lycopene (peak 1) and $\\\\beta$ -carotene (peak 2). \"]","image_footnote":"[]","img_path":"images/0012/17f6b61dddfde612549267464a374faf0f7ed4a602ad05ca6b10e3e9324936c3.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,871,939,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The compounds were separated and identified based on their retention time and the calibration curves and by comparison with the data reported in the literature. The major compounds identified were lycopene (peak 1) and $\\beta$ -carotene (peak 2). For the S40 extract, the content of lycopene was $92.23\\%$ (corresponding to a concentration of $0.875\\mathrm{mg/mL}$ ) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,112,939,277]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"from the total carotenoids, whereas the content of $\\beta$ -carotene was $1.51\\%$ (corresponding to a concentration of $0.015\\mathrm{mg/mL}$ ). The results obtained for the S45 extract were significantly lower compared to S40 extract, as such, the content of lycopene was $76.36\\%$ (corresponding to a concentration of $0.345\\mathrm{mg/mL}$ ), whereas the content of $\\beta$ -carotene was $4.78\\%$ (corresponding to a concentration lower than $0.010\\mathrm{mg/mL}$ ) of the total carotenoids content. Our results were similar to those reported by Rizk, El-Kady, and El-Bialy [21], who stated that lycopene was the major carotenoid compound extracted from tomatoes, with a content of $86.13\\%$ of the total carotenoids, whereas $\\beta$ -carotene displayed content of about $2.11\\%$ . Moreover, Ooe et al. [22] determined the Japanese blue tomato carotenoids content and identified two major compounds, lycopene (with a content of $1.13\\mathrm{mg/g}$ extract) and $\\beta$ -carotene $(0.10\\mathrm{mg/g})$ , respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,288,673,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Microencapsulation Efficiency of the Selected Extracts ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,307,939,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"High encapsulation efficiency is needed to reduce oxidative degradation of lycopene on the particle surface and to increase powders' stability [23]. In our study, similar values for microencapsulation efficiency of lycopene in both powders, with values of $41.06 \\pm 0.33\\%$ for P40 and $40.42 \\pm 0.59\\%$ for P45, respectively. Jia et al. [14] encapsulated lycopene in whey protein isolate-xylo-oligosaccharide conjugates prepared by Maillard reaction, reporting significantly higher encapsulation efficiency and encapsulation of $94\\%$ and $86\\%$ , respectively, at specific conditions to prepare the conjugates of protein-oligosaccharide ratio of 1:2, heating time $3\\mathrm{h}$ and $\\mathrm{pH}9.0$ . Jain et al. [24] established maximum entrapment efficiencies $(63.1 \\pm 3.6\\%)$ for lycopene at 1:2 of Gum tragacanth:casein and $0.75\\mathrm{wt}\\%$ of total biopolymers concentration, by complex coacervation. These authors suggested that on increasing the quantity of lycopene loaded oil, while keeping the total polymeric strength constant, \\% entrapment efficiency increased up to a certain level. Microcapsules obtained with $2.5\\mathrm{mL}$ of oil containing lycopene led to a bioactive entrapment of $66.6 \\pm 24.5\\%$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,513,695,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. Powders Phytochemical Profile and Antioxidant Activity ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,531,939,620]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lycopene content in the particles produced with WPI and acacia gum were of $10.83 \\pm 0.09 \\mathrm{mg/g}$ DW in P40 and of $10.49 \\pm 0.23 \\mathrm{mg/g}$ DW in P45 (Table 1). Souza et al. [13] reported a lycopene content varying from 333.7 to $494.4 \\mu \\mathrm{g/g}$ , using as encapsulating agent's maltodextrin, WPI, and the modified starch Capsul®. The antioxidant activity of the powders showed similar values of $8.57 \\pm 0.74 \\mathrm{mMol}$ TEAC/g DW in P40 and $9.37 \\pm 0.48 \\mathrm{mMol}$ TEAC/g DW in P45 (Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,633,687,646]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.4. Structural and Morphological Properties of the Powders ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,651,939,784]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The prepared microscope slides from the native powders (Figure 2A,B) indicate the microencapsulation of the phytochemical compounds from the tomato peels in the form of large, polygonal scales, with dimensions between $163.68 - 209.36\\mu \\mathrm{m}$ inside of which spherical vesicles (spherosomes) with diameters of $5.29 - 16.77\\mu \\mathrm{m}$ (in P40) or $7.94 - 23.5\\mu \\mathrm{m}$ (in P45) can be observed. As the major compound in the extract, the lycopene, with an autofluorescence in the range of $500 - 580\\mathrm{nm}$ , was captured in the microencapsulating matrix formed by WPI (in green) and acacia gum (in blue). The results were similar to those obtained in the native state by Neagu et al. [25], who microencapsulated oleoresin supercritical extracts from sea buckthorn into WPI and casein. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[282,114,559,325]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0832/9fbfab0972275675ded049cf1fe276d0b8849dd50d7b7ad6e1091c005e85b1b0.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[581,111,855,322]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0335/78ddf58058f7f2600391fe010c76900d6fd5d6ad76f54666aeb689d680fa7e20.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[282,332,559,542]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0668/06707819a8c6c22df75d9136b9a12b97ffe97f806354487cb9b3b5c531244dcd.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[581,331,852,542]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. The confocal laser scanning microscopy (CLSM) images $(20\\\\times$ apochromatic objective, zoom 1) of the unstained P40 (A) and P45 (B) native powders and the fluorophore dyed P40 (C) and P45 powders (D). \"]","image_footnote":"[]","img_path":"images/0970/063aa4e13afda50c4636601dd7140cd17b3cdbc9714a6624bc312a1abf94e1d4.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,608,939,758]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"By fluorescent labeling, various significant differences between the two powders were highlighted (Figure 2C,D). Thus, the P40 powder formed several spherosomes, with sizes ranging between $15.87\\mu \\mathrm{m}$ and $38.54\\mu \\mathrm{m}$ , showing a coalescent tendency. In the P45, the ultrastructural aspect was different, highlighting the presence of fine microparticles with sizes of $1 - 2\\mu \\mathrm{m}$ , with an emission predominantly in the yellow domain and aggregated into coacervates. The fluorophore bounded to WPI, incorporating lycopene, which caused the fluorescent emission migration to the green-yellow range ( $560 - 580\\mathrm{nm}$ ), more obvious in the P45 powder. The larger size of the microcapsules in the P40 was correlated with better stability over time, better retention of the valuable phytochemicals, and better antioxidant activity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,769,721,784]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.5. Antiproliferative Activity of the Microencapsulated Powders ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,787,939,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In vitro cytotoxicity of the microencapsulated powders was assessed in HT-29 and L929 cells, after 24 and $48\\mathrm{h}$ of cultivation by NR assay. The results showed a dose-dependent decrease of HT-29 cell viability for both tested powders (Figure 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,832,941,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"P40 significantly inhibited $(p < 0.05)$ cell proliferation of HT-29 cells in the range of concentrations $5 - 1000\\mu \\mathrm{g / mL}$ with 30 to $60\\%$ at $24\\mathrm{h}$ of cultivation. At $48\\mathrm{h}$ of cultivation, the same descending pattern was observed, but slightly higher values were recorded for each concentration value and maximum inhibition of $55\\%$ at $1000~\\mu \\mathrm{g / mL}$ . Similar, P45 induced $25 - 55\\%$ inhibition of HT-29 cell proliferation, in the range of concentrations ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,60,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,941,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[273,112,941,143]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"between $25 - 1000\\mu \\mathrm{g / mL}$ , at both 24 and $48\\mathrm{h}$ of incubation, showing both dose- and time-dependent antiproliferative activity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,159,489,357]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0895/1fb21e939321a42b4a8d84925448ec47942b9fb40c400b4165afdd45dae3dab1.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,158,927,357]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Cell viability of HT-29 cells cultivated in the presence of different concentrations of P40 and P45 microencapsulated samples, for $24\\\\mathrm{h}$ and $48\\\\mathrm{h}$ , assessed by NR assay. The results were expressed as mean $\\\\pm$ SD $(n = 3)$ . * $p < 0.05$ , compared to untreated control. \"]","image_footnote":"[]","img_path":"images/0237/1a8bb96bbac0c9d946c25515bf9e3858d5b3ba8447ddf055e14ae32860183126.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,420,946,483]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The half-maximal inhibitory concentration (IC50) values were $100~\\mu \\mathrm{g / mL}$ for P40 and $750~\\mu \\mathrm{g / mL}$ for P45, indicating a higher antiproliferative effect of P40 over P45 microencapsulated powders in HT-29 cell culture. Cell morphology observations followed NR quantitative data (Figure 4). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,499,297,604]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0337/1350f0d8c2538989323a6c44d0d96986bcbc8c4d151c2a73ff431d80d3ef419f.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,605,295,707]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0885/0a6624b3e446889b381fce470971195a5fc89b65ef18b648ffd625ec1099d3fb.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[295,605,495,707]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0070/a7690c9d7035d6e50a50c9d3bbe8b7f6410525d05b0a7bc8e6a9f824270d46aa.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[495,605,697,707]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0800/3466bd78ee1c6ba77a670ef9a028c3906ad47df4a25e036120ebddd28c4f128d.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[697,605,892,707]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0921/5f4fedd8089b33f5e18df2acf1d7872b778414dbb02aeb584a666034e4b9b6e8.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,708,295,812]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0337/4d1b2c27f78b2db1682ba73e627c1e467ce3cbf0e0aad126e85ad49546d1dc70.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[295,708,497,812]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0871/3838ef52c3760adab31cd0690418f5c4ccd7451a1ac3150622c95d9721f8aff3.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[497,708,697,812]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0829/81d735028901bc9eb6410757d8c5e83f10b6a7dad04cfc8e6f792ec75c4cd925.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[697,708,892,812]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Representative light micrographs of HT-29 cells cultivated in the presence of different concentrations of P40 (second line) and P45 (third line) microencapsulated materials, for $48\\\\mathrm{h}$ . The untreated culture served as control (first line). (Giemsa staining). Bar scale = 100 $\\\\mu$ m. \"]","image_footnote":"[]","img_path":"images/0140/838c348a6d13cb265ded3e7f154f07b9bfb7323e4c9796c1531f74d9caa43587.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,877,946,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The micrographs showed that increasing concentrations of P40 and P45 powders decreased the cell density in HT-29 treated cultures, compared to the control culture, in a dose-dependent manner. It was observed that treated cells maintained their normal ag ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,60,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,60,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,112,939,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"gregative phenotype, but their viability and proliferation were severely affected. The same concentrations of P40 and P45 microencapsulated powders were tested for possible toxic compounds release in normal L929 cells by NR assay. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,158,939,187]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The results showed no cytotoxicity of both samples, in the range of concentrations $1 - 1000\\mu \\mathrm{g / mL}$ (Figure 5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,204,505,388]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0799/dcd76a9ded9a331f00f471b7094bd10b99ebd9f640e3dac9c8d7b12e9a061cad.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[505,203,944,388]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. Cell viability of L929 cells cultivated in the presence of different concentrations of S40 and S45 microencapsulated materials, for $24\\\\mathrm{h}$ and $48\\\\mathrm{h}$ , determined by NR assay. The results were expressed as mean $\\\\pm$ SD $(n = 3)$ . * $p < 0.05$ , compared to untreated control. \"]","image_footnote":"[]","img_path":"images/0464/9bcb702014373e30edb4ac022da21373d4f558ec4ad8985baa803d882eec45dc.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,453,939,557]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thus, the values of cell viability varied between $77.9 - 116.4\\%$ for P40 and $83.6 - 112.4\\%$ for P45, at $48\\mathrm{h}$ of cultivation. Significantly lower values $(p < 0.05)$ of cell viability were recorded only for 750 and $1000~\\mu \\mathrm{g / mL}$ concentrations, compared to untreated control cells (100% cell viability), but they were within the non-cytotoxic domain (80-100% cell viability), except for $1000~\\mu \\mathrm{g / mL}$ P40 at $48\\mathrm{h}$ of cultivation (77.9%). In addition, concentrations in the range of $1 - 500~\\mu \\mathrm{g / mL}$ P40 and $1 - 10~\\mu \\mathrm{g / mL}$ P45 significantly stimulated $(p < 0.05)$ cell proliferation of normal cells, compared to the control culture, after $48\\mathrm{h}$ of cultivation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,557,939,602]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Light micrographs showed that cell morphology and density observations of L929 treated with different concentrations of microencapsulated powders were in accordance with NR quantitative data (Figure 6). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,602,939,781]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The images showed that treated fibroblasts maintained their characteristic fusiform phenotype and were homogeneously distributed on the culture plate, similar to the control culture, for all tested concentrations. At low concentrations (1–100 μg/mL), the cell density was higher than that of control culture, while at high concentrations (750–1000 μg/mL), the cell density moderately decreased in treated cultures. All these data demonstrated that the novel encapsulated powders exhibited antiproliferative activity in tumor cells, while extending the range of cytocompatibility in normal cells. They indicated that P40 and P45 microencapsulated powders had exerted an antiproliferative effect at minimal concentrations of 5 μg/mL and 25 μg/mL, respectively, in HT-29 cells, after 24 h of cultivation. At the same time, it is worth noticing that these powders presented an extended range of cytocompatibility, up to 1000 μg/mL, in L929 normal cells and even stimulated the cell growth. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,781,941,929]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Previous studies on standard lycopene have tested its effect on cell proliferation, at physiological concentrations or higher than $0.5\\mu \\mathrm{g / mL}$ , in several non-tumoral and tumoral cell lines. A wide range of low lycopene concentrations ranging between $0.00005 - 0.5\\mu \\mathrm{g / mL}$ showed minimal inhibition of cell proliferation in IMR-90 normal lung fibroblasts culture, and cell viability decreased by only $10\\%$ , after $48\\mathrm{h}$ of cultivation [26]. In vitro cultivation of $0.5 - 3\\mu \\mathrm{g / mL}$ lycopene in several human cancer cell lines showed an inhibitory effect of HT-29 cells with $20\\%$ and T84 cells with $30\\%$ , after $48\\mathrm{h}$ of cultivation, due to its internalization and induction of changes in the cell cycle, but no effect on other cell types (A549, DU145, HepG2, Hela, Hep-2) [27]. A lycopene-rich extract of red guava, encapsulated in $200\\mathrm{nm}$ lipid nanoparticles or not, showed good cytocompatibility in NIH-3 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[273,112,941,174]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"T3 normal mice fibroblasts and decreased the viability of MCF-7 human adenocarcinoma cells down to $30\\%$ , at $100~\\mu \\mathrm{g / mL}$ , thus indicating antiproliferative activity, while protecting healthy cells [28]. No studies on the antiproliferative activity of lycopene encapsulated in a protein-polysaccharide complex were found. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[105,191,295,288]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0421/114da501762bdbfc3a72eb0e4da67c71deea00688a644f384298e156f208ce55.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[105,292,295,388]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0205/a7146a63c4733a67de88f5ece41d7f8a008529c0a99e1d3238eeae40a117af1b.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[105,392,295,488]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0759/bfb837650ae56685863b53fb7399f31537526b83e42a4942873ee9b7bc73a068.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[297,292,489,388]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0206/4eb0c01e81903a478f8a8f3feb6131512d44a28221a830a692a1b289c96fba91.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[297,392,489,488]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0933/524f969cb6a974b8a6982079e67b9f692b70c1ada9b0587227edda811af85d30.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[492,292,695,388]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0515/329f3f0340645e27391ae2f6414467c85f23fcb24d56579fda5febabc5c8ad23.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[492,392,695,488]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0795/3d6b27b3cd426cf8f10bf346da3094f63e089f3b412f68be1153727ecc2263eb.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[697,292,892,388]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0726/5834efe76e099c56d863c6574e52594eb59bdf87d598f95044bf236235e6043b.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[697,392,892,488]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 6. Representative light micrographs of L929 cells cultivated in the presence of different concentrations of P40 (second line) and P45 (third line) microencapsulated materials, for $48\\\\mathrm{h}$ . The untreated culture served as control (first line). (Giemsa staining). Bar scale = 100 $\\\\mu$ m. \"]","image_footnote":"[]","img_path":"images/0410/7e65fa0755b4a63587529e15b6b5f0402e451eb16eefa4af49071b09b8ba85d7.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,555,944,690]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Recent studies have shown that lycopene administration together with doxorubicin was able to attenuate the drug's cardiotoxicity and to improve its antitumor activity [29]. Lycopene is a carotenoid known as a potent antioxidant agent, while doxorubicin is a chemotherapy drug belonging to anthracyclines class. It was supposed that the role of lycopene was mainly as a preventive factor against the formation of cancer cells, and its mechanism of action was different from that of doxorubicin in tumor cells. Several in vitro studies showed that lycopene inhibited intercellular gap junction, the progression of cell cycle and cell invasion, and important signaling pathways within tumor cell cultures, acting also as an antiproliferative agent [30]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,700,601,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.6. Retention Rate of Lycopene at Storage Test ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,719,944,929]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The retention rate of the core material is an important indicator to measure the storage stability of microencapsulated lycopene. In this study, the retention rate of the lycopene was studied in dark and $25^{\\circ}\\mathrm{C}$ , for three weeks. The retention rate of lycopene in the microcapsules was approximately $48\\%$ and $29\\%$ in P40 and P45, respectively, after storage for 21 days at $25^{\\circ}\\mathrm{C}$ . Jia et al. [14] reported similar values for the retention rate of lycopene in the conjugate microcapsules of $46\\%$ and $40\\%$ after storage for 36 days at $25^{\\circ}\\mathrm{C}$ and $40^{\\circ}\\mathrm{C}$ , respectively. The degradation of lycopene in powders during storage was fitted to a first-order kinetic model. The degradation rate of lycopene in P45 is significantly higher when compared with P40, the $k$ values for the first-order kinetic model being of $85.44 \\pm 1.23 \\times 10^{-3} \\, \\text{days}^{-1}$ for lycopene degradation in P40 and significantly higher, of $144.16 \\pm 2.56 \\times 10^{-13} \\, \\text{days}^{-1}$ in P45. The different pattern of lycopene degradation in P45 is due to the higher content of the surface, non-encapsulated lycopene, when compared with P40, which enhanced the degradation of lycopene by oxidation and isomerization. The half time of total lycopene content was $8.11 \\pm 0.94$ days in P40 and $4.80 \\pm 0.34$ days ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,60,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,60,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,112,939,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in P45. Surface carotenoids were reduced to one-half in P40 in 13 days, whereas in P45, more than $78\\%$ indicated the sensitivity of lycopene toward oxidation, isomerization, and degradation despite moderate storage temperature and the exclusion of light. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,170,393,183]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,187,941,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this study, two complementary approaches were employed for recovery and uses of bioactives from tomato peels to develop added-value ingredients with multiple uses. Therefore, supercritical fluid extraction parameters were optimized to obtain extracts with superior characteristics, followed by microencapsulation and testing of resulting powders. The $\\mathrm{SC - CO_2}$ extraction of tomato peels by-product at a temperature of $74^{\\circ}\\mathrm{C}$ , pressure of $40\\mathrm{MPa}$ , and extraction time of $155\\mathrm{min}$ yielded high amounts of lycopene-enriched oleoresin. The two extracts corresponding to the equipment separators were microencapsulated in whey protein isolates and acacia gum by complex coacervation and freeze-drying, resulting in two powders with similar microencapsulation efficiency, phytochemicals content, and antioxidant activity. However, although using the same microencapsulation technique, the powders showed different morphological, stability, and biological properties. The ultrastructural aspect highlighted the presence of different sizes of spherosomes, with a coalescent tendency in the powder containing extract separated at $20\\mathrm{MPa}$ , whereas finer microparticles up to $2\\mu \\mathrm{m}$ , aggregated into coacervates were observed in the powder containing the extract obtained in the second separator at $5\\mathrm{MPa}$ . A significant effect of cell proliferation in a normal cell at concentrations up to $500~\\mu \\mathrm{g / mL}$ for the powder with the extract separated at $20\\mathrm{MPa}$ , and up to $10~\\mu \\mathrm{g / mL}$ for the powder with the extract separated at $5\\mathrm{MPa}$ was observed, whereas an antiproliferative effect at minimal concentrations of $5\\mu \\mathrm{g / mL}$ and $25~\\mu \\mathrm{g / mL}$ , respectively, in HT-29 cells was highlighted. Both powders presented an extended range of cytocompatibility, up to $1000~\\mu \\mathrm{g / mL}$ , in L929 normal cells. The degradation of lycopene in powders during storage was fitted to a first-order kinetic model, highlighting a higher degradation rate of lycopene in the powder with the extract separated at $5\\mathrm{MPa}$ , namely, due to the higher content of the surface, non-encapsulated lycopene, thus enhancing its degradation by oxidation and isomerization. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,546,941,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our results are promising in opening new opportunities to identify sustainable solutions for the development of value-added ingredients with multiple uses, such as food, pharmaceuticals, cosmeceuticals, and nutraceuticals. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,611,941,681]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author Contributions: Conceptualization, N.S.; methodology, L.M., V.B. and O.C.; validation, N.S., G.R. and A.O.; formal analysis, I.G. and A.-M.P.; investigation, L.M., E.E., V.B. and A.-M.P.; resources, G.E.B. and G.R.; writing—original draft preparation, N.S., L.M. and E.E.; writing—review and editing, N.S.; supervision, N.S.; project administration, N.S.; funding acquisition, G.E.B. All authors have read and agreed to the published version of the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,688,939,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding: The authors are grateful for the technical support offered by the Grant POSCCE ID 1815, Code SMIS 48745 (www.moras.ugal.ro). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,722,648,737]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Institutional Review Board Statement: Not applicable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,745,589,758]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Informed Consent Statement: Not applicable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,765,939,807]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data Availability Statement: HT-29 human colorectal adenocarcinoma cell line was purchased from American Type Culture Collection (ATCC), and NCTC clone L929 mouse fibroblast cell line came from European Collection of Authenticated Cell Culture (ECACC) (Sigma-Aldrich, Steineim, Germany). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,814,939,841]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments: The Integrated Center for Research, Expertise and Technological Transfer in Food Industry is acknowledged for providing technical support. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,848,702,860]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflicts of Interest: The authors declare no conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 of 15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,112,144,124]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[55,129,942,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. 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[CrossRef] \"]","page_idx":"14","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[55,61,208,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Antioxidants 2021, 10, 222 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,60,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 of 15 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[57,118,107,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,133,927,203]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supercritical $\\\\mathrm{CO}_{2}$ Extraction and Microencapsulation of Lycopene-Enriched Oleoresins from Tomato Peels: Evidence on Antiproliferative and Cytocompatibility Activities \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,219,882,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Liliana Mihalcea $^{1}$ , Oana Crăciunescu $^{2}$ , Ionica Gheonea (Dima) $^{1}$ , Ana-Maria Prelipcean $^{2}$ , Elena Enachi $^{1}$ , Vasilica Barbu $^{1}$ , Gabriela Elena Bahrim $^{1}$ , Gabriela Râpeanu $^{1}$ , Anca Oancea $^{2}$ and Nicoleta Stanciuč $^{1,*}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,272,910,363]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"$^{1}$ Faculty of Food Science and Engineering, Dunărea de Jos University of Galati, 800201 Galati, Romania; 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Supercritical $\\\\mathrm{CO}_{2}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,504,255,516]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Extraction and Microencapsulation of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,519,247,529]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lycopene-Enriched Oleoresins from \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n 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\"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cytocompatibility Activities. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,575,245,587]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222. https:// \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,590,228,600]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi.org/10.3390/antiox10020222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,618,149,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Academic Editor: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,632,181,644]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Soraya Rodriguez-Rojo \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,646,201,657]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 9 December 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,659,196,671]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted: 26 January 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,675,200,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published: 2 February 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,703,258,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,778,154,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0253/c13a26d0dd7f61af69bd530c3ba2c74ef386bfd73559eba57a8233d8d3012a84.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,810,258,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,380,941,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: Tomato peels are used as a valuable material to extract lycopene-rich oleoresins by supercritical $\\\\mathrm{CO}_{2}$ extraction. The extraction involves continuous circling of $\\\\mathrm{CO}_{2}$ to the extractor after removing the solute in the separators, S40 and S45, where the solvent power of the $\\\\mathrm{CO}_{2}$ is reduced by reducing pressure down to $20\\\\mathrm{MPa}$ in S40 and $5\\\\mathrm{MPa}$ in S45, respectively, leading to two extracts. Lycopene is found to be the major compound, representing $93\\\\%$ and $76\\\\%$ of the total carotenoids in S40 and S45 extracts, respectively. The two extracts are microencapsulated in whey protein concentrate and acacia gum by complex coacervation and freeze-drying, leading to corresponding P40 and P45 powders, with antioxidant activity of $8.57\\\\pm 0.74$ and $9.37\\\\pm 0.48\\\\mathrm{mMol}$ TEAC/g DW in P40 and P45, respectively. Different structural and morphological patterns are observed, with finer microparticles of $1 - 2\\\\mu \\\\mathrm{m}$ in P45. Both powders show dose and time-dependent antiproliferative activity. The half-maximal inhibitory concentration values are $100~\\\\mu \\\\mathrm{g / mL}$ for P40 and $750~\\\\mu \\\\mathrm{g / mL}$ for P45 sample, indicating a higher antiproliferative effect of P40 over P45 in HT-29 cell culture. The powders have an extended range of cytocompatibility, up to $1000~\\\\mu \\\\mathrm{g / mL}$ , in L929 normal cells, stimulating the cell growth. Lycopene retention is tested, and values of $48\\\\%$ and $29\\\\%$ in P40 and P45 are found after 21 days at $25^{\\\\circ}C$ , with the degradation rate in P45 significantly higher, due to the higher content of the surface lycopene, which favored its degradation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,640,941,671]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: lycopene; supercritical $\\\\mathrm{CO}_{2}$ extraction; microencapsulation; antiproliferative activity; cytocompatibility \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,715,394,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,733,941,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is well known that tomato processing is one of the most developed within the vegetable processing industry at an international level, being responsible for important amounts of waste, thus causing a major disposal problem, both in terms of costs and impact on the environment [1]. Colle et al. [2] suggested that millions of tons of tomatoes are processed into products (saues, juices, soups, and dried tomatoes) or used as ingredients of ready-to-eat meals, resulting in large amounts of by-products, such as peel, pulp, and seeds, representing $10 - 40\\\\%$ of the total processed tomatoes. A significant part of these by-products is currently being disposed of in the environment or used as animal feed. However, the abundance of lycopene in the peels fraction suggests the possibility of utilizing it as a cheap source for lycopene extraction [3]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,883,941,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The main carotenoid in tomatoes is lycopene, representing approximately $80 - 90\\\\%$ of the total carotenoids. Due to its open-chain structure with 13 double bonds, with 11 of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,53,115,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[122,64,292,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"antioxidants \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,60,937,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MDPI \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[55,964,458,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222. https://doi.org/10.3390/antiox10020222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[653,964,936,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://www.mdpi.com/journal/antioxidants \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[278,110,939,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"them conjugated, lycopene has the highest degree of unsaturation among all carotenoids. The presence of the 13 conjugated double bonds gives the characteristic deep red color of ripe tomato fruits and tomato products and the antioxidant activity [4]. Due to its structural particularities, growing demand has been observed for the natural form of lycopene, due to the specific properties to be effective in quenching the destructive free radicals (nitrogen dioxide— $\\\\mathrm{NO}_2\\\\bullet$ , sulfide— $\\\\mathrm{RS}\\\\bullet$ and singlet oxygen— $\\\\mathrm{O}_2\\\\bullet$ ) and in inhibiting DNA and cellular membrane damage [5]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,214,939,498]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Different benefits associated with the increased dietary consumption of tomatoes and derived products containing lycopene were reported—such as cardiovascular protection, and the decrease of prostate and breast cancer, and coronary heart disease incidence [6], inhibition of the oxidation of low-density lipoproteins, thus, helping to lower the level of blood cholesterol [7], and anti-inflammatory response, by inhibiting the activation of inducible nitric oxide synthase proteins [8]. From a marketing point of view, Scaglia et al. [9] suggested that lycopene is one of ten carotenoids that are currently marketed, with an estimated economic value in 2017 of 1.5 USD billion and an annual growth rate of $2.3\\\\%$ . Therefore, the extraction of the lycopene from tomato waste may bring significant benefits by further introducing the extracts in different foods, cosmeceuticals, and nutraceuticals. However, extractions of the bioactives from food matrices are limited by the requirement of non-toxic solvents that do not remain as residue in the product. Since the lycopene is stored in the tomato peels, it degrades easily during processing [10], supercritical carbon dioxide $(\\\\mathrm{SC - CO_2})$ extraction has been used as an emerging method to extract tomato oleoresin [11]. $\\\\mathrm{SC - CO_2}$ extraction is a greener alternative to organic solvent extraction, which operates above the solvent's critical pressure and temperature, enhancing the solvating power of the solvent. $\\\\mathrm{SC - CO_2}$ is a solvent frequently used, due to its main advantages as, low critical pressure and temperature, non-toxic, non-inflammable, high purity, low cost, and its availability. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,499,939,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Precisely due to the high content of unsaturated bonds, responsible for the specific biological properties, isolated lycopene is prone to degradation, being sensitive to oxidants, light, and heat during storage and processing [12], especially in the presence of oxygen [13]. In addition, the application of lycopene in the food industry as an added-value ingredient is drastically limited, due to its characteristics of low solubility in an aqueous environment and low bioaccessibility [14]. Therefore, design strategies are needed to produce lycopene in a stable form, with improved solubility and bioaccessibility. Recently, in order to improve the solubility and bioaccessibility of lycopene, several delivery systems have been developed, such as protein-based nanoparticles [15], emulsions [16], liposomes [17], and microcapsules [18]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,648,939,810]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Therefore, this study extends the possibility of using tomato peels as a valuable source of lycopene, by $\\\\mathrm{SC - CO_2}$ extraction and microencapsulation. In the first step, the valorization of fresh tomato peels by supercritical carbon dioxide extraction without modifiers at different extraction parameters, whereas the extracts were characterized in terms of total carotenoids, lycopene content, and antioxidant activity. Further, the extracts with the higher bioactives content were used to produce microcapsules, using whey protein isolates and acacia gum as microencapsulating agents, by complex coacervation and freeze-drying. The resulting powders were tested for microencapsulation efficiency, phytochemicals content and antioxidant activity, structural and morphological appearance, and antiproliferative and cytotoxic properties. In addition, the short-term storage stability of lycopene microcapsules was studied. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,824,475,835]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Materials and Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,840,379,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1. Chemicals \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,858,941,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Whey protein isolates (protein content of $95\\\\%$ ) was purchased from Fonterra (Auckland, New Zealand). The HPLC analytical-grade hexane, acetone, acetonitrile, ethyl acetate, methanol, and analytical grade [2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt] (ABTS), 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[273,112,939,231]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"acacia gum, lycopene, and $\\\\beta$ -carotene standards were obtained from Sigma-Aldrich (Steinheim, Germany). Carbon dioxide with a purity of $99.9\\\\%$ vol. was supplied by Messer Romania Gaz SRL (Bucharest, Romania). Dulbecco's Modified Eagle Medium (DMEM), Minimum Essential Medium (MEM), fetal calf serum (FCS), L-glutamine, a mixture of antibiotics (penicillin, streptomycin, neomycin) (PSN), and neutral red (NR) were purchased from Merck (Germany). HT-29 human colorectal adenocarcinoma cell line was purchased from ATCC, and NCTC clone L929 mouse fibroblast cell line came from ECACC (Sigma-Aldrich, Steinheim, Germany). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,243,408,256]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2. Tomato Fruits \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,262,941,367]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Red ripped tomatoes (Lycopersicon esculentum var. Buzău 1600) were purchased at commercial maturity from a local supermarket (Galati, Romania) in August 2019 and stored at $4^{\\\\circ}\\\\mathrm{C}$ until processing. The fruits were visually inspected for uniformity of color and selected based on similar characteristics. To obtain peels without any residual pulp, the tomatoes were first washed with distilled water, and the peels were removed manually, washed several times, and then blotted on paper towels to remove any residual pulp. The peels were stored at $-20^{\\\\circ}\\\\mathrm{C}$ until analyses. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,378,657,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.3. Tomato Peels Supercritical $\\\\mathrm{CO}_{2}$ Extraction Process \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,397,941,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The extractions with $\\\\mathrm{SC - CO_2}$ were performed with the pilot plant equipped with an extractor vessel with a total internal volume of $2\\\\mathrm{L}$ , and two separators S40 and S45, each with a volume of $1.5\\\\mathrm{L}$ (Natex Prozesstechnologie GesmbH, Ternitz, Austria). $\\\\mathrm{SC - CO_2}$ flow was monitored with a Coriolis mass flow meter. Several $\\\\mathrm{SC - CO_2}$ extraction batches have been tested without modifiers. The amount of $0.165\\\\mathrm{kg}$ of tomato peels, with a moisture content of $79.46\\\\pm 0.41\\\\%$ , was ground and placed in the extractor vessel, and liquid $\\\\mathrm{CO_2}$ from a cylinder tank with a siphon was passed through a chiller kept at $-3^{\\\\circ}\\\\mathrm{C}$ and compressed by a high-pressure membrane pump. The solvent was continuously cycled to the extractor after removing the solute in the separators, S40 and S45, where the solvent power of the $\\\\mathrm{CO_2}$ was reduced by reducing pressure down to $20\\\\mathrm{MPa}$ in S40 and 5 MPa in S45, respectively. The temperature was set at the same values as in the extractor for the S40 and at $25^{\\\\circ}\\\\mathrm{C}$ for the S45, respectively. The extraction parameters were automatically controlled and indicated by ABB software (ABB, Mannheim, Germany). The temperatures of the extractor and both separators were controlled by a surrounding heated jacket, whereas the pressure was controlled by the pressure control valves. Extracting conditions were set as follows: Pressure $40\\\\mathrm{MPa}$ , temperatures $70^{\\\\circ}\\\\mathrm{C}, 74^{\\\\circ}\\\\mathrm{C}$ and $80^{\\\\circ}\\\\mathrm{C}$ and time $155\\\\mathrm{min}$ according to previous studies [1]. The $\\\\mathrm{SC - CO_2}$ extracts (named S40 and S45) were collected in vials, then concentrated at $40^{\\\\circ}\\\\mathrm{C}$ using a vacuum rotary evaporator (AVC 2-18, Christ, UK), whereas all vials were protected from light and ambient oxygen with aluminum foil to minimize decomposition and oxidation. The obtained extracts were weighed to calculate the gravimetric yield and stored at $-20^{\\\\circ}\\\\mathrm{C}$ until further analyses. The gravimetric extraction yield was expressed as the ratio between the weight of extracted oleoresin and the weight of matrices loaded in the extractor vessel. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,751,813,766]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.4. Evaluation of Carotenoids and Lycopene Content in Extracts and Powders \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,770,941,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A spectrophotometric method was employed to determine the lycopene and total carotenoid contents in the extracts and powders. Therefore, about $5\\\\mathrm{mg}$ of dried extracts and $100\\\\mathrm{mg}$ of each microencapsulated powder were dissolved in $10\\\\mathrm{mL}$ of a mixture of $n$ -hexane:acetone (ratio of 3:1), in a volumetric flask. The absorbance was measured at $470\\\\mathrm{nm}$ and $503\\\\mathrm{nm}$ . The amount of lycopene and $\\\\beta$ -carotene was calculated according to the following equation [13]: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[442,870,939,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\operatorname {C a r o t e n o i d} \\\\left(\\\\frac {\\\\mathrm {g}}{\\\\mathrm {L}}\\\\right) = A \\\\times M _ {W} \\\\times D _ {f} / \\\\left(M _ {a} \\\\times L\\\\right) \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[55,60,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,112,939,173]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $A$ is absorbance of the hexane phase at 503 and $470\\\\mathrm{nm}$ ; $Mw$ is the molecular weight for lycopene, and $\\\\beta$ -carotene (536.873 and $536.87\\\\mathrm{g}\\\\cdot \\\\mathrm{mol}^{-1}$ , respectively), $D_{f}$ I sample dilution rate, $M_{a}$ I molar absorptivity in $n$ -hexane ( $3450\\\\mathrm{L mol}^{-1}\\\\mathrm{cm}^{-1}$ for lycopene and $2592\\\\mathrm{L mol}^{-1}\\\\mathrm{cm}^{-1}$ for $\\\\beta$ -carotene), and $L$ I cell diameter of the spectrophotometer ( $1\\\\mathrm{cm}$ ). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[314,174,907,187]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The amount of lycopene and $\\\\beta$ -carotene were expressed as mg/g DW of extract. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,200,910,215]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.5. High-Performance Liquid Chromatography (HPLC) Analysis of Lycopene in the Extracts \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,219,941,398]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the spectrophotometric profile, the extract with the higher content in lycopene and $\\\\beta$ -carotene was selected for HPLC analysis. A Thermo Finnigan Surveyor HPLC system coupled with a DAD UV-visible detector (Finnigan Surveyor LC, Thermo Scientific, USA) was used. The system was controlled by the Xcalibur software (Finnigan Surveyor LC, Thermo Scientific, Waltham, MA, USA), whereas the carotenoids compounds were assessed at $450~\\\\mathrm{nm}$ on a Lichrosorb RP-18 ( $5\\\\mu \\\\mathrm{m}$ ) Hibar RT 125-4 column. The mobile phase consisted of two solvents, namely, $90\\\\%$ acetonitrile (A) and $100\\\\%$ ethyl acetate (B). The injection volume was $10~\\\\mu \\\\mathrm{L}$ , while the flow rate was $1000~\\\\mathrm{mL / min}$ . The elution gradient was: $0 - 16\\\\mathrm{min}$ , $15\\\\%$ B; $16 - 54\\\\mathrm{min}$ , $15 - 62\\\\%$ B, $54 - 56\\\\mathrm{min}$ , $62\\\\%$ B; $56 - 60\\\\mathrm{min}$ , $62 - 15\\\\%$ B; $60 - 70\\\\mathrm{min}$ , $15\\\\%$ B. The quantification of lycopene (LOD $0.05\\\\mathrm{mgkg}^{-1}$ and LOQ $0.10\\\\mathrm{mgkg}^{-1}$ ) and $\\\\beta$ -carotene (LOD $0.05\\\\mathrm{mgkg}^{-1}$ and LOQ $0.10\\\\mathrm{mgkg}^{-1}$ ) was performed using the calibration curves for each compound. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,410,657,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.6. Determination of Free Radical Scavenging Activity \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,429,941,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The antioxidant activity of the extracts and powders was measured by using the TEAC (Trolox Equivalent Antioxidant Capacity) assay by evaluating the 2,2-azinobis-3-ethylbenzothialzoline-6-sulfonic acid $(\\\\mathrm{ABTS}^{+})$ radical cation decoloring reaction, as described by Scaglia et al. [9], with slight modifications. Briefly, the working $\\\\mathrm{ABTS}^{+}$ solution was obtained by mixing the $\\\\mathrm{ABTS}^{+}$ aqueous solution $(7\\\\mathrm{mM})$ with potassium persulfate (2.45 mM final concentration), followed by keeping the mixture to react in the dark at room temperature for $16\\\\mathrm{h}$ . An amount of $5\\\\mathrm{mg}$ of extracts and $100\\\\mathrm{mg}$ of powders, respectively, were previously dissolved in $10\\\\mathrm{mL}$ of a mixture of $n$ -hexane:acetone (ratio of 3:1), in a volumetric flask. A volume of $2.85\\\\mathrm{mL}$ of the $\\\\mathrm{ABTS}^{+}$ solution was mixed with $0.15\\\\mathrm{mL}$ of the extract or powders solution and allowed to react for $2\\\\mathrm{h}$ in a dark room, followed by an absorbance reading at $734\\\\mathrm{nm}$ . The $\\\\mathrm{ABTS}^{+}$ antioxidant activity of the samples was expressed as mM TEAC/g DW of extract based on the calibration curve using Trolox. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,619,855,634]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.7. Microencapsulation of the Extracts by Complex Coacervation and Freeze-Drying \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,638,941,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Two extracts were selected for microencapsulation, based on the highest lycopene content, namely, the two fractions corresponding to the two separators (S40 and S45), obtained in the following conditions: $40\\\\mathrm{MPa}$ , temperature $74^{\\\\circ}\\\\mathrm{C}$ , and an extraction time of $155\\\\mathrm{min}$ . The microencapsulation of the extracts was performed as described by Gheonea (Dima) et al. [18], with modifications. As microencapsulating materials, whey proteins isolate (WPI) and acacia gum were selected and dissolved in distilled water at a ratio of 5:1 $(w / w)$ . The solution was mixed on a magnetic stirrer until complete hydration at 450 rpm and $40^{\\\\circ}\\\\mathrm{C}$ . To obtain a coarse emulsion, an amount of $0.5\\\\mathrm{g}$ of each extract (S40 and S45) was first dissolved in $5\\\\mathrm{mL}$ of sunflower oil and dripped into the aqueous solution by stirring. The emulsion was then obtained by homogenization using an Ultra Turrax mixer (IKA T18 basic, Staufen, Germany) at $5000\\\\times g$ for $10\\\\mathrm{min}$ . To promote coacervation, the pH of the solutions was adjusted to 3.5 with $1\\\\mathrm{N}$ HCl solution at approximately $40^{\\\\circ}\\\\mathrm{C}$ , under constant mechanical stirring at $600\\\\mathrm{rpm}$ . The reaction mixtures were cooled in ice bath and stored at $4 - 6^{\\\\circ}\\\\mathrm{C}$ overnight to promote decantation. The coacervates were separated and freeze-dried (CHRIST Alpha 1-4 LD plus, Osterode am Harz, Germany) at $-42^{\\\\circ}\\\\mathrm{C}$ under a pressure of $10\\\\mathrm{Pa}$ for $48\\\\mathrm{h}$ . The resulting powders (coded P40 and P45) were collected and packed in metalized bags and kept in the refrigerator at $4^{\\\\circ}\\\\mathrm{C}$ until further analysis. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,112,517,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.8. Microencapsulation Efficiency \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,131,941,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The microencapsulation efficiency was calculated based on Equation (2), involving the measurement of total and free lycopene content. The total and free lycopene content were determined as described by Gheonea (Dima) et al. [18], with slight modifications. The method involved the quantification of total lycopene content $(Lyc_{total})$ in the powders and lycopene content on the surface of the microparticles $(Lyc_{surface})$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,206,941,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$Lyc_{total}$ were determined by weighing $100\\\\mathrm{mg}$ of the powders, which were dissolved in $6\\\\mathrm{mL}$ of $10\\\\%$ NaCl:methanol (ratio of 1:1, $v / v$ ). The solutions were sonicated for $30\\\\mathrm{min}$ to break the microcapsules, followed by addition of a volume of $30\\\\mathrm{mL}$ $n$ -hexane:acetone mixture (ratio of 1:1, $v / v$ ) and centrifugation at $6000\\\\times g$ for $10\\\\mathrm{min}$ . $Lyc_{surface}$ involved the use of $50\\\\mathrm{mg}$ of powders dissolved in $10\\\\mathrm{mL}$ of 1:1 $(v / v)$ $n$ -hexane:acetone mixture (ratio of 1:1, $v / v$ ). The solutions were agitated for maximum $2\\\\mathrm{min}$ using a vortex and centrifugated at $1500\\\\times g$ for $3\\\\mathrm{min}$ . In both cases, the optical density of the upper organic fraction was measured at $503\\\\mathrm{nm}$ . The lycopene content was calculated based on Equation (1). Microencapsulation efficiency was calculated using Equation (2): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[369,351,939,384]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\text {Microencapsulation efficiency} (\\\\%) = \\\\frac {\\\\text {Lyc}_{\\\\text {total}} - \\\\text {Lyc}_{\\\\text {surface}}}{\\\\text {Lyc}_{\\\\text {total}}} \\\\times 100 \\\\tag{2}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[275,395,680,411]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.9. Structural and Morphological Analysis of the Powders \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,414,941,564]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The structure and the morphology of the obtained powders were determined using a confocal analysis performed on a Zeiss Axio Z1 Observer confocal inverted microscope (Carl Zeiss Microscopy GmbH, Köln, Germany). The LSM 710 microscope uses several laser scanning systems: Diode laser $(405\\\\mathrm{nm})$ , Ar laser $(458,488,$ and $514\\\\mathrm{nm})$ , DPSS $(561\\\\mathrm{nm}$ pumped solid-state diodes), and HeNe laser $(633\\\\mathrm{nm})$ . The distribution of bioactives into the complex biopolymer matrix was observed using the $20\\\\times$ apochromatic objective and the 0.6 magnification. The obtained powders were observed both in their native state and fluorescently labeled with Red Congo $(40~\\\\mu \\\\mathrm{M})$ , in a ratio of 3:1. The confocal images of the powders were captured and analyzed with the ZEN 2012 SP1 software (Black Edition, Carl Zeiss Microscopy GmbH, Jena, Germany). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,574,890,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.10. In Vitro Cytotoxicity of the Powders in HT-29 and L929 Cells by Neutral Red Assay \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,593,944,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell culture tests were performed according to SR EN ISO 10993-5 for medical device cytotoxicity using the direct contact method of cultivation and neutral red (NR) assay for quantitative assessment of cell viability, as previously described [19]. Briefly, HT-29 human colon cancer cells were cultured in DMEM supplemented with $20\\\\%$ $(v / v)$ FCS, $2\\\\mathrm{mM}$ L-glutamine and $1\\\\%$ $(v / v)$ PSN mixture in humidified atmosphere with $5\\\\%$ $\\\\mathrm{CO}_{2}$ , at $37^{\\\\circ}\\\\mathrm{C}$ , until subconfluence. Mouse fibroblasts from NCTC clone L929 cell line were cultured in MEM supplemented with $10\\\\%$ $(v / v)$ FCS, $2\\\\mathrm{mM}$ L-glutamine and $1\\\\%$ $(v / v)$ PSN mixture in humidified atmosphere with $5\\\\%$ $\\\\mathrm{CO}_{2}$ , at $37^{\\\\circ}\\\\mathrm{C}$ , until subconfluence. For the experiment, HT-29 cells and L929 cells were cultured in 24-well microplates, at a density of $4\\\\times 10^{4}$ cells/mL, in specific culture media, and the plates were incubated in a humidified atmosphere with $5\\\\%$ $\\\\mathrm{CO}_{2}$ , at $37^{\\\\circ}\\\\mathrm{C}$ for $24\\\\mathrm{h}$ , in order to allow cell adhesion to the plastic substrate. Then, the culture medium was replaced by a serially diluted stock solution of the microencapsulated powders, to give final concentrations between $1 - 1000~\\\\mu \\\\mathrm{g} / \\\\mathrm{mL}$ , and the incubation continued in standard conditions, for 24 and $48\\\\mathrm{h}$ , respectively. At the end of each incubation period, the conditioned medium was replaced with $50~\\\\mu \\\\mathrm{g} / \\\\mathrm{mL}$ NR solution, and the plate was incubated at $37^{\\\\circ}\\\\mathrm{C}$ , for $3\\\\mathrm{h}$ . After cell washing, the incorporated dye was released in $1\\\\%$ $(v / v)$ acetic acid solution in $50\\\\%$ $(v / v)$ ethanol by gentle shaking, for $15\\\\mathrm{min}$ . The amount of up taken dye was directly proportional to the number of viable cells. The optical density (OD) was recorded at $540\\\\mathrm{nm}$ in a Spectrostar nano microplate \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,60,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[273,112,939,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"reader (BMG Labtech, Germany). The results of cell viability were expressed as a percentage from untreated cells (control) using the following equation: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[436,155,939,171]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\text {Cell viability} (\\\\%) = \\\\mathrm {OD} _ {\\\\text {sample}} / \\\\mathrm {OD} _ {\\\\text {control}} \\\\times 100 \\\\tag{3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[275,184,440,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.11. Light Microscopy \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,202,941,278]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell morphology of the control and powders-treated cultures was observed by light microscopy for the qualitative evaluation of the powders cytocompatibility. After $48\\\\mathrm{h}$ of cultivation in the presence of the microencapsulated powders, the cells were washed, fixed in methanol, and Giemsa stained. Micrographs were acquired at an Axio Observer D1 microscope equipped with a digital camera (Carl Zeiss, Germany). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,288,425,304]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.12. Stability Study \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,307,941,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For storage stability study, the powders were kept in light-resistant glass bottles at $25 \\\\pm 1^{\\\\circ}\\\\mathrm{C}$ for 21 days and observed for any change and percent residual content of lycopene. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,363,507,379]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.13. Statistical Analysis of Data \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,382,941,443]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All the experiments were performed in triplicates, with duplicate samples. The results were expressed in terms of average values. Statistical analysis of the data was performed by univariate analysis of variance (ANOVA) with a significance level of $95\\\\%$ $(p < 0.05)$ using the Tukey's test. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,454,356,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,469,863,483]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. The Phytochemical Content and Antioxidant Activity of the Tomato Peels Extract \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,488,941,563]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the first extraction batch, freshly grinded peels with value $(\\\\%)$ of the dry matter of $20.54 \\\\pm 0.41\\\\%$ were extracted using $\\\\mathrm{SC - CO_2}$ at the following parameters: Pressure $40\\\\mathrm{MPa}$ , different temperature of $70^{\\\\circ}\\\\mathrm{C}$ , $74^{\\\\circ}\\\\mathrm{C}$ , and $80^{\\\\circ}\\\\mathrm{C}$ , and the $\\\\mathrm{CO_2}$ masic flow of $0.32\\\\mathrm{kg / min}$ . The phytochemicals content of the extracts obtained in different separators is given in Table 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,612,942,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0127/bbf747bb780d9941ee8a75e62f17ce518a9a3a563d01bb1863f9ca4f40e515a8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"3\\\">Matrix</td><td colspan=\\\"6\\\">Phytochemicals</td></tr><tr><td colspan=\\\"2\\\">Lycopene (mg/g DW)</td><td colspan=\\\"2\\\">β-Carotene (mg/g DW)</td><td colspan=\\\"2\\\">Antioxidant Activity (mM TEAC/g DW)</td></tr><tr><td>S40</td><td>S45</td><td>S40</td><td>S45</td><td>S40</td><td>S45</td></tr><tr><td>SCE extract (70 °C)</td><td>6.06 ± 0.06b</td><td>9.48 ± 0.41c</td><td>10.88 ± 0.33b</td><td>18.93 ± 0.73c</td><td>48.52 ± 3.63b</td><td>24.35 ± 0.71c</td></tr><tr><td>SCE extract (74 °C)</td><td>5.28 ± 0.07b</td><td>39.11 ± 0.59a</td><td>12.57 ± 0.11a</td><td>68.24 ± 0.71a</td><td>77.61 ± 0.99a</td><td>62.74 ± 1.74a</td></tr><tr><td>SCE extract (80 °C)</td><td>8.11 ± 0.65a</td><td>30.59 ± 0.63b</td><td>11.85 ± 0.59ab</td><td>47.08 ± 1.05b</td><td>39.99 ± 1.02c</td><td>38.34 ± 2.13b</td></tr><tr><td>Microencapsulated powder (P40)</td><td colspan=\\\"2\\\">10.83 ± 0.09A</td><td colspan=\\\"2\\\">22.49 ± 1.00A</td><td colspan=\\\"2\\\">8.57 ± 0.74A</td></tr><tr><td>Microencapsulated powder (P45)</td><td colspan=\\\"2\\\">10.49 ± 0.23A</td><td colspan=\\\"2\\\">19.93 ± 0.42B</td><td colspan=\\\"2\\\">9.37 ± 0.48A</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. The phytochemicals content of the extracts, obtained in different separators (S40 and S45) and the corresponding microencapsulated powders. \\\"]\",\n \"table_footnote\": \"[\\\"SCE—supercritical $\\\\\\\\mathrm{CO}_{2}$ fluids extraction. The results were expressed as mean $\\\\\\\\pm$ SD $(n = 3)$ . Means that do not share the same letter (a, b, c for the extracts and A and B for the powders) are significantly different $(p < 0.05)$ . \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[273,863,941,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The different phytochemical profiles, in terms of lycopene and $\\\\beta$ -carotene showed in Table 1, may be explained by temperature effect on the extraction rate of carotenoids. Therefore, for the extract separated at $20\\\\mathrm{MPa}$ in the first separator S40, it can be observed that the increase of the extraction temperature, from the $70^{\\\\circ}\\\\mathrm{C}$ to $80^{\\\\circ}\\\\mathrm{C}$ led to the increase \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,60,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[895,60,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,112,941,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of the lycopene content from $6.06 \\\\pm 0.06 \\\\, \\\\mathrm{mg/g}$ DW to $8.11 \\\\pm 0.65 \\\\, \\\\mathrm{mg/g}$ DW, respectively. This can be explained by the effect of the temperature on the improvement of the mass transfer and the solvent diffusion through the ground vegetable matrix. Likewise, the $\\\\beta$ -carotene concentrations were positively correlated with the increase of extraction temperature from $70^{\\\\circ}\\\\mathrm{C}$ to $74^{\\\\circ}\\\\mathrm{C}$ in both fractions. At the extraction temperatures of $70^{\\\\circ}\\\\mathrm{C}$ , the gravimetric yield was in the range of $3.39\\\\%$ for first separation S40 and $6.18\\\\%$ at the second separator S45, respectively. At the higher extraction temperature up to $80^{\\\\circ}\\\\mathrm{C}$ , the gravimetric yield was at $3.81\\\\%$ in the first separator S40 and $5.99\\\\%$ in the second one, S45, respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,247,941,485]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our results could be explained according to the separation conditions after the extraction process. Therefore, at the same extraction pressure of $40\\\\mathrm{MPa}$ , the fractionating of the oleoresins was performed using two consecutive separators with controlled temperature and pressure conditions. Our results indicate that at $5\\\\mathrm{MPa}$ in the second separator, S45, recovers the higher lycopene and $\\\\beta$ -carotene content. From Table 1 it can be seen that, overall, a higher content in lycopene and $\\\\beta$ -carotene was obtained when extracting at a temperature of $74^{\\\\circ}\\\\mathrm{C}$ , leading to an extract with a lycopene content of $39.11 \\\\pm 0.59\\\\mathrm{mg/g}$ DW and $\\\\beta$ -carotene of $68.24 \\\\pm 0.71\\\\mathrm{mg/g}$ DW in S45 separator. Machmudah et al. [20] reported a lycopene concentration of $459.20\\\\mathrm{mg/kg}$ at $40\\\\mathrm{MPa}$ at $90^{\\\\circ}\\\\mathrm{C}$ and a $\\\\mathrm{CO}_{2}$ flow rate of $4\\\\mathrm{mL/min}$ for $180\\\\mathrm{min}$ . The antioxidant activity was higher for the extract separated at $20\\\\mathrm{MPa}$ with $77.61 \\\\pm 0.99\\\\mathrm{mM}$ TEAC/g DW in S40 separator. Due to the highest concentration values of bioactive, it has been found that the extraction conditions of temperature $74^{\\\\circ}\\\\mathrm{C}$ , pressure $40\\\\mathrm{MPa}$ , $155\\\\mathrm{min}$ and $\\\\mathrm{SC - CO_2}$ flow rate $0.32\\\\mathrm{kg/min}$ allowed to obtain a gravimetric extraction yield of $2.12\\\\%$ in the first separator (pressure $20\\\\mathrm{MPa}$ and temperature $74^{\\\\circ}\\\\mathrm{C}$ ) and $8.06\\\\%$ for the second separator (pressure $5\\\\mathrm{MPa}$ and the temperature $25^{\\\\circ}\\\\mathrm{C}$ ), respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,485,939,529]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 1 shows the chromatographic profile of the two selected extracts, obtained at the best $\\\\mathrm{SC - CO_2}$ extraction condition of pressure $40\\\\mathrm{MPa}$ , temperature $74^{\\\\circ}\\\\mathrm{C}$ , and extraction time of $155\\\\mathrm{min}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[282,544,852,788]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. The chromatographic profile of the tomato peels supercritical $\\\\\\\\mathrm{CO}_{2}$ extracts at $450\\\\\\\\mathrm{nm}$ (S40—the extract fraction separated at $20\\\\\\\\mathrm{MPa}$ in the first separator, S45—the extract fraction separated at $5\\\\\\\\mathrm{MPa}$ in the second separator), the major identified compounds being lycopene (peak 1) and $\\\\\\\\beta$ -carotene (peak 2). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0012/17f6b61dddfde612549267464a374faf0f7ed4a602ad05ca6b10e3e9324936c3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,871,939,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The compounds were separated and identified based on their retention time and the calibration curves and by comparison with the data reported in the literature. The major compounds identified were lycopene (peak 1) and $\\\\beta$ -carotene (peak 2). For the S40 extract, the content of lycopene was $92.23\\\\%$ (corresponding to a concentration of $0.875\\\\mathrm{mg/mL}$ ) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,112,939,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"from the total carotenoids, whereas the content of $\\\\beta$ -carotene was $1.51\\\\%$ (corresponding to a concentration of $0.015\\\\mathrm{mg/mL}$ ). The results obtained for the S45 extract were significantly lower compared to S40 extract, as such, the content of lycopene was $76.36\\\\%$ (corresponding to a concentration of $0.345\\\\mathrm{mg/mL}$ ), whereas the content of $\\\\beta$ -carotene was $4.78\\\\%$ (corresponding to a concentration lower than $0.010\\\\mathrm{mg/mL}$ ) of the total carotenoids content. Our results were similar to those reported by Rizk, El-Kady, and El-Bialy [21], who stated that lycopene was the major carotenoid compound extracted from tomatoes, with a content of $86.13\\\\%$ of the total carotenoids, whereas $\\\\beta$ -carotene displayed content of about $2.11\\\\%$ . Moreover, Ooe et al. [22] determined the Japanese blue tomato carotenoids content and identified two major compounds, lycopene (with a content of $1.13\\\\mathrm{mg/g}$ extract) and $\\\\beta$ -carotene $(0.10\\\\mathrm{mg/g})$ , respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,288,673,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Microencapsulation Efficiency of the Selected Extracts \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,307,939,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"High encapsulation efficiency is needed to reduce oxidative degradation of lycopene on the particle surface and to increase powders' stability [23]. In our study, similar values for microencapsulation efficiency of lycopene in both powders, with values of $41.06 \\\\pm 0.33\\\\%$ for P40 and $40.42 \\\\pm 0.59\\\\%$ for P45, respectively. Jia et al. [14] encapsulated lycopene in whey protein isolate-xylo-oligosaccharide conjugates prepared by Maillard reaction, reporting significantly higher encapsulation efficiency and encapsulation of $94\\\\%$ and $86\\\\%$ , respectively, at specific conditions to prepare the conjugates of protein-oligosaccharide ratio of 1:2, heating time $3\\\\mathrm{h}$ and $\\\\mathrm{pH}9.0$ . Jain et al. [24] established maximum entrapment efficiencies $(63.1 \\\\pm 3.6\\\\%)$ for lycopene at 1:2 of Gum tragacanth:casein and $0.75\\\\mathrm{wt}\\\\%$ of total biopolymers concentration, by complex coacervation. These authors suggested that on increasing the quantity of lycopene loaded oil, while keeping the total polymeric strength constant, \\\\% entrapment efficiency increased up to a certain level. Microcapsules obtained with $2.5\\\\mathrm{mL}$ of oil containing lycopene led to a bioactive entrapment of $66.6 \\\\pm 24.5\\\\%$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,513,695,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. Powders Phytochemical Profile and Antioxidant Activity \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,531,939,620]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lycopene content in the particles produced with WPI and acacia gum were of $10.83 \\\\pm 0.09 \\\\mathrm{mg/g}$ DW in P40 and of $10.49 \\\\pm 0.23 \\\\mathrm{mg/g}$ DW in P45 (Table 1). Souza et al. [13] reported a lycopene content varying from 333.7 to $494.4 \\\\mu \\\\mathrm{g/g}$ , using as encapsulating agent's maltodextrin, WPI, and the modified starch Capsul®. The antioxidant activity of the powders showed similar values of $8.57 \\\\pm 0.74 \\\\mathrm{mMol}$ TEAC/g DW in P40 and $9.37 \\\\pm 0.48 \\\\mathrm{mMol}$ TEAC/g DW in P45 (Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,633,687,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.4. Structural and Morphological Properties of the Powders \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,651,939,784]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The prepared microscope slides from the native powders (Figure 2A,B) indicate the microencapsulation of the phytochemical compounds from the tomato peels in the form of large, polygonal scales, with dimensions between $163.68 - 209.36\\\\mu \\\\mathrm{m}$ inside of which spherical vesicles (spherosomes) with diameters of $5.29 - 16.77\\\\mu \\\\mathrm{m}$ (in P40) or $7.94 - 23.5\\\\mu \\\\mathrm{m}$ (in P45) can be observed. As the major compound in the extract, the lycopene, with an autofluorescence in the range of $500 - 580\\\\mathrm{nm}$ , was captured in the microencapsulating matrix formed by WPI (in green) and acacia gum (in blue). The results were similar to those obtained in the native state by Neagu et al. [25], who microencapsulated oleoresin supercritical extracts from sea buckthorn into WPI and casein. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[282,114,559,325]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0832/9fbfab0972275675ded049cf1fe276d0b8849dd50d7b7ad6e1091c005e85b1b0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[581,111,855,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0335/78ddf58058f7f2600391fe010c76900d6fd5d6ad76f54666aeb689d680fa7e20.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[282,332,559,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0668/06707819a8c6c22df75d9136b9a12b97ffe97f806354487cb9b3b5c531244dcd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[581,331,852,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. The confocal laser scanning microscopy (CLSM) images $(20\\\\\\\\times$ apochromatic objective, zoom 1) of the unstained P40 (A) and P45 (B) native powders and the fluorophore dyed P40 (C) and P45 powders (D). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0970/063aa4e13afda50c4636601dd7140cd17b3cdbc9714a6624bc312a1abf94e1d4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,608,939,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"By fluorescent labeling, various significant differences between the two powders were highlighted (Figure 2C,D). Thus, the P40 powder formed several spherosomes, with sizes ranging between $15.87\\\\mu \\\\mathrm{m}$ and $38.54\\\\mu \\\\mathrm{m}$ , showing a coalescent tendency. In the P45, the ultrastructural aspect was different, highlighting the presence of fine microparticles with sizes of $1 - 2\\\\mu \\\\mathrm{m}$ , with an emission predominantly in the yellow domain and aggregated into coacervates. The fluorophore bounded to WPI, incorporating lycopene, which caused the fluorescent emission migration to the green-yellow range ( $560 - 580\\\\mathrm{nm}$ ), more obvious in the P45 powder. The larger size of the microcapsules in the P40 was correlated with better stability over time, better retention of the valuable phytochemicals, and better antioxidant activity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,769,721,784]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.5. Antiproliferative Activity of the Microencapsulated Powders \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,787,939,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In vitro cytotoxicity of the microencapsulated powders was assessed in HT-29 and L929 cells, after 24 and $48\\\\mathrm{h}$ of cultivation by NR assay. The results showed a dose-dependent decrease of HT-29 cell viability for both tested powders (Figure 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,832,941,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"P40 significantly inhibited $(p < 0.05)$ cell proliferation of HT-29 cells in the range of concentrations $5 - 1000\\\\mu \\\\mathrm{g / mL}$ with 30 to $60\\\\%$ at $24\\\\mathrm{h}$ of cultivation. At $48\\\\mathrm{h}$ of cultivation, the same descending pattern was observed, but slightly higher values were recorded for each concentration value and maximum inhibition of $55\\\\%$ at $1000~\\\\mu \\\\mathrm{g / mL}$ . Similar, P45 induced $25 - 55\\\\%$ inhibition of HT-29 cell proliferation, in the range of concentrations \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,60,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,941,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[273,112,941,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"between $25 - 1000\\\\mu \\\\mathrm{g / mL}$ , at both 24 and $48\\\\mathrm{h}$ of incubation, showing both dose- and time-dependent antiproliferative activity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,159,489,357]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0895/1fb21e939321a42b4a8d84925448ec47942b9fb40c400b4165afdd45dae3dab1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,158,927,357]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Cell viability of HT-29 cells cultivated in the presence of different concentrations of P40 and P45 microencapsulated samples, for $24\\\\\\\\mathrm{h}$ and $48\\\\\\\\mathrm{h}$ , assessed by NR assay. The results were expressed as mean $\\\\\\\\pm$ SD $(n = 3)$ . * $p < 0.05$ , compared to untreated control. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0237/1a8bb96bbac0c9d946c25515bf9e3858d5b3ba8447ddf055e14ae32860183126.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,420,946,483]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The half-maximal inhibitory concentration (IC50) values were $100~\\\\mu \\\\mathrm{g / mL}$ for P40 and $750~\\\\mu \\\\mathrm{g / mL}$ for P45, indicating a higher antiproliferative effect of P40 over P45 microencapsulated powders in HT-29 cell culture. Cell morphology observations followed NR quantitative data (Figure 4). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,499,297,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0337/1350f0d8c2538989323a6c44d0d96986bcbc8c4d151c2a73ff431d80d3ef419f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,605,295,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0885/0a6624b3e446889b381fce470971195a5fc89b65ef18b648ffd625ec1099d3fb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[295,605,495,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0070/a7690c9d7035d6e50a50c9d3bbe8b7f6410525d05b0a7bc8e6a9f824270d46aa.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[495,605,697,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0800/3466bd78ee1c6ba77a670ef9a028c3906ad47df4a25e036120ebddd28c4f128d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[697,605,892,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0921/5f4fedd8089b33f5e18df2acf1d7872b778414dbb02aeb584a666034e4b9b6e8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,708,295,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0337/4d1b2c27f78b2db1682ba73e627c1e467ce3cbf0e0aad126e85ad49546d1dc70.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[295,708,497,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0871/3838ef52c3760adab31cd0690418f5c4ccd7451a1ac3150622c95d9721f8aff3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[497,708,697,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0829/81d735028901bc9eb6410757d8c5e83f10b6a7dad04cfc8e6f792ec75c4cd925.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[697,708,892,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Representative light micrographs of HT-29 cells cultivated in the presence of different concentrations of P40 (second line) and P45 (third line) microencapsulated materials, for $48\\\\\\\\mathrm{h}$ . The untreated culture served as control (first line). (Giemsa staining). Bar scale = 100 $\\\\\\\\mu$ m. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0140/838c348a6d13cb265ded3e7f154f07b9bfb7323e4c9796c1531f74d9caa43587.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,877,946,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The micrographs showed that increasing concentrations of P40 and P45 powders decreased the cell density in HT-29 treated cultures, compared to the control culture, in a dose-dependent manner. It was observed that treated cells maintained their normal ag \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,60,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,60,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,112,939,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"gregative phenotype, but their viability and proliferation were severely affected. The same concentrations of P40 and P45 microencapsulated powders were tested for possible toxic compounds release in normal L929 cells by NR assay. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,158,939,187]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The results showed no cytotoxicity of both samples, in the range of concentrations $1 - 1000\\\\mu \\\\mathrm{g / mL}$ (Figure 5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,204,505,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0799/dcd76a9ded9a331f00f471b7094bd10b99ebd9f640e3dac9c8d7b12e9a061cad.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[505,203,944,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. Cell viability of L929 cells cultivated in the presence of different concentrations of S40 and S45 microencapsulated materials, for $24\\\\\\\\mathrm{h}$ and $48\\\\\\\\mathrm{h}$ , determined by NR assay. The results were expressed as mean $\\\\\\\\pm$ SD $(n = 3)$ . * $p < 0.05$ , compared to untreated control. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0464/9bcb702014373e30edb4ac022da21373d4f558ec4ad8985baa803d882eec45dc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,453,939,557]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thus, the values of cell viability varied between $77.9 - 116.4\\\\%$ for P40 and $83.6 - 112.4\\\\%$ for P45, at $48\\\\mathrm{h}$ of cultivation. Significantly lower values $(p < 0.05)$ of cell viability were recorded only for 750 and $1000~\\\\mu \\\\mathrm{g / mL}$ concentrations, compared to untreated control cells (100% cell viability), but they were within the non-cytotoxic domain (80-100% cell viability), except for $1000~\\\\mu \\\\mathrm{g / mL}$ P40 at $48\\\\mathrm{h}$ of cultivation (77.9%). In addition, concentrations in the range of $1 - 500~\\\\mu \\\\mathrm{g / mL}$ P40 and $1 - 10~\\\\mu \\\\mathrm{g / mL}$ P45 significantly stimulated $(p < 0.05)$ cell proliferation of normal cells, compared to the control culture, after $48\\\\mathrm{h}$ of cultivation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,557,939,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Light micrographs showed that cell morphology and density observations of L929 treated with different concentrations of microencapsulated powders were in accordance with NR quantitative data (Figure 6). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,602,939,781]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The images showed that treated fibroblasts maintained their characteristic fusiform phenotype and were homogeneously distributed on the culture plate, similar to the control culture, for all tested concentrations. At low concentrations (1–100 μg/mL), the cell density was higher than that of control culture, while at high concentrations (750–1000 μg/mL), the cell density moderately decreased in treated cultures. All these data demonstrated that the novel encapsulated powders exhibited antiproliferative activity in tumor cells, while extending the range of cytocompatibility in normal cells. They indicated that P40 and P45 microencapsulated powders had exerted an antiproliferative effect at minimal concentrations of 5 μg/mL and 25 μg/mL, respectively, in HT-29 cells, after 24 h of cultivation. At the same time, it is worth noticing that these powders presented an extended range of cytocompatibility, up to 1000 μg/mL, in L929 normal cells and even stimulated the cell growth. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,781,941,929]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Previous studies on standard lycopene have tested its effect on cell proliferation, at physiological concentrations or higher than $0.5\\\\mu \\\\mathrm{g / mL}$ , in several non-tumoral and tumoral cell lines. A wide range of low lycopene concentrations ranging between $0.00005 - 0.5\\\\mu \\\\mathrm{g / mL}$ showed minimal inhibition of cell proliferation in IMR-90 normal lung fibroblasts culture, and cell viability decreased by only $10\\\\%$ , after $48\\\\mathrm{h}$ of cultivation [26]. In vitro cultivation of $0.5 - 3\\\\mu \\\\mathrm{g / mL}$ lycopene in several human cancer cell lines showed an inhibitory effect of HT-29 cells with $20\\\\%$ and T84 cells with $30\\\\%$ , after $48\\\\mathrm{h}$ of cultivation, due to its internalization and induction of changes in the cell cycle, but no effect on other cell types (A549, DU145, HepG2, Hela, Hep-2) [27]. A lycopene-rich extract of red guava, encapsulated in $200\\\\mathrm{nm}$ lipid nanoparticles or not, showed good cytocompatibility in NIH-3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[273,112,941,174]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"T3 normal mice fibroblasts and decreased the viability of MCF-7 human adenocarcinoma cells down to $30\\\\%$ , at $100~\\\\mu \\\\mathrm{g / mL}$ , thus indicating antiproliferative activity, while protecting healthy cells [28]. No studies on the antiproliferative activity of lycopene encapsulated in a protein-polysaccharide complex were found. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[105,191,295,288]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0421/114da501762bdbfc3a72eb0e4da67c71deea00688a644f384298e156f208ce55.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[105,292,295,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0205/a7146a63c4733a67de88f5ece41d7f8a008529c0a99e1d3238eeae40a117af1b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[105,392,295,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0759/bfb837650ae56685863b53fb7399f31537526b83e42a4942873ee9b7bc73a068.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[297,292,489,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0206/4eb0c01e81903a478f8a8f3feb6131512d44a28221a830a692a1b289c96fba91.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[297,392,489,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0933/524f969cb6a974b8a6982079e67b9f692b70c1ada9b0587227edda811af85d30.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[492,292,695,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0515/329f3f0340645e27391ae2f6414467c85f23fcb24d56579fda5febabc5c8ad23.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[492,392,695,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0795/3d6b27b3cd426cf8f10bf346da3094f63e089f3b412f68be1153727ecc2263eb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[697,292,892,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0726/5834efe76e099c56d863c6574e52594eb59bdf87d598f95044bf236235e6043b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[697,392,892,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 6. Representative light micrographs of L929 cells cultivated in the presence of different concentrations of P40 (second line) and P45 (third line) microencapsulated materials, for $48\\\\\\\\mathrm{h}$ . The untreated culture served as control (first line). (Giemsa staining). Bar scale = 100 $\\\\\\\\mu$ m. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0410/7e65fa0755b4a63587529e15b6b5f0402e451eb16eefa4af49071b09b8ba85d7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,555,944,690]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Recent studies have shown that lycopene administration together with doxorubicin was able to attenuate the drug's cardiotoxicity and to improve its antitumor activity [29]. Lycopene is a carotenoid known as a potent antioxidant agent, while doxorubicin is a chemotherapy drug belonging to anthracyclines class. It was supposed that the role of lycopene was mainly as a preventive factor against the formation of cancer cells, and its mechanism of action was different from that of doxorubicin in tumor cells. Several in vitro studies showed that lycopene inhibited intercellular gap junction, the progression of cell cycle and cell invasion, and important signaling pathways within tumor cell cultures, acting also as an antiproliferative agent [30]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,700,601,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.6. Retention Rate of Lycopene at Storage Test \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,719,944,929]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The retention rate of the core material is an important indicator to measure the storage stability of microencapsulated lycopene. In this study, the retention rate of the lycopene was studied in dark and $25^{\\\\circ}\\\\mathrm{C}$ , for three weeks. The retention rate of lycopene in the microcapsules was approximately $48\\\\%$ and $29\\\\%$ in P40 and P45, respectively, after storage for 21 days at $25^{\\\\circ}\\\\mathrm{C}$ . Jia et al. [14] reported similar values for the retention rate of lycopene in the conjugate microcapsules of $46\\\\%$ and $40\\\\%$ after storage for 36 days at $25^{\\\\circ}\\\\mathrm{C}$ and $40^{\\\\circ}\\\\mathrm{C}$ , respectively. The degradation of lycopene in powders during storage was fitted to a first-order kinetic model. The degradation rate of lycopene in P45 is significantly higher when compared with P40, the $k$ values for the first-order kinetic model being of $85.44 \\\\pm 1.23 \\\\times 10^{-3} \\\\, \\\\text{days}^{-1}$ for lycopene degradation in P40 and significantly higher, of $144.16 \\\\pm 2.56 \\\\times 10^{-13} \\\\, \\\\text{days}^{-1}$ in P45. The different pattern of lycopene degradation in P45 is due to the higher content of the surface, non-encapsulated lycopene, when compared with P40, which enhanced the degradation of lycopene by oxidation and isomerization. The half time of total lycopene content was $8.11 \\\\pm 0.94$ days in P40 and $4.80 \\\\pm 0.34$ days \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,60,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,60,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,112,939,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in P45. Surface carotenoids were reduced to one-half in P40 in 13 days, whereas in P45, more than $78\\\\%$ indicated the sensitivity of lycopene toward oxidation, isomerization, and degradation despite moderate storage temperature and the exclusion of light. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,170,393,183]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,187,941,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this study, two complementary approaches were employed for recovery and uses of bioactives from tomato peels to develop added-value ingredients with multiple uses. Therefore, supercritical fluid extraction parameters were optimized to obtain extracts with superior characteristics, followed by microencapsulation and testing of resulting powders. The $\\\\mathrm{SC - CO_2}$ extraction of tomato peels by-product at a temperature of $74^{\\\\circ}\\\\mathrm{C}$ , pressure of $40\\\\mathrm{MPa}$ , and extraction time of $155\\\\mathrm{min}$ yielded high amounts of lycopene-enriched oleoresin. The two extracts corresponding to the equipment separators were microencapsulated in whey protein isolates and acacia gum by complex coacervation and freeze-drying, resulting in two powders with similar microencapsulation efficiency, phytochemicals content, and antioxidant activity. However, although using the same microencapsulation technique, the powders showed different morphological, stability, and biological properties. The ultrastructural aspect highlighted the presence of different sizes of spherosomes, with a coalescent tendency in the powder containing extract separated at $20\\\\mathrm{MPa}$ , whereas finer microparticles up to $2\\\\mu \\\\mathrm{m}$ , aggregated into coacervates were observed in the powder containing the extract obtained in the second separator at $5\\\\mathrm{MPa}$ . A significant effect of cell proliferation in a normal cell at concentrations up to $500~\\\\mu \\\\mathrm{g / mL}$ for the powder with the extract separated at $20\\\\mathrm{MPa}$ , and up to $10~\\\\mu \\\\mathrm{g / mL}$ for the powder with the extract separated at $5\\\\mathrm{MPa}$ was observed, whereas an antiproliferative effect at minimal concentrations of $5\\\\mu \\\\mathrm{g / mL}$ and $25~\\\\mu \\\\mathrm{g / mL}$ , respectively, in HT-29 cells was highlighted. Both powders presented an extended range of cytocompatibility, up to $1000~\\\\mu \\\\mathrm{g / mL}$ , in L929 normal cells. The degradation of lycopene in powders during storage was fitted to a first-order kinetic model, highlighting a higher degradation rate of lycopene in the powder with the extract separated at $5\\\\mathrm{MPa}$ , namely, due to the higher content of the surface, non-encapsulated lycopene, thus enhancing its degradation by oxidation and isomerization. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,546,941,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our results are promising in opening new opportunities to identify sustainable solutions for the development of value-added ingredients with multiple uses, such as food, pharmaceuticals, cosmeceuticals, and nutraceuticals. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,611,941,681]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author Contributions: Conceptualization, N.S.; methodology, L.M., V.B. and O.C.; validation, N.S., G.R. and A.O.; formal analysis, I.G. and A.-M.P.; investigation, L.M., E.E., V.B. and A.-M.P.; resources, G.E.B. and G.R.; writing—original draft preparation, N.S., L.M. and E.E.; writing—review and editing, N.S.; supervision, N.S.; project administration, N.S.; funding acquisition, G.E.B. All authors have read and agreed to the published version of the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,688,939,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding: The authors are grateful for the technical support offered by the Grant POSCCE ID 1815, Code SMIS 48745 (www.moras.ugal.ro). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,722,648,737]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Institutional Review Board Statement: Not applicable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,745,589,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Informed Consent Statement: Not applicable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,765,939,807]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data Availability Statement: HT-29 human colorectal adenocarcinoma cell line was purchased from American Type Culture Collection (ATCC), and NCTC clone L929 mouse fibroblast cell line came from European Collection of Authenticated Cell Culture (ECACC) (Sigma-Aldrich, Steineim, Germany). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,814,939,841]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments: The Integrated Center for Research, Expertise and Technological Transfer in Food Industry is acknowledged for providing technical support. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,848,702,860]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflicts of Interest: The authors declare no conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,112,144,124]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,129,942,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Effects of carrier agents on powder properties, stability of carotenoids, and encapsulation efficiency of goldenberry (Physalis peruviana L.) powder produced by co-current spray drying. Curr. Res. Food Sci. 2020, 3, 73-81. [CrossRef] [PubMed] \\\",\\\"24. Jain, A.; Thakura, D.; Ghoshala, G.; Katare, O.P.; Singh, B.; Shivhare, U.S. Formation and functional attributes of electrostatic complexes involving casein and anionic polysaccharides: An approach to enhance oral absorption of lycopene in rats In Vivo. Int. J. Biol. Macromol. 2016, 93, 746-756. [CrossRef] [PubMed] \\\"]\",\n \"page_idx\": \"13\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[55,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,60,941,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[55,112,941,334]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"25. Neagu, C.; Mihalcea, L.; Enachi, E.; Barbu, V.; Borda, D.; Bahrim, G.E.; Stanciuc, N. Cross-Linked Microencapsulation of $\\\\\\\\mathrm{CO}_{2}$ Supercritical Extracted Oleoresins from Sea Buckthorn: Evidence of Targeted Functionality and Stability. *Molecules* 2020, 25, 2442. [CrossRef] [PubMed] \\\",\\\"26. Burgess, L.C.; Rice, E.; Fischer, T.; Seekins, J.R.; Burgess, T.P.; Sticka, S.J.; Klatt, K. Lycopene has limited effect on cell proliferation in only two of seven human cell lines (both cancerous and noncancerous) in an In Vitro system with doses across the physiological range. Toxicol. In Vitro 2008, 22, 1297-1300. [CrossRef] \\\",\\\"27. Teodoro, A.J.; Oliveira, F.L.; Martins, N.B.; de Azevedo Maia, G.; Martucci, R.B.; Borojevic, R. Effect of lycopene on cell viability and cell cycle progression in human cancer cell lines. Cancer Cell Int. 2012, 12, 36. [CrossRef] \\\",\\\"28. Vasconcelos, A.G.; Valim, M.O.; Amorim, A.G.N.; do Amaral, C.P.; de Almeida, M.P.; Borges, T.K.S.; Socodato, R.; Portugal, C.C.; Brand, G.D.; Mattos, J.S.C.; et al. Cytotoxic activity of poly-ε-caprolactone lipid-core nanocapsules loaded with lycopene-rich extract from red guava (Psidium guajava L.) on breast cancer cells. Food Res. Int. 2020, 136, 109548. [CrossRef] \\\",\\\"29. Imran, M.; Ghorat, F.; Ul-Haq, I.; Ur-Rehman, H.; Aslam, F.; Heydari, M.; Shariati, M.A.; Okuskhanova, E.; Yessimbekov, Z.; Thiruvengadam, M. Lycopene as a natural antioxidant used to prevent human health disorders. Antioxidants 2020, 9, 706. [CrossRef] \\\",\\\"30. Mirahmadi, M.; Azimi-Hashemi, S.; Saburi, E.; Kamali, H.; Pishbin, M.; Hadizadeh, F. Potential inhibitory effect of lycopene on prostate cancer. Biomed. Pharmacother. 2020, 129, 110459. [CrossRef] \\\"]\",\n \"page_idx\": \"14\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[55,61,208,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Antioxidants 2021, 10, 222 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,60,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"15 of 15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.3390/antiox10020222"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences/Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"b5deb973d2b9e022469bdaf7d64760d3e763fd2e8daa1f51781142e5be904365"},"title":{"kind":"string","value":"Supercritical CO2 Extraction and Microencapsulation of Lycopene-Enriched Oleoresins from Tomato Peels: Evidence on Antiproliferative and Cytocompatibility Activities"}}},{"rowIdx":157,"cells":{"abstract":{"kind":"string","value":"Selective photocatalytic reduction of CO2 has been regarded as one of the most amazing ways for re-using CO2. However, its application is still limited by the low CO2 conversion efficiency. This work developed a novel Pt/In2O3/g-C3N4 multifunctional catalyst, which exhibited high activity and selectivity to HCOOH during photocatalytic CO2 reduction under visible light irradiation owing to the synergistic effect between photocatalyst, thermocatalyst, and heterojunctions. Both In2O3 and g-C3N4 acted as visible photocatalysts, in which porous g-C3N4 facilitated H2 production from water splitting while the In2O3 nanosheets embedded in g-C3N4 pores favored CO2 fixation and H adsorption onto the Lewis acid sites. Besides, the In2O3/g-C3N4 heterojunctions could efficiently inhibit the photoelectron-hole recombination, leading to enhanced quantum efficiency. The Pt could act as a co-catalyst in H2 production from photocatalytic water splitting and also accelerated electron transfer to inhibit electron-hole recombination and generated a plasma effect. More importantly, the Pt could activate H atoms and CO2 molecules toward the formation of HCOOH. At normal pressure and room temperature, the TON of HCOOH in CO2 conversion was 63.1 μmol g-1 h-1 and could reach up to 736.3 μmol g-1 h-1 at 40 atm."},"author":{"kind":"string","value":"Jiehong He|Pin Lv|Jian Zhu|Hexing Li"},"content_list":{"kind":"list like","value":[{"bbox":"[84,120,169,139]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PAPER ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[754,116,899,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[756,133,884,143]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Journal | View Issue ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,175,100,193]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0807/2e18a9bb2803fb8dbf78b0d8eef8bce7389ae15c9187765abb4987ed817baefe.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[105,177,228,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,207,260,220]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cite this: RSC Adv., 2020, 10, 22460 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[285,168,929,216]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Selective $\\mathrm{CO}_{2}$ reduction to HCOOH on a $\\mathrm{Pt} / \\mathrm{In}_{2} \\mathrm{O}_{3} /$ g- $\\mathrm{C}_{3} \\mathrm{~N}_{4}$ multifunctional visible-photocatalyst† ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[285,225,677,243]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Jiehong He, Pin Lv, Jian Zhu* and Hexing Li ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[282,256,931,455]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Selective photocatalytic reduction of $\\mathrm{CO}_{2}$ has been regarded as one of the most amazing ways for re-using $\\mathrm{CO}_{2}$ . However, its application is still limited by the low $\\mathrm{CO}_{2}$ conversion efficiency. This work developed a novel $\\mathrm{Pt} / \\mathrm{In}_{2}\\mathrm{O}_{3} / \\mathrm{g} - \\mathrm{C}_{3}\\mathrm{N}_{4}$ multifunctional catalyst, which exhibited high activity and selectivity to HCOOH during photocatalytic $\\mathrm{CO}_{2}$ reduction under visible light irradiation owing to the synergistic effect between photocatalyst, thermocatalyst, and heterojunctions. Both $\\mathrm{In}_{2}\\mathrm{O}_{3}$ and $\\mathrm{g} - \\mathrm{C}_{3}\\mathrm{N}_{4}$ acted as visible photocatalysts, in which porous $\\mathrm{g} - \\mathrm{C}_{3}\\mathrm{N}_{4}$ facilitated $\\mathrm{H}_{2}$ production from water splitting while the $\\mathrm{In}_{2}\\mathrm{O}_{3}$ nanosheets embedded in $\\mathrm{g} - \\mathrm{C}_{3}\\mathrm{N}_{4}$ pores favored $\\mathrm{CO}_{2}$ fixation and H adsorption onto the Lewis acid sites. Besides, the $\\mathrm{In}_{2}\\mathrm{O}_{3} / \\mathrm{g} - \\mathrm{C}_{3}\\mathrm{N}_{4}$ heterojunctions could efficiently inhibit the photoelectron-hole recombination, leading to enhanced quantum efficiency. The Pt could act as a co-catalyst in $\\mathrm{H}_{2}$ production from photocatalytic water splitting and also accelerated electron transfer to inhibit electron-hole recombination and generated a plasma effect. More importantly, the Pt could activate H atoms and $\\mathrm{CO}_{2}$ molecules toward the formation of HCOOH. At normal pressure and room temperature, the TON of HCOOH in $\\mathrm{CO}_{2}$ conversion was $63.1\\mu \\mathrm{mol} g^{-1} h^{-1}$ and could reach up to $736.3\\mu \\mathrm{mol} g^{-1} h^{-1}$ at 40 atm. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,390,206,401]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received 2nd May 2020 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,401,211,412]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted 2nd June 2020 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,421,216,433]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DOI: 10.1039/d0ra03959d ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,442,169,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"rsc.li/rsc-advances ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,481,247,499]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[63,510,492,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{CO}_{2}$ conversion has attracted increasing interest owing to the consideration to both reduce the green-house effect and recycle carbon resources. The key problem is the $\\mathrm{CO}_{2}$ fixation and activation steps, which play a critical role in determining the activity and selectivity. $^{1,2}$ Previously, $\\mathrm{CO}_{2}$ reduction was mainly driven by metal thermocatalysts, $^{3-6}$ but it was usually performed at high temperature due to the highly stable $\\mathrm{CO}_{2}$ molecule. Electrocatalytic $\\mathrm{CO}_{2}$ reduction has also been reported, but additional energy is needed and the special reactor limits large scale-production. $^{5,6}$ Photocatalytic $\\mathrm{CO}_{2}$ reduction represents a promising way for $\\mathrm{CO}_{2}$ conversion due to it being an energy saving and green process, which uses mild conditions, and has long durability. $^{7-10}$ However, the photocatalytic efficiency is still very low because of the poor $\\mathrm{CO}_{2}$ adsorption/activation ability and the easy photoelectron-hole recombination. $^{11,12}$ Moreover, such a reaction usually displays low selectivity with the formation of various products like methane, methanol, formaldehyde, formic acid, etc. $\\mathrm{TiO}_{2}$ has been frequently employed as in photocatalysis owing to its environmental friendship, easy availability, high activity, and excellent stability. $^{13}$ However, $\\mathrm{TiO}_{2}$ can only be activated by UV lights due to its large bandgap ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,854,490,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Education Ministry Key and International Joint Lab of Resource Chemistry, Shanghai Key Laboratory of Rare Earth Functional Materials, Department of Chemistry, Shanghai Normal University, Shanghai 200234, China. E-mail: hexing-li@shnu.edu.cn; jianzhu@shnu.edu.cn; Fax: +86 21 64322272; Tel: +86 21 64322272 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,908,490,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra03959d ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,478,931,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(3.2 eV) and thus cannot sufficiently make use of sunlight. $^{14}$ In addition, the radical reaction steps disfavor the selectivity toward the target product. $\\mathrm{In}_2\\mathrm{O}_3$ can be activated by visible light and also can easily adsorb/activate $\\mathrm{CO}_{2}$ molecules via Lewis acid sites, which greatly benefits the photocatalytic $\\mathrm{CO}_{2}$ reduction toward HCOOH. $^{15,16}$ But, pure $\\mathrm{In}_2\\mathrm{O}_3$ exhibits poor activity to generate H atoms through photocatalytic water splitting. The $\\mathrm{g - C_3N_4}$ is a typical visible photocatalyst for efficient water splitting, $^{17}$ but could effectively adsorb and activate $\\mathrm{CO}_{2}$ molecules. In addition, both $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ exhibit low activities due to the rapid combination between photoelectrons and holes. $^{18}$ Construction of heterojunction structures is frequently used in designing photocatalysts with the low photoelectron-hole recombination rate and the high photocatalytic activity in pollutant-degradation, water splitting, and $\\mathrm{CO}_{2}$ reduction. $^{19,20}$ Many efforts have been devoted to improving the photocatalytic $\\mathrm{CO}_{2}$ reduction efficiency. $^{21-24}$ Obviously, the combination of $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ could mainly overcome their individual shortcomings in photocatalytic $\\mathrm{CO}_{2}$ reduction. More importantly, the $\\mathrm{In}_2\\mathrm{O}_3$ displays energy level matching well with the $\\mathrm{g - C_3N_4}$ . Thus, $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ heterojunctions can be easily established, which can promote the photoelectron-hole separation to diminish photoelectron-hole recombination, leading to the high quantum efficiency in photocatalysis, which has applied into $\\mathrm{H}_{2}$ evolution, $\\mathrm{CO}_{2}$ reduction and pollutants degradation. Cao et al. reported an $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ with enhanced activity in photocatalytic $\\mathrm{H}_{2}$ evolution and $\\mathrm{CO}_{2}$ reduction owing to the heterojunctions between $\\mathrm{g - C_3N_4}$ and $\\mathrm{In}_2\\mathrm{O}_3$ , which promoted the transfer of photo-generated electrons and thus decreased the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[3,114,47,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n© CC BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[67,66,300,91]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[687,29,929,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ROYAL SOCIETY OF CHEMISTRY ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,962,112,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22460 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,962,329,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[606,962,929,975]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[63,59,492,182]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"photoelectron-hole recombination. $^{25}$ Non-noble metal like B and S has also been induced in $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C}_3\\mathrm{N}_4$ to promote photocatalytic efficiency. $^{26,27}$ Besides, noble metals like Pt and Pd have been widely applied in catalytic $\\mathrm{CO}_{2}$ reduction with high activity and selectivity. $^{28,29}$ Meanwhile, they could also be used as co-catalysts in photocatalysis to facilitate electron transfer owing to the excellent electric conductivity $^{30,31}$ and to activate reactant molecules owing to the low work function. $^{32}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,183,492,367]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Herein, we reported for the first time a $\\mathrm{Pt / In_2O_3 / g - C_3N_4}$ nanocomposite and used as a multifunctional catalyst in photocatalytic $\\mathrm{CO}_{2}$ reduction under visible light irradiation. The $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C}_3\\mathrm{N}_4$ was prepared via a solvothermal route, while Pt was loaded through a photo-reduced method. The unique structural assemble and the strong interaction between nanoparticle Pt, nanosheet $\\mathrm{In}_2\\mathrm{O}_3$ , and porous $\\mathrm{g - C_3N_4}$ . As a result, the $\\mathrm{Pt / In_2O_3 / g - C_3N_4}$ exhibited high activity and selectivity to HCOOH owing to the synergetic effects. The $\\mathrm{CO}_{2}$ conversion TON reached up to $736.3~\\mu \\mathrm{mol}~\\mathrm{g}^{-1}~\\mathrm{h}^{-1}$ at 40 atm and the catalyst exhibited excellent durability, showing good potential in the practical application. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,383,257,401]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Experimental ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,408,238,423]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1 Sample preparation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[63,428,492,596]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{In}_2\\mathrm{O}_3$ was prepared through a hydrothermal method. In a typical run of synthesis, 6 mmol $\\mathrm{In(NO_3)_3}$ (Aladdin) was added into a $40~\\mathrm{mL}$ aqueous solution, followed by stirring for $10\\mathrm{min}$ to get a clear solution. Then, $24\\mathrm{mmol}$ urea (Aladdin) was added and the solution was continuously stirred for $2\\textrm{h}$ at room temperature. Subsequently, the solution was transferred into a $50~\\mathrm{mL}$ Teflon lined autoclave and was kept at $140^{\\circ}\\mathrm{C}$ for $16\\mathrm{h}$ . The obtained solid product was washed thoroughly by water and ethanol, followed by drying at $60^{\\circ}\\mathrm{C}$ for $12\\mathrm{h}$ . Finally, it was calcined at $450^{\\circ}\\mathrm{C}$ for $2\\textrm{h}$ to improve the crystallization degree of $\\mathrm{In}_2\\mathrm{O}_3$ and remove impurities. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,596,492,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{g - C_3N_4}$ was prepared by calcination of melamine (Aladdin) in a special reactor at $500^{\\circ}\\mathrm{C}$ for $2\\mathrm{h}$ , followed by calcining at $520^{\\circ}\\mathrm{C}$ for another $2\\mathrm{h}$ until the formation of faint yellow powder. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,643,494,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For preparing $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C}_3\\mathrm{N}_4$ , a certain amount of $\\mathrm{g - C_3N_4}$ was dispersed into $20~\\mathrm{mL}$ aqueous solution containing a certain amount of urea and was stirred for $2\\textrm{h}$ at room temperature. Meanwhile, a certain amount of indium nitrate was added to another $20~\\mathrm{mL}$ aqueous solution and was stirred until transparent. Then, the solution containing $\\mathrm{In(NO_3)_3}$ was carefully added into the solution containing $\\mathrm{g - C_3N_4}$ and urea. After being stirred for $2\\textrm{h}$ , the mixed solution was transferred into a $50~\\mathrm{mL}$ Teflon lined autoclave and kept at $140^{\\circ}\\mathrm{C}$ for $16\\mathrm{h}$ . The obtained solid product was washed by water and ethanol, followed by drying at $60^{\\circ}\\mathrm{C}$ for $12\\mathrm{h}$ , and finally, calcining at $450^{\\circ}\\mathrm{C}$ for $2\\mathrm{h}$ in argon atmosphere. The as-received sample was donated as xINCN, where $x$ refers to the theoretical mass ratio of $\\mathrm{In}_2\\mathrm{O}_3$ to $\\mathrm{g - C_3N_4}$ , which is adjusted by the added amount of $\\mathrm{g - C_3N_4}$ in mother solution. For comparison, the mechanical mixture of $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ was also prepared and was designated as INCN-mix. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,903,492,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Pt-deposited photocatalysts were prepared by photoreduction of Pt ions. Briefly, $100\\mathrm{mg}$ xINCN was dispersed in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,59,931,166]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$10~\\mathrm{mL}$ ultra-pure water containing the desired amount of chloroplatinic acid and $1\\mathrm{mL}$ TEOA (Aladdin). Then, the solution was irradiated with LED lamps for $30\\mathrm{min}$ . After separation, the solid product was washed thoroughly with $\\mathrm{H}_2\\mathrm{O}$ and ethyl alcohol, followed by drying at $60^{\\circ}\\mathrm{C}$ for $8\\mathrm{h}$ . The as-received sample was marked as $y\\mathrm{Pt - xINCN}$ , where $y$ is theoretical mass ratio of Pt to $x\\mathrm{INCN}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,184,655,198]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2 Characterization ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,205,931,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The real contents of different components in composites were determined by using Inductive Coupled Plasma Emission Spectrometer (ICP, a Jarrel-Asm Atom Scan 2000). The $\\mathrm{N}_2$ adsorption-desorption isotherms were obtained at $77\\mathrm{K}$ using a Micromeritics ASAP 2010 instrument in which the specific surface area $(S_{\\mathrm{BET}})$ and pore volume $(V_{\\mathrm{p}})$ were calculated by applying Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH) models. X-ray diffraction (XRD) patterns were recorded on a Bruker D8 Advance X-ray diffractometer with CuK radiation at a scan rate of $0.02^{\\circ}\\mathrm{s}^{-1}$ . The morphologies were measured on a field emission scanning electronic micrograph (FESEM, JEOL JSM-6380LV) and transmission electronic micrograph (TEM, JEM-2010). Energy-dispersive X-ray spectroscopy (EDS) was also performed by the JSM. The surface electronic states were investigated by X-ray photoelectron spectroscopy (XPS; ULVAC-PHI PHI5000 VersaProbe using Al Kα radiation). UV-Vis diffuse reflection spectra (DRS) were obtained on a Shimadzu UV-2450 Spectrophotometer using $\\mathrm{BaSO_4}$ as a reference. The steady-state photoluminescence (PL) spectra were obtained by a Varian Cary-Eclipse 500 fluorometer at an excitation wavelength of $350\\mathrm{nm}$ . Photocurrents were measured using an electrochemical analyzer (CHI660D Instruments) containing a standard three-electrode system in $0.5\\mathrm{MNa_2SO_4}$ aqueous solution as the electrolyte. The as-prepared sample was used as a working electrode with an active area of $20\\times 20\\mathrm{mm}^2$ . The sample was prepared by traditional technology. First, $2\\mathrm{mg}$ PVDF was added into $2\\mathrm{mL}$ DMF solution under ultrasonic condition. Then, $20\\mathrm{mg}$ catalyst was added. The suspension was obtained and treated by ultrasound for another $5\\mathrm{min}$ , followed by dropping onto a FTO piece $(20\\times 20\\mathrm{mm}^2)$ , vacuum drying at $80^{\\circ}\\mathrm{C}$ for $8\\mathrm{h}$ , and calcination at $150^{\\circ}\\mathrm{C}$ for $1\\mathrm{h}$ . A Pt piece with an area of $20\\times 20\\mathrm{mm}^2$ was used as a counter electrode and a saturated calomel electrode was used as a reference electrode. Each run of the measurements was performed by irradiating with a $300\\mathrm{W}$ Xe lamp for $30\\mathrm{s}$ at an interval of $30\\mathrm{s}$ . Electrochemical impedance spectra (EIS) were obtained under the open-circuit potential condition, with an amplitude of $10\\mathrm{mV}$ and frequency span from $10\\mathrm{kHz}$ to $0.01\\mathrm{Hz}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,807,623,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.3 Activity test ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,826,929,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The photocatalytic $\\mathrm{CO}_{2}$ reduction was performed in a self-made $50~\\mathrm{mL}$ quartz reactor. Before reaction, $20~\\mathrm{mg}$ catalyst was dispersed in $10~\\mathrm{mL}$ ultra-pure water under ultrasonication for $30\\mathrm{min}$ . Then, $1\\mathrm{mL}$ TEOA (Aladdin) was introduced as a sacrificial agent. The suspension was transferred onto a $50~\\mathrm{mL}$ quartz reactor with two vents. High purity $\\mathrm{CO}_{2}$ $(99.99\\%)$ was introduced into the reactor and bubbled for $0.5\\mathrm{h}$ to evacuate ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[1,114,45,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n© CC BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[67,29,115,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,11,926,20]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[816,28,927,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,961,391,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[672,961,878,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[887,961,927,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22461 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[63,59,492,213]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the air inside the reactor. Then, the reactor was sealed and filled with $\\mathrm{CO}_{2}$ to 1 atm. For each run of reactions, the reaction system was irradiated for $4\\mathrm{h}$ by four 3 W LED lights with the wavelength of $420~\\mathrm{nm}$ at a constant temperature of $35^{\\circ}\\mathrm{C}$ and stirring rate of $800~\\mathrm{rpm}$ . The gas products were analyzed by a gas chromatography equipped by HP-PLOT Q column connected with the FID detector and TDX-01 connected with TCD detector. The liquid products were detected by ion chromatography (Dionex DX-320) with an analytical column (Dionex IonPac AS19-4 $\\mu$ m Analytical Column). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,229,357,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results and discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,255,273,268]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1 Structural characteristics ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[63,275,490,458]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As shown in Fig. 1, the XRD patterns revealed that all the samples were present in well crystalline states of $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ . The pure $\\mathrm{g - C_3N_4}$ displayed two peaks around $13.1^{\\circ}$ and $27.4^{\\circ}$ characteristic of (100) and (002) facets. The $\\mathrm{In}_2\\mathrm{O}_3$ was present in cubic structure (JCPDS card no. 06-0416) with the characteristic peaks at $30^{\\circ}$ , $35^{\\circ}$ , $51^{\\circ}$ , and $60^{\\circ}$ , corresponding (111), (100), (110), (622) facets, respectively. All the $\\mathrm{Pt / In_2O_3 / g - }$ $\\mathrm{C_3N_4}$ showed typical peaks indicative of individual $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - }$ $\\mathrm{C_3N_4}$ , indicating no chemical bonding formed between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ . No significant diffraction peaks indicative of Pt were observed in $\\mathrm{Pt / In_2O_3}$ , $\\mathrm{Pt / g - C_3N_4}$ , or Pt-INCN owing to the low Pt-loading with high dispersion of Pt nanoparticles. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,459,492,673]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The SEM and TEM images in Fig. 2 demonstrated that the $\\mathrm{In}_2\\mathrm{O}_3$ was present in nanosheets with an average length of $1 - 2\\mu \\mathrm{m}$ and widths of $50 - 100\\mathrm{nm}$ , while the $\\mathrm{g - C_3N_4}$ was present in a lamina structure with uniform porous structure. The 10INCN composite displayed well dispersion of $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets onto the $\\mathrm{g - C_3N_4}$ . From 2Pt-10INCN, we could see very tiny Pt nanoparticles uniformly distributed onto the $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ support. Interestingly, most of Pt nanoparticles were deposited onto the $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets. This could be easily understood since Pt ions would be more easily reduced on the $\\mathrm{In}_2\\mathrm{O}_3$ than on the $\\mathrm{g - C_3N_4}$ owing to the presence of Lewis acid sites which favored the adsorption of $\\mathrm{PtCl_6}^{2 - }$ ions. The HRTEM image further confirmed that the Pt nanoparticles were embedded on the interface between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ in 2Pt-10INCN. Both $\\mathrm{In}_2\\mathrm{O}_3$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,708,442,898]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1 XRD patterns of pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , pure $\\\\mathsf{g - C_3N_4}$ and their corresponding composites with or without Pt-loading. \"]","image_footnote":"[]","img_path":"images/0131/c602f2d412edd7b398e96ae2b4a9a887942c0d3d08960269099a8710b6bbf9d9.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[534,62,653,132]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0735/af6af188aac7f09de653a0ce9dda36300e40f2a7b09ede5ebc41f36c23ea19c0.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[657,62,774,133]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0792/8918e01458196e5dafb52dfe5f8f697e48e6b6032a22bbb23fbe12495006aa13.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[776,62,900,133]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0403/f5d3c38ba1bb6dfd3c28536b79f2c4a32fa959f083fc4213b332d33787f6c382.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[534,134,655,201]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0633/d6b76dea8afd69b179c5f3dc4441706aee2664eb6dc7da4c8ff7a22acce4e10b.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[657,134,776,201]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0894/b880d71277d558051fc4990d5c5039bf620a73c1f9da6b4fe7d53ff1c3d9f329.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[778,134,899,201]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0050/c4928be7b21de52c70d30800e566849704f7044da3389193fec63f5e52f1ac6b.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[534,202,653,270]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0023/a0e902540979b9409c18172e8db1449fbf29b01797d944d91ece179ccd97e5d8.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[657,202,776,270]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0553/4c5a06f3d434dba8d4569ff7122f3bdd9d2ce80402a60011779f83c23e3d60f3.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[778,202,900,269]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2 SEM images of (a) $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , (b) $\\\\mathrm{g - C_3N_4}$ and (c) 10INCN. TEM images of (d) $\\\\mathrm{g - C_3N_4}$ , (e) $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , (f) 10INCN, and (g) 2Pt-10INCN. (h) HRTEM image of 2Pt-10INCN. (i) Mapping images of 2Pt-10INCN. \"]","image_footnote":"[]","img_path":"images/0539/963d2a37aa103b41810e606b878819481806ce798a3457283883b75734dd4915.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[502,351,929,427]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and $\\mathrm{g - C_3N_4}$ were present in well-defined crystals, in good accordance with the XRD patterns. The heterojunction was formed between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ . The mapping images clarified the existence of $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ in 2Pt-10INCN, together with the uniform distribution of Pt nanoparticles. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,428,929,794]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The actual $\\mathrm{In}_2\\mathrm{O}_3$ -contents and Pt-loading in the composite photocatalysts were determined by ICP and expressed in mass percentage (Table S1†), which generally matched with the theoretical contents in the mother solution. All samples displayed type-IV $\\mathrm{N}_2$ adsorption-desorption isotherms with a hysteresis loop of type H3 characteristic of porous structure (Fig. S1†). Based on the $\\mathrm{N}_2$ adsorption-desorption isotherms, the surface area, pore size, and pore volume were calculated (Table S2†). Although the similar pore volume, the $\\mathrm{In}_2\\mathrm{O}_3$ exhibited higher surface area and bigger pore size than the g- $\\mathrm{C}_3\\mathrm{N}_4$ owing to the porous structure constructed layer-by-layer from $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets. The INCN exhibited decreased surface area and pore size due to the incorporation of $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets into the porous g- $\\mathrm{C}_3\\mathrm{N}_4$ , leading to the close package of $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets. The pore volume of INCN greatly increased in comparison with both $\\mathrm{In}_2\\mathrm{O}_3$ and g- $\\mathrm{C}_3\\mathrm{N}_4$ , possibly owing to the formation of new micropores during the co-assembling process of $\\mathrm{In}_2\\mathrm{O}_3$ and g- $\\mathrm{C}_3\\mathrm{N}_4$ . All the Pt-INCN displayed lower surface area and larger pore size as well as smaller pore volume, suggesting most Pt nanoparticles were embedded into the pore channels constructed layer-by-layer from $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets. Some micropores were blocked by those Pt nanoparticles, which could account for the increase of average pore size and abrupt decrease of pore volume. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,795,929,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The XPS spectra in Fig. 3 revealed that all the In species were present in $\\mathrm{In}^{3+}$ state, corresponding to the binding energies (BE) of $445.8\\mathrm{eV}$ and $453.4\\mathrm{eV}$ at In $3\\mathrm{d}_{5/2}$ and $3\\mathrm{d}_{3/2}$ levels.[33] The negative BE shift suggested the strong interaction between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ , in which partial electrons transferred from $\\mathrm{g - C_3N_4}$ to $\\mathrm{In}^{3+}$ due to the d- $\\pi$ feedback. Meanwhile, all the Pt species on $\\mathrm{In}_2\\mathrm{O}_3$ , $\\mathrm{g - C_3N_4}$ , and xINCN exhibited two principal peaks around BE of $71.4\\mathrm{eV}$ and $74.5\\mathrm{eV}$ in Pt $4\\mathrm{f}_{7/2}$ and Pt $4\\mathrm{f}_{5/2}$ energy levels (also see Fig. S2†), indicating they were all present ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[3,114,43,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[68,28,181,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,11,926,20]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[880,28,927,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,962,110,973]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22462 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,962,326,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv, 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[606,962,929,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[137,66,394,323]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0626/11832fb8a107c706a21697a0e3d24bc30bfa079eec2675ca239611452b5354f7.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[391,62,615,322]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0202/b4436a8bb436464687e0dd05ab57ef7b2e181e1de2c0524283acfeb0302726ff.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[616,65,855,322]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0856/f92fb76a5356ec3020d478c5e93382f630c13d36440499158db2b934cb72623a.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[243,329,485,492]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0925/91630235fefb5238cf5b82be39d29bec3fdddca4e81a6233ae347b240eb86dd8.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[502,329,744,491]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3 XPS spectra in (a) C 1s, (b) N 1s, (c) O 1s and (d) In 3d and (e) Pt 4f levels. \"]","image_footnote":"[]","img_path":"images/0458/4568f60b5da8b25e1d5b4a72a8a912ca334f9b7ad0732c18317a2efab3e60a39.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[63,546,492,898]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in the metallic state. $^{34}$ The $\\mathrm{Pt / In_2O_3}$ displayed negative BE shift of Pt and positive BE shift of $\\mathrm{In}^{3+}$ , which further confirmed that most Pt nanoparticles deposited onto $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets, in which partial electrons transferred from $\\mathrm{In}^{3+}$ to Pt owing to the strong metal-support interaction, taking into account of the higher electronegativity of Pt (2.28) than that of $\\mathrm{In}^{3+}$ (1.78). $^{32}$ All the O species were present in $\\mathrm{O}^{2-}$ state. The peak at 531.4 eV was assigned to lattice-oxygen and the peak at 532.5 eV was ascribed to chemisorbed oxygen. $^{35}$ After Pt-loading, the BE of lattice-oxygen showed a negative shift owing to the acceptance of partial electrons from metallic Pt. Besides, the well-dispersed Pt nanoparticles on the $\\mathrm{In}_2\\mathrm{O}_3$ surface promoted the chemisorption of oxygen, leading to the enhanced intensity of the peak around 532.5 eV. $^{36}$ The C species in 10INCN were mainly presented in C-N-C coordination, corresponding to the BE at 288.2 eV in C 1s level. The weak shoulder peak at 284.5 eV was ascribed to the $\\mathfrak{sp}^2$ C-C bond. $^{37}$ The N species displayed various states, corresponding to the different binding energies in the N 1s level. The main signal around 398.6 eV corresponded to the N in C-N-C bond, while the shoulder peak at 400.3 eV was ascribed to the N in the $\\mathrm{N - (C)^3}$ group. $^{38}$ No significant BE shift of either the C or the N was observed, possibly due to the symmetric structure in C-N-C bond. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,899,490,930]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Due to the $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathfrak{g}\\text{-C}_3\\mathrm{N}_4$ are both indirect band semiconductors.39-42 It is reasonable that $(\\alpha h\\nu)^{0.5}$ vs. photon energy ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[500,546,929,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"plot was used to estimate band-gap energy of them. From UV-Vis DRS spectra and their corresponding plots of $(\\alpha h\\nu)^{1 / 2}$ vs. photon energy $(h\\nu)$ (Fig. 4a and S3†), together with the calculated energy bandgaps and light absorbance edge wavelength (Table S3†), we could see that both $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ could be activated by visible lights. The 5INCN displayed a broader adsorption area with an obvious red-shift in comparison with the pure $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ , which could be understood by considering the appearance of some intermediate energy bands owing to the formation of heterojunctions between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ . Further increase in the ratio of $\\mathrm{In}_2\\mathrm{O}_3$ to $\\mathrm{g - C_3N_4}$ (from 5INCN to 20INCN) had no significant influence on the light absorbance edge, suggesting no more heterojunctions formed. Meanwhile, both $\\mathrm{Pt / In_2O_3}$ and $\\mathrm{Pt / g - C_3N_4}$ exhibited red-shift comparing to pure $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ , obviously owing to plasma effect from Pt nanoparticles, which could also account for the red-shift of light absorbance by loading Pt onto INCN. However, the change of Pt-loading from $1\\mathrm{wt}\\%$ to $2\\mathrm{wt}\\%$ had a very limited effect on the light adsorption edge, suggesting the similar size of Pt nanoparticles, and thus, the increased Pt-loading could only enhance the light adsorption intensity. However, 2.5Pt-10INCN displayed a blue-shift of light absorbance wavelength due to the gathering of Pt nanoparticles, which reduced the plasma effect. All the increasing ratio of $\\mathrm{In}_2\\mathrm{O}_3$ to $\\mathrm{g - C_3N_4}$ had almost on effect on the light absorbance ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[3,114,43,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[68,29,115,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,11,927,20]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[816,29,927,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,961,391,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[670,961,873,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[885,961,927,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22463 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[95,62,278,165]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0107/f2273d368a9ef1a2183238806074552a584421beb44560fa7c5d86d39c4efcc3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[282,68,460,169]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0399/2829842ea26b6c0d5d000c2345f22990d7cafb322cb2fd7c1c26a4eaa71d81b7.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,166,273,275]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0895/b6bb49c8d103145d3e6dc9c62f2bad00a1a3e863232cb4f691fafbd30d8388d2.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,165,463,279]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0601/ae0f83e1ae79131ce6be656875d5521335bd6ccde5e54c5b6f8909538141982a.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[203,279,389,390]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4 (a) UV-Vis DRS spectra and their corresponding plots of $(\\\\alpha h\\\\nu)^{1/2}$ vs. photon energy, (b) steady-state PL spectra at $\\\\lambda_{\\\\mathrm{ex}}$ of $350~\\\\mathrm{nm}$ , (c) electrochemical impedances, and (d) photocurrent response spectra obtained under irradiation of a $300~\\\\mathrm{W}$ Xe lamp. \"]","image_footnote":"[]","img_path":"images/0462/c208d4607db00e1731cc906a7bcd93f3b4a7781269a0c869dc450c9759d3adb8.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[63,482,490,559]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"wavelength in INCN, it caused remarkable red-shift in 2Pt-xINCN. This could be ascribed to the enhanced plasma effect from Pt nanoparticles at high-content $\\mathrm{In}_2\\mathrm{O}_3$ since the above TEM images demonstrated that the Pt ions were preferentially reduced and deposited onto $\\mathrm{In}_2\\mathrm{O}_3$ rather than $\\mathrm{g - C_3N_4}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,560,492,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The steady-state PL spectra obtained at an excited wavelength of $350\\mathrm{nm}$ (Fig. 4b and $\\mathrm{S}4\\dagger$ ) displayed an emission peak around $450~\\mathrm{nm}$ indicative of the recombination between photoelectrons and holes. The 10INCN exhibited lower intensity compared to $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ , implying the lowest photoelectron-hole combination rate, which could be attributed to the rapid charge transfer through the $\\mathrm{In}_2\\mathrm{O}_3\\mathrm{-C}_3\\mathrm{N}_4$ heterojunctions. With the increase of the $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{C}_3\\mathrm{N}_4$ ratio up to 10INCN, the PL peak intensity decreased gradually owing to the formation of more $\\mathrm{In}_2\\mathrm{O}_3\\mathrm{-C}_3\\mathrm{N}_4$ heterojunctions, corresponding to the reduced photoelectron-hole combination rate. However, further increase in the $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{C}_3\\mathrm{N}_4$ ratio resulted in the increasing PL peak intensity due to the presence of more free $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets, leading to the enhanced photoelectron-hole combination rate. Loading Pt could greatly decrease the PL peak intensity, corresponding to the efficient inhibition of photoelectron-hole combination, obviously owing to the rapid electron transfer through Pt nanoparticles to separate from holes. The 2Pt-10INCN showed the lowest photoelectron-hole combination rate. This could be further by the electrochemical impedance spectra (Fig. 4c and S5†). The loading of Pt nanoparticles onto $\\mathrm{In}_2\\mathrm{O}_3$ , $\\mathrm{C}_3\\mathrm{N}_4$ , and INCN resulted in a significant decrease of arc radius, corresponding to the reduced electric resistance owing to the excellent electric conductivity of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,60,929,136]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"metallic Pt. The 2Pt-10INCN displayed the smallest arc radius, corresponding to the lowest electric resistance. Further increase in the Pt-loading caused an enlarged arc radius corresponding to the enhanced electric resistance, which could attribute to the gathering of Pt nanoparticles. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,137,929,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The photocurrent response spectra (Fig. 4d and S6†) clearly demonstrated that the INCN exhibited higher photocurrent than either the pure $\\mathrm{In}_2\\mathrm{O}_3$ or the pure $\\mathrm{g - C_3N_4}$ , which could attribute to the enhanced light absorbance and decreased photoelectron-hole recombination rate as discussed above. Increasing the $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ ratio from 5 to $10\\mathrm{wt}\\%$ resulted in the enhanced photocurrent intensity. A possible reason was the rapid electron transfer from $\\mathrm{g - C_3N_4}$ to $\\mathrm{In}_2\\mathrm{O}_3$ since $\\mathrm{In}_2\\mathrm{O}_3$ was present in well-defined crystals with better electric conductivity than $\\mathrm{g - C_3N_4}$ in poor crystallization, which might decrease the photoelectron-hole recombination. Further increasing the $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ ratio to $15\\mathrm{wt}\\%$ caused a decrease in photocurrent intensity due to the presence of more free $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets. Those free $\\mathrm{In}_2\\mathrm{O}_3$ displayed higher photoelectron-hole recombination rate than the $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ nanocomposite due to the absence of heterojunctions (Fig. S4a†).<sup>43</sup> Meanwhile, the Pt-INCN showed a higher photocurrent than the INCN owing to the enhanced light absorbance and decreased photoelectron-hole recombination rate as discussed above. The highest photocurrent was observed on the 2Pt-10INCN, corresponding to the highest light absorbance and the lowest photoelectron-hole recombination rate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,500,699,514]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2 Catalytic performances ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,519,929,749]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Controlled experiments (Fig. S7†) demonstrated that only trace HCOOH and $\\mathrm{CH_4}$ obtained during $\\mathrm{CO}_{2}$ reduction on 2Pt-10INCN without light irradiation or $\\mathrm{CO}_{2}$ , suggesting the $\\mathrm{CO}_{2}$ reduction was mainly driven by photocatalysis. The addition of $\\mathrm{K}_2\\mathrm{Cr}_2\\mathrm{O}_7$ as an electron capture agent resulted in an abrupt decrease in $\\mathrm{CO}_{2}$ conversion efficiency, showing the photoelectrons played a key role in photocatalytic $\\mathrm{CO}_{2}$ reduction. Meanwhile, it was also found that the HCOOH yield greatly decreased without adding TEOA in the reaction system. TEOA was frequently used as a hole capturing agent in photocatalysis,[44] which could consume photo-induced holes from the photocatalyst through its oxidation (see Scheme S1†) and thus could inhibit their recombination with photoelectrons. Therefore, TEOA was a necessary sacrifice agent in the present photocatalytic $\\mathrm{CO}_{2}$ reduction. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,750,929,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Under UV light irradiation, the 2Pt-10INCN exhibited higher HCOOH and $\\mathrm{CH}_4$ yields than that under visible light irradiation (Fig. S8a†) since the UV light could generate more photoelectrons and holes. Taking into account that the sunlight contained only less than $5\\%$ UV lights, we still employed the visible light irradiation for driving the photocatalysis to simulate the natural photosynthesis. The 2Pt-10INCN exhibited extremely high selectivity to HCOOH in photocatalytic $\\mathrm{CO}_{2}$ . Only very little $\\mathrm{CH}_4$ could be obtained and no other side-products were detected. With the increase of reaction time to $4\\mathrm{h}$ , the HCOOH yield increased rapidly and an only slight increase in $\\mathrm{CH}_4$ yield was observed. However, further increase in the reaction time had no ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[3,116,43,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[68,28,181,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,11,927,21]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[880,28,929,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,962,112,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22464 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,962,327,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[606,962,929,975]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[63,59,492,242]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"significant influence on the $\\mathrm{CO}_{2}$ reduction efficiency (Fig. S8b†), indicating the reaction arrived equilibrium point. So, $4\\mathrm{h}$ was used as the reaction time in the following activity tests. Meanwhile, the increase of $\\mathrm{CO}_{2}$ pressure could also greatly promote photocatalytic $\\mathrm{CO}_{2}$ reduction toward HCOOH (see Fig. S8c†). The HCOOH yield could reach up to $736.3~\\mu \\mathrm{mol}~\\mathrm{g}^{-1}~\\mathrm{h}^{-1}$ at $4.0\\mathrm{MPa}$ , which represented a high level in $\\mathrm{CO}_{2}$ conversion in photosynthesis. However, the increasing $\\mathrm{CO}_{2}$ pressure resulted in a rapid increase of the $\\mathrm{CH}_4$ yield (see Fig. S8d†), the high cost, and the difficult operation. Thus, we employed the normal $\\mathrm{CO}_{2}$ pressure (1 atm) in the following tests to meet the requirement of industrial production. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,243,490,336]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 5 demonstrated that both $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ could be activated by visible lights. Although the $\\mathrm{In}_2\\mathrm{O}_3$ contained sufficient Lewis acid sites to absorb $\\mathrm{CO}_{2}$ molecules, it showed very low activity due to its high CB potential $(-0.62\\mathrm{V}$ vs. NHE) which could not efficiently generate H atoms by photocatalytic water splitting. The $\\mathrm{g - C_3N_4}$ was active to produce H atoms ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[107,368,448,545]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0189/ced5b0e89256135182b5561206a9e27011d815e76f56003eac4b51e26eb54d4a.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[115,546,448,709]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0025/0db1cf5d0b45965b854e6f3b80b9ebab6d0e28a8beebc0b24b97b1efd3f8b116.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[107,712,448,885]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5 HCOOH and $\\\\mathsf{CH}_4$ yields on different catalysts. Reaction conditions: Four 3 W LED (420 nm), 1 atm $\\\\mathsf{CO}_2$ , 20 mg catalyst, 10 mL $\\\\mathsf{H}_2\\\\mathsf{O}$ , 1 mL TEOA, $35^{\\\\circ}\\\\mathsf{C}$ , 4 h. \"]","image_footnote":"[]","img_path":"images/0154/9d5e09f89ef0d7204dafef1c555cac2a38575eb9f2772db34596ecc9fe8046a6.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[500,59,929,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"photocatalytic water splitting owing to its low CB potential $(-1.1\\mathrm{V}$ vs. NHE). However, its adsorption for $\\mathrm{CO}_{2}$ molecules was very poor due to the lack of active sites together with the low surface area, leading to the poor activity of photocatalytic $\\mathrm{CO}_{2}$ reduction. The INCN exhibited higher activity than either the $\\mathrm{In}_{2}\\mathrm{O}_{3}$ or $\\mathrm{g - C_3N_4}$ owing to the cooperation between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - }$ $\\mathrm{C_3N_4}$ to adsorb $\\mathrm{CO}_{2}$ molecules and produce H atoms. Meanwhile, the INCN contained narrow energy bandgap owing to the presence of intermediate energy bands and thus could be more easily and effectively activated by visible lights. More importantly, the INCN contained enriched heterojunctions between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ , which facilitated the electron transfer from the CB of $\\mathrm{g - C_3N_4}$ to that of $\\mathrm{In}_2\\mathrm{O}_3$ , leading to the lower photoelectron-hole recombination rate. Although the pure $\\mathrm{In}_2\\mathrm{O}_3$ exhibited very poor activity in photocatalytic $\\mathrm{CO}_{2}$ reduction, the $\\mathrm{Pt / In_2O_3}$ exhibited remarkable enhancement on the activity since the metallic Pt could act as a co-catalyst to produce H atoms by collecting electrons from $\\mathrm{In}_2\\mathrm{O}_3$ semiconductor and plasma during photocatalytic water splitting.[45] More importantly, the $\\mathrm{Pt / In_2O_3}$ displayed much higher selectivity to HCOOH than the pure $\\mathrm{In}_2\\mathrm{O}_3$ , which could be understood based on a plausible reaction pathway in photocatalytic $\\mathrm{CO}_{2}$ reduction (Scheme S1†). The noble-metal Pt was a typical metal catalyst with low work function to activate H atoms while the $\\mathrm{In}_2\\mathrm{O}_3$ could efficiently adsorb $\\mathrm{CO}_{2}$ molecules owing to the presence of enriched Lewis acid sites.[46,47] The Lewis acid sites also enhanced the interaction between Pt and $\\mathrm{In}_2\\mathrm{O}_3$ , which induced the unique bridged co-adsorption model of the $\\mathrm{CO}_{2}$ molecule on Pt and $\\mathrm{In}_2\\mathrm{O}_3$ . Such co-adsorbed $\\mathrm{CO}_{2}$ molecules favored the reaction with active H atoms to HCOO*,[48-50] which was a key intermediate in determining the selectivity to HCOOH.[16] Besides, the metallic Pt nanoparticles also promoted the activation of $\\mathrm{In}_2\\mathrm{O}_3$ by visible lights owing to the plasma effect and facilitated the electron transfer to diminish photoelectron-hole recombination, which could further promote the photocatalytic $\\mathrm{CO}_{2}$ reduction. Similarly, the $\\mathrm{Pt / g - C_3N_4}$ also exhibited higher activity and selectivity than the $\\mathrm{g - C_3N_4}$ , which could also be explained based on the above discussions. It was noted that the Pt-loading exhibited much weaker promoting effect on the HCOOH production in $\\mathrm{g - C_3N_4}$ than that in $\\mathrm{In}_2\\mathrm{O}_3$ . A possible reason was that the $\\mathrm{g - C_3N_4}$ could not effectively adsorb $\\mathrm{CO}_{2}$ molecules due to the absence of Lewis acid sites. Although the presence of Pt could greatly enhance the production of H atoms, no enough adsorbed $\\mathrm{CO}_{2}$ molecules could be activated and subsequently reacted with those H atoms. Meanwhile, the $\\mathrm{Pt / g - C_3N_4}$ displayed poor interaction between Pt and $\\mathrm{g - C_3N_4}$ due to the absence of Lewis acid sites, leading to the low number of bridge-coadsorbed $\\mathrm{CO}_{2}$ molecules on both Pt and $\\mathrm{g - C_3N_4}$ , which could account for the lower selectivity to HCOOH in comparison with the $\\mathrm{Pt / In_2O_3}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,827,929,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As expected, the Pt-loading onto INCN also greatly enhanced the activity and selectivity in photocatalytic $\\mathrm{CO}_{2}$ reduction, which could also be accounted by considering various Pt-functions discussed above. Interestingly, the Pt-INCN exhibited a much stronger promoting effect than either the $\\mathrm{Pt / In_2O_3}$ or $\\mathrm{Pt / g - C_3N_4}$ possibly owing to the enhanced role of heterojunctions. The presence of metallic Pt nanoparticles facilitated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[1,114,45,629]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[67,28,115,42]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,11,926,21]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[816,28,927,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,961,391,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[670,961,873,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[885,961,927,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22465 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[107,61,447,231]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0354/cdeab22338f6a3619b8897fea0785bd3d3e748b6d022612069717de4ea34943b.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[107,232,447,396]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0750/d00ec578afa0ccf80f5a7302ab1a496b7ab6b7f304ff2fbb6d8dbddc63b8cf38.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[107,397,447,564]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 6 Recycling test of $2\\\\mathrm{Pt - In_2O_3}$ , $2\\\\mathrm{Pt - g - C_3N_4}$ and $2\\\\mathrm{Pt - 10INCN}$ . Reaction conditions are given in Fig. 5. \"]","image_footnote":"[]","img_path":"images/0471/ec616bcd17026bc80bb504a87aa10422a4d1c2e119488c80d433b6f74cc4f893.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[68,634,489,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"electron-transfer from $\\mathrm{In}_2\\mathrm{O}_3$ to $\\mathrm{g - C_3N_4}$ and hole-transfer from $\\mathrm{g - }$ $\\mathrm{C_3N_4}$ to $\\mathrm{In}_2\\mathrm{O}_3$ , which could greatly diminish photoelectron-hole recombination (see Scheme S1†). By fixing the Pt-loading at $2\\mathrm{wt}\\%$ , the Pt-INCN showed a rapid increase in HCOOH yield while only very slight increase in $\\mathrm{CH}_4$ yield with the increasing ratio of $\\mathrm{In}_2\\mathrm{O}_3 / \\mathrm{g - C_3N_4}$ up to $10\\mathrm{wt}\\%$ . This could be ascribed to the enhanced adsorption of $\\mathrm{CO}_{2}$ molecules by $\\mathrm{In}_2\\mathrm{O}_3$ . Besides, the increase of heterojunctions played a key role in promoting the photocatalytic $\\mathrm{CO}_{2}$ reduction by inhibiting photoelectron-hole recombination. However, further increase of the $\\mathrm{In}_2\\mathrm{O}_3$ content caused slight decrease in the HCOOH yield due to the appearance of free $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets. Such a free $\\mathrm{In}_2\\mathrm{O}_3$ displayed higher photoelectron-hole recombination rate than the $\\mathrm{In}_2\\mathrm{O}_3/$ $\\mathrm{g - C_3N_4}$ nanocomposite due to the absence of heterojunctions.51 In addition, since the $\\mathrm{In}_2\\mathrm{O}_3$ favored the photocatalytic reduction of $\\mathrm{PtCl_6}^{2 + }$ , some of Pt nanoparticles would deposit onto the free $\\mathrm{In}_2\\mathrm{O}_3$ nanosheets, leading to the reduced promoting effect on the role of heterojunctions between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,60,927,319]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"By fixing the $\\mathrm{In}_2\\mathrm{O}_3$ -content at $10~\\mathrm{wt}\\%$ ,the Pt-10INCN exhibited increasing HCOOH yield and $\\mathrm{CH_4}$ yield with the increase of Pt-loading up to $2\\mathrm{wt}\\%$ since more Pt nanoparticles would enhance the plasma effect, the activity for activating H atoms and $\\mathrm{CO}_{2}$ molecules, the electron transfer ability to inhibit photoelectron-hole recombination. However, further increase in the Pt-loading caused slight decrease in either the HCOOH yield or the $\\mathrm{CH_4}$ yield due to the gathering of Pt nanoparticles to reduce above promoting effects. Besides, the large Pt nanoparticles may also block the pore channels, leading to an abrupt decrease in surface area (see Table S2). The 2Pt-10INCN exhibited the highest HCOOH yield $(63.1\\mu \\mathrm{mol}g^{-1}\\mathrm{h}^{-1})$ at the normal pressure of $\\mathrm{CO}_{2}$ and room temperature. In addition, the 2Pt-10INCN exhibited much higher activity than the 2Pt10INCN-mix obtained by mechanical mixing $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ see Fig.S7),obviously due to the absence of heterojunctions and the synergetic effect between $\\mathrm{In}_2\\mathrm{O}_3$ and $\\mathrm{g - C_3N_4}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,320,927,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The lifetime is also a key parameter to determine the practical application of a photocatalyst. As shown in Fig. 6, both $2\\mathrm{Pt}-10\\mathrm{INCN}$ and $2\\mathrm{Pt}-\\mathrm{In}_2\\mathrm{O}_3$ could be used repetitively for more than 5 times without a significant decrease in their activities. The slight decrease might be caused by the loss of photocatalysts during separation and wash processes. However, the $2\\mathrm{Pt}-\\mathrm{g}-\\mathrm{C}_3\\mathrm{N}_4$ showed a rapid decrease in photocatalytic activity during the recycling test. The XRD patterns (Fig. S9†) revealed that, similar to $2\\mathrm{Pt}-\\mathrm{In}_2\\mathrm{O}_3$ and $2\\mathrm{Pt}-\\mathrm{g}-\\mathrm{C}_3\\mathrm{N}_4$ , no significant change in the structure of $2\\mathrm{Pt}-10\\mathrm{INCN}$ was observed, indicating the excellent stability during the reaction process. Meanwhile, ICP analysis demonstrated no significant Pt leaching occurred on either $2\\mathrm{Pt}-10\\mathrm{INCN}$ or $2\\mathrm{Pt}-\\mathrm{In}_2\\mathrm{O}_3$ occurred during the reaction, which could be attributed to the strong adsorption of Pt nanoparticles onto $\\mathrm{In}_2\\mathrm{O}_3$ owing to the presence of Lewis acid sites. However, the $2\\mathrm{Pt}-\\mathrm{g}-\\mathrm{C}_3\\mathrm{N}_4$ showed Pt leaching during the reaction process, leading to a decrease in photocatalytic activity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,622,684,637]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,650,927,848]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We developed a $\\mathrm{Pt / In_2O_3 / g - C_3N_4}$ multifunctional catalyst by controlling the assembling method. This catalyst exhibited high activity and selectivity to HCOOH during visible-light-driven photocatalytic $\\mathrm{CO}_{2}$ reduction owing to the synergetic effects in producing H atoms via water splitting, adsorbing/activating $\\mathrm{CO}_{2}$ molecules, and inhibiting photoelectron-hole recombination by accelerating electron transfer and forming heterojunctions. Besides, it also displayed a long lifetime owing to the high structural stability and the strong interaction to inhibit Pt leaching. This work supplied a promising way for designing new catalysts with multiple functions for photocatalytic $\\mathrm{CO}_{2}$ reduction at normal pressure and room temperature with a high yield of target products. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,890,722,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflicts of interest ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,920,727,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There are no conflicts to declare. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[1,114,45,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n© CC BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[70,29,179,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,12,926,20]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[882,29,927,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,962,110,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22466 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,962,326,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[606,962,927,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[67,61,284,82]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,91,490,152]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was supported by NSFC (21761142011, 51572174) and Shanghai Government (18JC1412900, 19YF1436600, 19160712900, 17SG44) as well as Shanghai Engineering Research Center of Green Energy Chemical Engineering. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,166,191,184]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,197,490,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1 K. Shimomaki, K. Murata, R. Martin and N. Iwasawa, J. Am. Chem. Soc., 2017, 139, 9467-9470. \",\"2 S. Zhang, W.-Q. Chen, A. Yu and L.-N. He, ChemCatChem, 2015, 7, 3972-3977. \",\"3 P. Riani, G. Garbarino, M. A. Lucchini, F. Canepa and G. Busca, J. Mol. Catal. A: Chem., 2014, 383-384, 10-16. \",\"4 P. Zhu, Q. Chen, Y. Yoneyama and N. Tsubaki, RSC Adv., 2014, 4, 64617-64624. \",\"5 S. Zhang, P. Kang and T. J. Meyer, J. Am. Chem. Soc., 2014, 136, 1734-1737. \",\"6 J. Shen, R. Kortlever, R. 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Kulak and P. Pichat, J. Photochem. Photobiol., A, 2004, 162, 423-430. \",\"50 M. Tasbihi, F. Fresno, U. Simon, I. J. Villar-Garcia, V. Pérez-Dieste, C. Escudero and V. A. de la Peña O'Shea, Appl. Catal., B, 2018, 239, 68-76. \",\"51 Y.-C. Chen, Y.-C. Pu and Y.-J. Hsu, J. Phys. Chem. C, 2012, 116, 2967-2975. \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[3,114,43,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[67,28,115,42]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[831,11,927,21]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View Article Online ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[816,28,927,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Advances ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,962,391,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This journal is © The Royal Society of Chemistry 2020 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[670,962,873,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RSC Adv., 2020, 10, 22460-22467 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[885,962,927,973]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22467 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[84,120,169,139]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PAPER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[754,116,899,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[756,133,884,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n 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\"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,207,260,220]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cite this: RSC Adv., 2020, 10, 22460 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[285,168,929,216]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Selective $\\\\mathrm{CO}_{2}$ reduction to HCOOH on a $\\\\mathrm{Pt} / \\\\mathrm{In}_{2} \\\\mathrm{O}_{3} /$ g- $\\\\mathrm{C}_{3} \\\\mathrm{~N}_{4}$ multifunctional visible-photocatalyst† \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[285,225,677,243]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Jiehong He, Pin Lv, Jian Zhu* and Hexing Li \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[282,256,931,455]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Selective photocatalytic reduction of $\\\\mathrm{CO}_{2}$ has been regarded as one of the most amazing ways for re-using $\\\\mathrm{CO}_{2}$ . However, its application is still limited by the low $\\\\mathrm{CO}_{2}$ conversion efficiency. This work developed a novel $\\\\mathrm{Pt} / \\\\mathrm{In}_{2}\\\\mathrm{O}_{3} / \\\\mathrm{g} - \\\\mathrm{C}_{3}\\\\mathrm{N}_{4}$ multifunctional catalyst, which exhibited high activity and selectivity to HCOOH during photocatalytic $\\\\mathrm{CO}_{2}$ reduction under visible light irradiation owing to the synergistic effect between photocatalyst, thermocatalyst, and heterojunctions. Both $\\\\mathrm{In}_{2}\\\\mathrm{O}_{3}$ and $\\\\mathrm{g} - \\\\mathrm{C}_{3}\\\\mathrm{N}_{4}$ acted as visible photocatalysts, in which porous $\\\\mathrm{g} - \\\\mathrm{C}_{3}\\\\mathrm{N}_{4}$ facilitated $\\\\mathrm{H}_{2}$ production from water splitting while the $\\\\mathrm{In}_{2}\\\\mathrm{O}_{3}$ nanosheets embedded in $\\\\mathrm{g} - \\\\mathrm{C}_{3}\\\\mathrm{N}_{4}$ pores favored $\\\\mathrm{CO}_{2}$ fixation and H adsorption onto the Lewis acid sites. Besides, the $\\\\mathrm{In}_{2}\\\\mathrm{O}_{3} / \\\\mathrm{g} - \\\\mathrm{C}_{3}\\\\mathrm{N}_{4}$ heterojunctions could efficiently inhibit the photoelectron-hole recombination, leading to enhanced quantum efficiency. The Pt could act as a co-catalyst in $\\\\mathrm{H}_{2}$ production from photocatalytic water splitting and also accelerated electron transfer to inhibit electron-hole recombination and generated a plasma effect. More importantly, the Pt could activate H atoms and $\\\\mathrm{CO}_{2}$ molecules toward the formation of HCOOH. At normal pressure and room temperature, the TON of HCOOH in $\\\\mathrm{CO}_{2}$ conversion was $63.1\\\\mu \\\\mathrm{mol} g^{-1} h^{-1}$ and could reach up to $736.3\\\\mu \\\\mathrm{mol} g^{-1} h^{-1}$ at 40 atm. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,390,206,401]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received 2nd May 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,401,211,412]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted 2nd June 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,421,216,433]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DOI: 10.1039/d0ra03959d \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,442,169,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"rsc.li/rsc-advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,481,247,499]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,510,492,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{CO}_{2}$ conversion has attracted increasing interest owing to the consideration to both reduce the green-house effect and recycle carbon resources. The key problem is the $\\\\mathrm{CO}_{2}$ fixation and activation steps, which play a critical role in determining the activity and selectivity. $^{1,2}$ Previously, $\\\\mathrm{CO}_{2}$ reduction was mainly driven by metal thermocatalysts, $^{3-6}$ but it was usually performed at high temperature due to the highly stable $\\\\mathrm{CO}_{2}$ molecule. Electrocatalytic $\\\\mathrm{CO}_{2}$ reduction has also been reported, but additional energy is needed and the special reactor limits large scale-production. $^{5,6}$ Photocatalytic $\\\\mathrm{CO}_{2}$ reduction represents a promising way for $\\\\mathrm{CO}_{2}$ conversion due to it being an energy saving and green process, which uses mild conditions, and has long durability. $^{7-10}$ However, the photocatalytic efficiency is still very low because of the poor $\\\\mathrm{CO}_{2}$ adsorption/activation ability and the easy photoelectron-hole recombination. $^{11,12}$ Moreover, such a reaction usually displays low selectivity with the formation of various products like methane, methanol, formaldehyde, formic acid, etc. $\\\\mathrm{TiO}_{2}$ has been frequently employed as in photocatalysis owing to its environmental friendship, easy availability, high activity, and excellent stability. $^{13}$ However, $\\\\mathrm{TiO}_{2}$ can only be activated by UV lights due to its large bandgap \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,854,490,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Education Ministry Key and International Joint Lab of Resource Chemistry, Shanghai Key Laboratory of Rare Earth Functional Materials, Department of Chemistry, Shanghai Normal University, Shanghai 200234, China. E-mail: hexing-li@shnu.edu.cn; jianzhu@shnu.edu.cn; Fax: +86 21 64322272; Tel: +86 21 64322272 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,908,490,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra03959d \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,478,931,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(3.2 eV) and thus cannot sufficiently make use of sunlight. $^{14}$ In addition, the radical reaction steps disfavor the selectivity toward the target product. $\\\\mathrm{In}_2\\\\mathrm{O}_3$ can be activated by visible light and also can easily adsorb/activate $\\\\mathrm{CO}_{2}$ molecules via Lewis acid sites, which greatly benefits the photocatalytic $\\\\mathrm{CO}_{2}$ reduction toward HCOOH. $^{15,16}$ But, pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ exhibits poor activity to generate H atoms through photocatalytic water splitting. The $\\\\mathrm{g - C_3N_4}$ is a typical visible photocatalyst for efficient water splitting, $^{17}$ but could effectively adsorb and activate $\\\\mathrm{CO}_{2}$ molecules. In addition, both $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ exhibit low activities due to the rapid combination between photoelectrons and holes. $^{18}$ Construction of heterojunction structures is frequently used in designing photocatalysts with the low photoelectron-hole recombination rate and the high photocatalytic activity in pollutant-degradation, water splitting, and $\\\\mathrm{CO}_{2}$ reduction. $^{19,20}$ Many efforts have been devoted to improving the photocatalytic $\\\\mathrm{CO}_{2}$ reduction efficiency. $^{21-24}$ Obviously, the combination of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ could mainly overcome their individual shortcomings in photocatalytic $\\\\mathrm{CO}_{2}$ reduction. More importantly, the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ displays energy level matching well with the $\\\\mathrm{g - C_3N_4}$ . Thus, $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ heterojunctions can be easily established, which can promote the photoelectron-hole separation to diminish photoelectron-hole recombination, leading to the high quantum efficiency in photocatalysis, which has applied into $\\\\mathrm{H}_{2}$ evolution, $\\\\mathrm{CO}_{2}$ reduction and pollutants degradation. Cao et al. reported an $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ with enhanced activity in photocatalytic $\\\\mathrm{H}_{2}$ evolution and $\\\\mathrm{CO}_{2}$ reduction owing to the heterojunctions between $\\\\mathrm{g - C_3N_4}$ and $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , which promoted the transfer of photo-generated electrons and thus decreased the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[3,114,47,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n© CC BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[67,66,300,91]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[687,29,929,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ROYAL SOCIETY OF CHEMISTRY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,962,112,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22460 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,962,329,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[606,962,929,975]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[63,59,492,182]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"photoelectron-hole recombination. $^{25}$ Non-noble metal like B and S has also been induced in $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C}_3\\\\mathrm{N}_4$ to promote photocatalytic efficiency. $^{26,27}$ Besides, noble metals like Pt and Pd have been widely applied in catalytic $\\\\mathrm{CO}_{2}$ reduction with high activity and selectivity. $^{28,29}$ Meanwhile, they could also be used as co-catalysts in photocatalysis to facilitate electron transfer owing to the excellent electric conductivity $^{30,31}$ and to activate reactant molecules owing to the low work function. $^{32}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,183,492,367]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Herein, we reported for the first time a $\\\\mathrm{Pt / In_2O_3 / g - C_3N_4}$ nanocomposite and used as a multifunctional catalyst in photocatalytic $\\\\mathrm{CO}_{2}$ reduction under visible light irradiation. The $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C}_3\\\\mathrm{N}_4$ was prepared via a solvothermal route, while Pt was loaded through a photo-reduced method. The unique structural assemble and the strong interaction between nanoparticle Pt, nanosheet $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , and porous $\\\\mathrm{g - C_3N_4}$ . As a result, the $\\\\mathrm{Pt / In_2O_3 / g - C_3N_4}$ exhibited high activity and selectivity to HCOOH owing to the synergetic effects. The $\\\\mathrm{CO}_{2}$ conversion TON reached up to $736.3~\\\\mu \\\\mathrm{mol}~\\\\mathrm{g}^{-1}~\\\\mathrm{h}^{-1}$ at 40 atm and the catalyst exhibited excellent durability, showing good potential in the practical application. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,383,257,401]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Experimental \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,408,238,423]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1 Sample preparation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,428,492,596]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{In}_2\\\\mathrm{O}_3$ was prepared through a hydrothermal method. In a typical run of synthesis, 6 mmol $\\\\mathrm{In(NO_3)_3}$ (Aladdin) was added into a $40~\\\\mathrm{mL}$ aqueous solution, followed by stirring for $10\\\\mathrm{min}$ to get a clear solution. Then, $24\\\\mathrm{mmol}$ urea (Aladdin) was added and the solution was continuously stirred for $2\\\\textrm{h}$ at room temperature. Subsequently, the solution was transferred into a $50~\\\\mathrm{mL}$ Teflon lined autoclave and was kept at $140^{\\\\circ}\\\\mathrm{C}$ for $16\\\\mathrm{h}$ . The obtained solid product was washed thoroughly by water and ethanol, followed by drying at $60^{\\\\circ}\\\\mathrm{C}$ for $12\\\\mathrm{h}$ . Finally, it was calcined at $450^{\\\\circ}\\\\mathrm{C}$ for $2\\\\textrm{h}$ to improve the crystallization degree of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and remove impurities. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,596,492,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{g - C_3N_4}$ was prepared by calcination of melamine (Aladdin) in a special reactor at $500^{\\\\circ}\\\\mathrm{C}$ for $2\\\\mathrm{h}$ , followed by calcining at $520^{\\\\circ}\\\\mathrm{C}$ for another $2\\\\mathrm{h}$ until the formation of faint yellow powder. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,643,494,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For preparing $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C}_3\\\\mathrm{N}_4$ , a certain amount of $\\\\mathrm{g - C_3N_4}$ was dispersed into $20~\\\\mathrm{mL}$ aqueous solution containing a certain amount of urea and was stirred for $2\\\\textrm{h}$ at room temperature. Meanwhile, a certain amount of indium nitrate was added to another $20~\\\\mathrm{mL}$ aqueous solution and was stirred until transparent. Then, the solution containing $\\\\mathrm{In(NO_3)_3}$ was carefully added into the solution containing $\\\\mathrm{g - C_3N_4}$ and urea. After being stirred for $2\\\\textrm{h}$ , the mixed solution was transferred into a $50~\\\\mathrm{mL}$ Teflon lined autoclave and kept at $140^{\\\\circ}\\\\mathrm{C}$ for $16\\\\mathrm{h}$ . The obtained solid product was washed by water and ethanol, followed by drying at $60^{\\\\circ}\\\\mathrm{C}$ for $12\\\\mathrm{h}$ , and finally, calcining at $450^{\\\\circ}\\\\mathrm{C}$ for $2\\\\mathrm{h}$ in argon atmosphere. The as-received sample was donated as xINCN, where $x$ refers to the theoretical mass ratio of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ to $\\\\mathrm{g - C_3N_4}$ , which is adjusted by the added amount of $\\\\mathrm{g - C_3N_4}$ in mother solution. For comparison, the mechanical mixture of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ was also prepared and was designated as INCN-mix. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,903,492,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Pt-deposited photocatalysts were prepared by photoreduction of Pt ions. Briefly, $100\\\\mathrm{mg}$ xINCN was dispersed in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,59,931,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$10~\\\\mathrm{mL}$ ultra-pure water containing the desired amount of chloroplatinic acid and $1\\\\mathrm{mL}$ TEOA (Aladdin). Then, the solution was irradiated with LED lamps for $30\\\\mathrm{min}$ . After separation, the solid product was washed thoroughly with $\\\\mathrm{H}_2\\\\mathrm{O}$ and ethyl alcohol, followed by drying at $60^{\\\\circ}\\\\mathrm{C}$ for $8\\\\mathrm{h}$ . The as-received sample was marked as $y\\\\mathrm{Pt - xINCN}$ , where $y$ is theoretical mass ratio of Pt to $x\\\\mathrm{INCN}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,184,655,198]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2 Characterization \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,205,931,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The real contents of different components in composites were determined by using Inductive Coupled Plasma Emission Spectrometer (ICP, a Jarrel-Asm Atom Scan 2000). The $\\\\mathrm{N}_2$ adsorption-desorption isotherms were obtained at $77\\\\mathrm{K}$ using a Micromeritics ASAP 2010 instrument in which the specific surface area $(S_{\\\\mathrm{BET}})$ and pore volume $(V_{\\\\mathrm{p}})$ were calculated by applying Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH) models. X-ray diffraction (XRD) patterns were recorded on a Bruker D8 Advance X-ray diffractometer with CuK radiation at a scan rate of $0.02^{\\\\circ}\\\\mathrm{s}^{-1}$ . The morphologies were measured on a field emission scanning electronic micrograph (FESEM, JEOL JSM-6380LV) and transmission electronic micrograph (TEM, JEM-2010). Energy-dispersive X-ray spectroscopy (EDS) was also performed by the JSM. The surface electronic states were investigated by X-ray photoelectron spectroscopy (XPS; ULVAC-PHI PHI5000 VersaProbe using Al Kα radiation). UV-Vis diffuse reflection spectra (DRS) were obtained on a Shimadzu UV-2450 Spectrophotometer using $\\\\mathrm{BaSO_4}$ as a reference. The steady-state photoluminescence (PL) spectra were obtained by a Varian Cary-Eclipse 500 fluorometer at an excitation wavelength of $350\\\\mathrm{nm}$ . Photocurrents were measured using an electrochemical analyzer (CHI660D Instruments) containing a standard three-electrode system in $0.5\\\\mathrm{MNa_2SO_4}$ aqueous solution as the electrolyte. The as-prepared sample was used as a working electrode with an active area of $20\\\\times 20\\\\mathrm{mm}^2$ . The sample was prepared by traditional technology. First, $2\\\\mathrm{mg}$ PVDF was added into $2\\\\mathrm{mL}$ DMF solution under ultrasonic condition. Then, $20\\\\mathrm{mg}$ catalyst was added. The suspension was obtained and treated by ultrasound for another $5\\\\mathrm{min}$ , followed by dropping onto a FTO piece $(20\\\\times 20\\\\mathrm{mm}^2)$ , vacuum drying at $80^{\\\\circ}\\\\mathrm{C}$ for $8\\\\mathrm{h}$ , and calcination at $150^{\\\\circ}\\\\mathrm{C}$ for $1\\\\mathrm{h}$ . A Pt piece with an area of $20\\\\times 20\\\\mathrm{mm}^2$ was used as a counter electrode and a saturated calomel electrode was used as a reference electrode. Each run of the measurements was performed by irradiating with a $300\\\\mathrm{W}$ Xe lamp for $30\\\\mathrm{s}$ at an interval of $30\\\\mathrm{s}$ . Electrochemical impedance spectra (EIS) were obtained under the open-circuit potential condition, with an amplitude of $10\\\\mathrm{mV}$ and frequency span from $10\\\\mathrm{kHz}$ to $0.01\\\\mathrm{Hz}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,807,623,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.3 Activity test \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,826,929,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The photocatalytic $\\\\mathrm{CO}_{2}$ reduction was performed in a self-made $50~\\\\mathrm{mL}$ quartz reactor. Before reaction, $20~\\\\mathrm{mg}$ catalyst was dispersed in $10~\\\\mathrm{mL}$ ultra-pure water under ultrasonication for $30\\\\mathrm{min}$ . Then, $1\\\\mathrm{mL}$ TEOA (Aladdin) was introduced as a sacrificial agent. The suspension was transferred onto a $50~\\\\mathrm{mL}$ quartz reactor with two vents. High purity $\\\\mathrm{CO}_{2}$ $(99.99\\\\%)$ was introduced into the reactor and bubbled for $0.5\\\\mathrm{h}$ to evacuate \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[1,114,45,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n© CC BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[67,29,115,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,11,926,20]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[816,28,927,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,961,391,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[672,961,878,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[887,961,927,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22461 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[63,59,492,213]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the air inside the reactor. Then, the reactor was sealed and filled with $\\\\mathrm{CO}_{2}$ to 1 atm. For each run of reactions, the reaction system was irradiated for $4\\\\mathrm{h}$ by four 3 W LED lights with the wavelength of $420~\\\\mathrm{nm}$ at a constant temperature of $35^{\\\\circ}\\\\mathrm{C}$ and stirring rate of $800~\\\\mathrm{rpm}$ . The gas products were analyzed by a gas chromatography equipped by HP-PLOT Q column connected with the FID detector and TDX-01 connected with TCD detector. The liquid products were detected by ion chromatography (Dionex DX-320) with an analytical column (Dionex IonPac AS19-4 $\\\\mu$ m Analytical Column). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,229,357,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results and discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,255,273,268]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1 Structural characteristics \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,275,490,458]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As shown in Fig. 1, the XRD patterns revealed that all the samples were present in well crystalline states of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ . The pure $\\\\mathrm{g - C_3N_4}$ displayed two peaks around $13.1^{\\\\circ}$ and $27.4^{\\\\circ}$ characteristic of (100) and (002) facets. The $\\\\mathrm{In}_2\\\\mathrm{O}_3$ was present in cubic structure (JCPDS card no. 06-0416) with the characteristic peaks at $30^{\\\\circ}$ , $35^{\\\\circ}$ , $51^{\\\\circ}$ , and $60^{\\\\circ}$ , corresponding (111), (100), (110), (622) facets, respectively. All the $\\\\mathrm{Pt / In_2O_3 / g - }$ $\\\\mathrm{C_3N_4}$ showed typical peaks indicative of individual $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - }$ $\\\\mathrm{C_3N_4}$ , indicating no chemical bonding formed between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ . No significant diffraction peaks indicative of Pt were observed in $\\\\mathrm{Pt / In_2O_3}$ , $\\\\mathrm{Pt / g - C_3N_4}$ , or Pt-INCN owing to the low Pt-loading with high dispersion of Pt nanoparticles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,459,492,673]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The SEM and TEM images in Fig. 2 demonstrated that the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ was present in nanosheets with an average length of $1 - 2\\\\mu \\\\mathrm{m}$ and widths of $50 - 100\\\\mathrm{nm}$ , while the $\\\\mathrm{g - C_3N_4}$ was present in a lamina structure with uniform porous structure. The 10INCN composite displayed well dispersion of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets onto the $\\\\mathrm{g - C_3N_4}$ . From 2Pt-10INCN, we could see very tiny Pt nanoparticles uniformly distributed onto the $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ support. Interestingly, most of Pt nanoparticles were deposited onto the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets. This could be easily understood since Pt ions would be more easily reduced on the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ than on the $\\\\mathrm{g - C_3N_4}$ owing to the presence of Lewis acid sites which favored the adsorption of $\\\\mathrm{PtCl_6}^{2 - }$ ions. The HRTEM image further confirmed that the Pt nanoparticles were embedded on the interface between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ in 2Pt-10INCN. Both $\\\\mathrm{In}_2\\\\mathrm{O}_3$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,708,442,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1 XRD patterns of pure $\\\\\\\\mathrm{In}_2\\\\\\\\mathrm{O}_3$ , pure $\\\\\\\\mathsf{g - C_3N_4}$ and their corresponding composites with or without Pt-loading. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0131/c602f2d412edd7b398e96ae2b4a9a887942c0d3d08960269099a8710b6bbf9d9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[534,62,653,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0735/af6af188aac7f09de653a0ce9dda36300e40f2a7b09ede5ebc41f36c23ea19c0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[657,62,774,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0792/8918e01458196e5dafb52dfe5f8f697e48e6b6032a22bbb23fbe12495006aa13.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[776,62,900,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0403/f5d3c38ba1bb6dfd3c28536b79f2c4a32fa959f083fc4213b332d33787f6c382.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[534,134,655,201]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0633/d6b76dea8afd69b179c5f3dc4441706aee2664eb6dc7da4c8ff7a22acce4e10b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[657,134,776,201]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0894/b880d71277d558051fc4990d5c5039bf620a73c1f9da6b4fe7d53ff1c3d9f329.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[778,134,899,201]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0050/c4928be7b21de52c70d30800e566849704f7044da3389193fec63f5e52f1ac6b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[534,202,653,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0023/a0e902540979b9409c18172e8db1449fbf29b01797d944d91ece179ccd97e5d8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[657,202,776,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0553/4c5a06f3d434dba8d4569ff7122f3bdd9d2ce80402a60011779f83c23e3d60f3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[778,202,900,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2 SEM images of (a) $\\\\\\\\mathrm{In}_2\\\\\\\\mathrm{O}_3$ , (b) $\\\\\\\\mathrm{g - C_3N_4}$ and (c) 10INCN. TEM images of (d) $\\\\\\\\mathrm{g - C_3N_4}$ , (e) $\\\\\\\\mathrm{In}_2\\\\\\\\mathrm{O}_3$ , (f) 10INCN, and (g) 2Pt-10INCN. (h) HRTEM image of 2Pt-10INCN. (i) Mapping images of 2Pt-10INCN. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0539/963d2a37aa103b41810e606b878819481806ce798a3457283883b75734dd4915.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[502,351,929,427]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and $\\\\mathrm{g - C_3N_4}$ were present in well-defined crystals, in good accordance with the XRD patterns. The heterojunction was formed between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ . The mapping images clarified the existence of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ in 2Pt-10INCN, together with the uniform distribution of Pt nanoparticles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,428,929,794]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The actual $\\\\mathrm{In}_2\\\\mathrm{O}_3$ -contents and Pt-loading in the composite photocatalysts were determined by ICP and expressed in mass percentage (Table S1†), which generally matched with the theoretical contents in the mother solution. All samples displayed type-IV $\\\\mathrm{N}_2$ adsorption-desorption isotherms with a hysteresis loop of type H3 characteristic of porous structure (Fig. S1†). Based on the $\\\\mathrm{N}_2$ adsorption-desorption isotherms, the surface area, pore size, and pore volume were calculated (Table S2†). Although the similar pore volume, the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ exhibited higher surface area and bigger pore size than the g- $\\\\mathrm{C}_3\\\\mathrm{N}_4$ owing to the porous structure constructed layer-by-layer from $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets. The INCN exhibited decreased surface area and pore size due to the incorporation of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets into the porous g- $\\\\mathrm{C}_3\\\\mathrm{N}_4$ , leading to the close package of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets. The pore volume of INCN greatly increased in comparison with both $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and g- $\\\\mathrm{C}_3\\\\mathrm{N}_4$ , possibly owing to the formation of new micropores during the co-assembling process of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and g- $\\\\mathrm{C}_3\\\\mathrm{N}_4$ . All the Pt-INCN displayed lower surface area and larger pore size as well as smaller pore volume, suggesting most Pt nanoparticles were embedded into the pore channels constructed layer-by-layer from $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets. Some micropores were blocked by those Pt nanoparticles, which could account for the increase of average pore size and abrupt decrease of pore volume. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,795,929,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The XPS spectra in Fig. 3 revealed that all the In species were present in $\\\\mathrm{In}^{3+}$ state, corresponding to the binding energies (BE) of $445.8\\\\mathrm{eV}$ and $453.4\\\\mathrm{eV}$ at In $3\\\\mathrm{d}_{5/2}$ and $3\\\\mathrm{d}_{3/2}$ levels.[33] The negative BE shift suggested the strong interaction between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ , in which partial electrons transferred from $\\\\mathrm{g - C_3N_4}$ to $\\\\mathrm{In}^{3+}$ due to the d- $\\\\pi$ feedback. Meanwhile, all the Pt species on $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , $\\\\mathrm{g - C_3N_4}$ , and xINCN exhibited two principal peaks around BE of $71.4\\\\mathrm{eV}$ and $74.5\\\\mathrm{eV}$ in Pt $4\\\\mathrm{f}_{7/2}$ and Pt $4\\\\mathrm{f}_{5/2}$ energy levels (also see Fig. S2†), indicating they were all present \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[3,114,43,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[68,28,181,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,11,926,20]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[880,28,927,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,962,110,973]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22462 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,962,326,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv, 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[606,962,929,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[137,66,394,323]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0626/11832fb8a107c706a21697a0e3d24bc30bfa079eec2675ca239611452b5354f7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[391,62,615,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0202/b4436a8bb436464687e0dd05ab57ef7b2e181e1de2c0524283acfeb0302726ff.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[616,65,855,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0856/f92fb76a5356ec3020d478c5e93382f630c13d36440499158db2b934cb72623a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[243,329,485,492]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0925/91630235fefb5238cf5b82be39d29bec3fdddca4e81a6233ae347b240eb86dd8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[502,329,744,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3 XPS spectra in (a) C 1s, (b) N 1s, (c) O 1s and (d) In 3d and (e) Pt 4f levels. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0458/4568f60b5da8b25e1d5b4a72a8a912ca334f9b7ad0732c18317a2efab3e60a39.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[63,546,492,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in the metallic state. $^{34}$ The $\\\\mathrm{Pt / In_2O_3}$ displayed negative BE shift of Pt and positive BE shift of $\\\\mathrm{In}^{3+}$ , which further confirmed that most Pt nanoparticles deposited onto $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets, in which partial electrons transferred from $\\\\mathrm{In}^{3+}$ to Pt owing to the strong metal-support interaction, taking into account of the higher electronegativity of Pt (2.28) than that of $\\\\mathrm{In}^{3+}$ (1.78). $^{32}$ All the O species were present in $\\\\mathrm{O}^{2-}$ state. The peak at 531.4 eV was assigned to lattice-oxygen and the peak at 532.5 eV was ascribed to chemisorbed oxygen. $^{35}$ After Pt-loading, the BE of lattice-oxygen showed a negative shift owing to the acceptance of partial electrons from metallic Pt. Besides, the well-dispersed Pt nanoparticles on the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ surface promoted the chemisorption of oxygen, leading to the enhanced intensity of the peak around 532.5 eV. $^{36}$ The C species in 10INCN were mainly presented in C-N-C coordination, corresponding to the BE at 288.2 eV in C 1s level. The weak shoulder peak at 284.5 eV was ascribed to the $\\\\mathfrak{sp}^2$ C-C bond. $^{37}$ The N species displayed various states, corresponding to the different binding energies in the N 1s level. The main signal around 398.6 eV corresponded to the N in C-N-C bond, while the shoulder peak at 400.3 eV was ascribed to the N in the $\\\\mathrm{N - (C)^3}$ group. $^{38}$ No significant BE shift of either the C or the N was observed, possibly due to the symmetric structure in C-N-C bond. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,899,490,930]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Due to the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathfrak{g}\\\\text{-C}_3\\\\mathrm{N}_4$ are both indirect band semiconductors.39-42 It is reasonable that $(\\\\alpha h\\\\nu)^{0.5}$ vs. photon energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[500,546,929,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"plot was used to estimate band-gap energy of them. From UV-Vis DRS spectra and their corresponding plots of $(\\\\alpha h\\\\nu)^{1 / 2}$ vs. photon energy $(h\\\\nu)$ (Fig. 4a and S3†), together with the calculated energy bandgaps and light absorbance edge wavelength (Table S3†), we could see that both $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ could be activated by visible lights. The 5INCN displayed a broader adsorption area with an obvious red-shift in comparison with the pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ , which could be understood by considering the appearance of some intermediate energy bands owing to the formation of heterojunctions between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ . Further increase in the ratio of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ to $\\\\mathrm{g - C_3N_4}$ (from 5INCN to 20INCN) had no significant influence on the light absorbance edge, suggesting no more heterojunctions formed. Meanwhile, both $\\\\mathrm{Pt / In_2O_3}$ and $\\\\mathrm{Pt / g - C_3N_4}$ exhibited red-shift comparing to pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ , obviously owing to plasma effect from Pt nanoparticles, which could also account for the red-shift of light absorbance by loading Pt onto INCN. However, the change of Pt-loading from $1\\\\mathrm{wt}\\\\%$ to $2\\\\mathrm{wt}\\\\%$ had a very limited effect on the light adsorption edge, suggesting the similar size of Pt nanoparticles, and thus, the increased Pt-loading could only enhance the light adsorption intensity. However, 2.5Pt-10INCN displayed a blue-shift of light absorbance wavelength due to the gathering of Pt nanoparticles, which reduced the plasma effect. All the increasing ratio of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ to $\\\\mathrm{g - C_3N_4}$ had almost on effect on the light absorbance \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[3,114,43,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[68,29,115,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,11,927,20]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[816,29,927,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,961,391,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[670,961,873,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[885,961,927,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22463 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[95,62,278,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0107/f2273d368a9ef1a2183238806074552a584421beb44560fa7c5d86d39c4efcc3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[282,68,460,169]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0399/2829842ea26b6c0d5d000c2345f22990d7cafb322cb2fd7c1c26a4eaa71d81b7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,166,273,275]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0895/b6bb49c8d103145d3e6dc9c62f2bad00a1a3e863232cb4f691fafbd30d8388d2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,165,463,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0601/ae0f83e1ae79131ce6be656875d5521335bd6ccde5e54c5b6f8909538141982a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[203,279,389,390]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4 (a) UV-Vis DRS spectra and their corresponding plots of $(\\\\\\\\alpha h\\\\\\\\nu)^{1/2}$ vs. photon energy, (b) steady-state PL spectra at $\\\\\\\\lambda_{\\\\\\\\mathrm{ex}}$ of $350~\\\\\\\\mathrm{nm}$ , (c) electrochemical impedances, and (d) photocurrent response spectra obtained under irradiation of a $300~\\\\\\\\mathrm{W}$ Xe lamp. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0462/c208d4607db00e1731cc906a7bcd93f3b4a7781269a0c869dc450c9759d3adb8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[63,482,490,559]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"wavelength in INCN, it caused remarkable red-shift in 2Pt-xINCN. This could be ascribed to the enhanced plasma effect from Pt nanoparticles at high-content $\\\\mathrm{In}_2\\\\mathrm{O}_3$ since the above TEM images demonstrated that the Pt ions were preferentially reduced and deposited onto $\\\\mathrm{In}_2\\\\mathrm{O}_3$ rather than $\\\\mathrm{g - C_3N_4}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,560,492,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The steady-state PL spectra obtained at an excited wavelength of $350\\\\mathrm{nm}$ (Fig. 4b and $\\\\mathrm{S}4\\\\dagger$ ) displayed an emission peak around $450~\\\\mathrm{nm}$ indicative of the recombination between photoelectrons and holes. The 10INCN exhibited lower intensity compared to $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ , implying the lowest photoelectron-hole combination rate, which could be attributed to the rapid charge transfer through the $\\\\mathrm{In}_2\\\\mathrm{O}_3\\\\mathrm{-C}_3\\\\mathrm{N}_4$ heterojunctions. With the increase of the $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{C}_3\\\\mathrm{N}_4$ ratio up to 10INCN, the PL peak intensity decreased gradually owing to the formation of more $\\\\mathrm{In}_2\\\\mathrm{O}_3\\\\mathrm{-C}_3\\\\mathrm{N}_4$ heterojunctions, corresponding to the reduced photoelectron-hole combination rate. However, further increase in the $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{C}_3\\\\mathrm{N}_4$ ratio resulted in the increasing PL peak intensity due to the presence of more free $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets, leading to the enhanced photoelectron-hole combination rate. Loading Pt could greatly decrease the PL peak intensity, corresponding to the efficient inhibition of photoelectron-hole combination, obviously owing to the rapid electron transfer through Pt nanoparticles to separate from holes. The 2Pt-10INCN showed the lowest photoelectron-hole combination rate. This could be further by the electrochemical impedance spectra (Fig. 4c and S5†). The loading of Pt nanoparticles onto $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , $\\\\mathrm{C}_3\\\\mathrm{N}_4$ , and INCN resulted in a significant decrease of arc radius, corresponding to the reduced electric resistance owing to the excellent electric conductivity of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,60,929,136]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"metallic Pt. The 2Pt-10INCN displayed the smallest arc radius, corresponding to the lowest electric resistance. Further increase in the Pt-loading caused an enlarged arc radius corresponding to the enhanced electric resistance, which could attribute to the gathering of Pt nanoparticles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,137,929,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The photocurrent response spectra (Fig. 4d and S6†) clearly demonstrated that the INCN exhibited higher photocurrent than either the pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ or the pure $\\\\mathrm{g - C_3N_4}$ , which could attribute to the enhanced light absorbance and decreased photoelectron-hole recombination rate as discussed above. Increasing the $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ ratio from 5 to $10\\\\mathrm{wt}\\\\%$ resulted in the enhanced photocurrent intensity. A possible reason was the rapid electron transfer from $\\\\mathrm{g - C_3N_4}$ to $\\\\mathrm{In}_2\\\\mathrm{O}_3$ since $\\\\mathrm{In}_2\\\\mathrm{O}_3$ was present in well-defined crystals with better electric conductivity than $\\\\mathrm{g - C_3N_4}$ in poor crystallization, which might decrease the photoelectron-hole recombination. Further increasing the $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ ratio to $15\\\\mathrm{wt}\\\\%$ caused a decrease in photocurrent intensity due to the presence of more free $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets. Those free $\\\\mathrm{In}_2\\\\mathrm{O}_3$ displayed higher photoelectron-hole recombination rate than the $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ nanocomposite due to the absence of heterojunctions (Fig. S4a†).<sup>43</sup> Meanwhile, the Pt-INCN showed a higher photocurrent than the INCN owing to the enhanced light absorbance and decreased photoelectron-hole recombination rate as discussed above. The highest photocurrent was observed on the 2Pt-10INCN, corresponding to the highest light absorbance and the lowest photoelectron-hole recombination rate. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,500,699,514]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2 Catalytic performances \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,519,929,749]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Controlled experiments (Fig. S7†) demonstrated that only trace HCOOH and $\\\\mathrm{CH_4}$ obtained during $\\\\mathrm{CO}_{2}$ reduction on 2Pt-10INCN without light irradiation or $\\\\mathrm{CO}_{2}$ , suggesting the $\\\\mathrm{CO}_{2}$ reduction was mainly driven by photocatalysis. The addition of $\\\\mathrm{K}_2\\\\mathrm{Cr}_2\\\\mathrm{O}_7$ as an electron capture agent resulted in an abrupt decrease in $\\\\mathrm{CO}_{2}$ conversion efficiency, showing the photoelectrons played a key role in photocatalytic $\\\\mathrm{CO}_{2}$ reduction. Meanwhile, it was also found that the HCOOH yield greatly decreased without adding TEOA in the reaction system. TEOA was frequently used as a hole capturing agent in photocatalysis,[44] which could consume photo-induced holes from the photocatalyst through its oxidation (see Scheme S1†) and thus could inhibit their recombination with photoelectrons. Therefore, TEOA was a necessary sacrifice agent in the present photocatalytic $\\\\mathrm{CO}_{2}$ reduction. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,750,929,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Under UV light irradiation, the 2Pt-10INCN exhibited higher HCOOH and $\\\\mathrm{CH}_4$ yields than that under visible light irradiation (Fig. S8a†) since the UV light could generate more photoelectrons and holes. Taking into account that the sunlight contained only less than $5\\\\%$ UV lights, we still employed the visible light irradiation for driving the photocatalysis to simulate the natural photosynthesis. The 2Pt-10INCN exhibited extremely high selectivity to HCOOH in photocatalytic $\\\\mathrm{CO}_{2}$ . Only very little $\\\\mathrm{CH}_4$ could be obtained and no other side-products were detected. With the increase of reaction time to $4\\\\mathrm{h}$ , the HCOOH yield increased rapidly and an only slight increase in $\\\\mathrm{CH}_4$ yield was observed. However, further increase in the reaction time had no \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[3,116,43,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[68,28,181,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,11,927,21]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[880,28,929,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,962,112,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22464 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,962,327,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[606,962,929,975]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[63,59,492,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"significant influence on the $\\\\mathrm{CO}_{2}$ reduction efficiency (Fig. S8b†), indicating the reaction arrived equilibrium point. So, $4\\\\mathrm{h}$ was used as the reaction time in the following activity tests. Meanwhile, the increase of $\\\\mathrm{CO}_{2}$ pressure could also greatly promote photocatalytic $\\\\mathrm{CO}_{2}$ reduction toward HCOOH (see Fig. S8c†). The HCOOH yield could reach up to $736.3~\\\\mu \\\\mathrm{mol}~\\\\mathrm{g}^{-1}~\\\\mathrm{h}^{-1}$ at $4.0\\\\mathrm{MPa}$ , which represented a high level in $\\\\mathrm{CO}_{2}$ conversion in photosynthesis. However, the increasing $\\\\mathrm{CO}_{2}$ pressure resulted in a rapid increase of the $\\\\mathrm{CH}_4$ yield (see Fig. S8d†), the high cost, and the difficult operation. Thus, we employed the normal $\\\\mathrm{CO}_{2}$ pressure (1 atm) in the following tests to meet the requirement of industrial production. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,243,490,336]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 5 demonstrated that both $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ could be activated by visible lights. Although the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ contained sufficient Lewis acid sites to absorb $\\\\mathrm{CO}_{2}$ molecules, it showed very low activity due to its high CB potential $(-0.62\\\\mathrm{V}$ vs. NHE) which could not efficiently generate H atoms by photocatalytic water splitting. The $\\\\mathrm{g - C_3N_4}$ was active to produce H atoms \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[107,368,448,545]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0189/ced5b0e89256135182b5561206a9e27011d815e76f56003eac4b51e26eb54d4a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[115,546,448,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0025/0db1cf5d0b45965b854e6f3b80b9ebab6d0e28a8beebc0b24b97b1efd3f8b116.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[107,712,448,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5 HCOOH and $\\\\\\\\mathsf{CH}_4$ yields on different catalysts. Reaction conditions: Four 3 W LED (420 nm), 1 atm $\\\\\\\\mathsf{CO}_2$ , 20 mg catalyst, 10 mL $\\\\\\\\mathsf{H}_2\\\\\\\\mathsf{O}$ , 1 mL TEOA, $35^{\\\\\\\\circ}\\\\\\\\mathsf{C}$ , 4 h. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0154/9d5e09f89ef0d7204dafef1c555cac2a38575eb9f2772db34596ecc9fe8046a6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[500,59,929,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"photocatalytic water splitting owing to its low CB potential $(-1.1\\\\mathrm{V}$ vs. NHE). However, its adsorption for $\\\\mathrm{CO}_{2}$ molecules was very poor due to the lack of active sites together with the low surface area, leading to the poor activity of photocatalytic $\\\\mathrm{CO}_{2}$ reduction. The INCN exhibited higher activity than either the $\\\\mathrm{In}_{2}\\\\mathrm{O}_{3}$ or $\\\\mathrm{g - C_3N_4}$ owing to the cooperation between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - }$ $\\\\mathrm{C_3N_4}$ to adsorb $\\\\mathrm{CO}_{2}$ molecules and produce H atoms. Meanwhile, the INCN contained narrow energy bandgap owing to the presence of intermediate energy bands and thus could be more easily and effectively activated by visible lights. More importantly, the INCN contained enriched heterojunctions between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ , which facilitated the electron transfer from the CB of $\\\\mathrm{g - C_3N_4}$ to that of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , leading to the lower photoelectron-hole recombination rate. Although the pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ exhibited very poor activity in photocatalytic $\\\\mathrm{CO}_{2}$ reduction, the $\\\\mathrm{Pt / In_2O_3}$ exhibited remarkable enhancement on the activity since the metallic Pt could act as a co-catalyst to produce H atoms by collecting electrons from $\\\\mathrm{In}_2\\\\mathrm{O}_3$ semiconductor and plasma during photocatalytic water splitting.[45] More importantly, the $\\\\mathrm{Pt / In_2O_3}$ displayed much higher selectivity to HCOOH than the pure $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , which could be understood based on a plausible reaction pathway in photocatalytic $\\\\mathrm{CO}_{2}$ reduction (Scheme S1†). The noble-metal Pt was a typical metal catalyst with low work function to activate H atoms while the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ could efficiently adsorb $\\\\mathrm{CO}_{2}$ molecules owing to the presence of enriched Lewis acid sites.[46,47] The Lewis acid sites also enhanced the interaction between Pt and $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , which induced the unique bridged co-adsorption model of the $\\\\mathrm{CO}_{2}$ molecule on Pt and $\\\\mathrm{In}_2\\\\mathrm{O}_3$ . Such co-adsorbed $\\\\mathrm{CO}_{2}$ molecules favored the reaction with active H atoms to HCOO*,[48-50] which was a key intermediate in determining the selectivity to HCOOH.[16] Besides, the metallic Pt nanoparticles also promoted the activation of $\\\\mathrm{In}_2\\\\mathrm{O}_3$ by visible lights owing to the plasma effect and facilitated the electron transfer to diminish photoelectron-hole recombination, which could further promote the photocatalytic $\\\\mathrm{CO}_{2}$ reduction. Similarly, the $\\\\mathrm{Pt / g - C_3N_4}$ also exhibited higher activity and selectivity than the $\\\\mathrm{g - C_3N_4}$ , which could also be explained based on the above discussions. It was noted that the Pt-loading exhibited much weaker promoting effect on the HCOOH production in $\\\\mathrm{g - C_3N_4}$ than that in $\\\\mathrm{In}_2\\\\mathrm{O}_3$ . A possible reason was that the $\\\\mathrm{g - C_3N_4}$ could not effectively adsorb $\\\\mathrm{CO}_{2}$ molecules due to the absence of Lewis acid sites. Although the presence of Pt could greatly enhance the production of H atoms, no enough adsorbed $\\\\mathrm{CO}_{2}$ molecules could be activated and subsequently reacted with those H atoms. Meanwhile, the $\\\\mathrm{Pt / g - C_3N_4}$ displayed poor interaction between Pt and $\\\\mathrm{g - C_3N_4}$ due to the absence of Lewis acid sites, leading to the low number of bridge-coadsorbed $\\\\mathrm{CO}_{2}$ molecules on both Pt and $\\\\mathrm{g - C_3N_4}$ , which could account for the lower selectivity to HCOOH in comparison with the $\\\\mathrm{Pt / In_2O_3}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,827,929,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As expected, the Pt-loading onto INCN also greatly enhanced the activity and selectivity in photocatalytic $\\\\mathrm{CO}_{2}$ reduction, which could also be accounted by considering various Pt-functions discussed above. Interestingly, the Pt-INCN exhibited a much stronger promoting effect than either the $\\\\mathrm{Pt / In_2O_3}$ or $\\\\mathrm{Pt / g - C_3N_4}$ possibly owing to the enhanced role of heterojunctions. The presence of metallic Pt nanoparticles facilitated \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[1,114,45,629]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[67,28,115,42]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,11,926,21]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[816,28,927,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,961,391,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[670,961,873,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[885,961,927,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22465 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[107,61,447,231]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0354/cdeab22338f6a3619b8897fea0785bd3d3e748b6d022612069717de4ea34943b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[107,232,447,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0750/d00ec578afa0ccf80f5a7302ab1a496b7ab6b7f304ff2fbb6d8dbddc63b8cf38.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[107,397,447,564]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 6 Recycling test of $2\\\\\\\\mathrm{Pt - In_2O_3}$ , $2\\\\\\\\mathrm{Pt - g - C_3N_4}$ and $2\\\\\\\\mathrm{Pt - 10INCN}$ . Reaction conditions are given in Fig. 5. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0471/ec616bcd17026bc80bb504a87aa10422a4d1c2e119488c80d433b6f74cc4f893.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[68,634,489,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"electron-transfer from $\\\\mathrm{In}_2\\\\mathrm{O}_3$ to $\\\\mathrm{g - C_3N_4}$ and hole-transfer from $\\\\mathrm{g - }$ $\\\\mathrm{C_3N_4}$ to $\\\\mathrm{In}_2\\\\mathrm{O}_3$ , which could greatly diminish photoelectron-hole recombination (see Scheme S1†). By fixing the Pt-loading at $2\\\\mathrm{wt}\\\\%$ , the Pt-INCN showed a rapid increase in HCOOH yield while only very slight increase in $\\\\mathrm{CH}_4$ yield with the increasing ratio of $\\\\mathrm{In}_2\\\\mathrm{O}_3 / \\\\mathrm{g - C_3N_4}$ up to $10\\\\mathrm{wt}\\\\%$ . This could be ascribed to the enhanced adsorption of $\\\\mathrm{CO}_{2}$ molecules by $\\\\mathrm{In}_2\\\\mathrm{O}_3$ . Besides, the increase of heterojunctions played a key role in promoting the photocatalytic $\\\\mathrm{CO}_{2}$ reduction by inhibiting photoelectron-hole recombination. However, further increase of the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ content caused slight decrease in the HCOOH yield due to the appearance of free $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets. Such a free $\\\\mathrm{In}_2\\\\mathrm{O}_3$ displayed higher photoelectron-hole recombination rate than the $\\\\mathrm{In}_2\\\\mathrm{O}_3/$ $\\\\mathrm{g - C_3N_4}$ nanocomposite due to the absence of heterojunctions.51 In addition, since the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ favored the photocatalytic reduction of $\\\\mathrm{PtCl_6}^{2 + }$ , some of Pt nanoparticles would deposit onto the free $\\\\mathrm{In}_2\\\\mathrm{O}_3$ nanosheets, leading to the reduced promoting effect on the role of heterojunctions between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,60,927,319]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"By fixing the $\\\\mathrm{In}_2\\\\mathrm{O}_3$ -content at $10~\\\\mathrm{wt}\\\\%$ ,the Pt-10INCN exhibited increasing HCOOH yield and $\\\\mathrm{CH_4}$ yield with the increase of Pt-loading up to $2\\\\mathrm{wt}\\\\%$ since more Pt nanoparticles would enhance the plasma effect, the activity for activating H atoms and $\\\\mathrm{CO}_{2}$ molecules, the electron transfer ability to inhibit photoelectron-hole recombination. However, further increase in the Pt-loading caused slight decrease in either the HCOOH yield or the $\\\\mathrm{CH_4}$ yield due to the gathering of Pt nanoparticles to reduce above promoting effects. Besides, the large Pt nanoparticles may also block the pore channels, leading to an abrupt decrease in surface area (see Table S2). The 2Pt-10INCN exhibited the highest HCOOH yield $(63.1\\\\mu \\\\mathrm{mol}g^{-1}\\\\mathrm{h}^{-1})$ at the normal pressure of $\\\\mathrm{CO}_{2}$ and room temperature. In addition, the 2Pt-10INCN exhibited much higher activity than the 2Pt10INCN-mix obtained by mechanical mixing $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ see Fig.S7),obviously due to the absence of heterojunctions and the synergetic effect between $\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $\\\\mathrm{g - C_3N_4}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,320,927,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The lifetime is also a key parameter to determine the practical application of a photocatalyst. As shown in Fig. 6, both $2\\\\mathrm{Pt}-10\\\\mathrm{INCN}$ and $2\\\\mathrm{Pt}-\\\\mathrm{In}_2\\\\mathrm{O}_3$ could be used repetitively for more than 5 times without a significant decrease in their activities. The slight decrease might be caused by the loss of photocatalysts during separation and wash processes. However, the $2\\\\mathrm{Pt}-\\\\mathrm{g}-\\\\mathrm{C}_3\\\\mathrm{N}_4$ showed a rapid decrease in photocatalytic activity during the recycling test. The XRD patterns (Fig. S9†) revealed that, similar to $2\\\\mathrm{Pt}-\\\\mathrm{In}_2\\\\mathrm{O}_3$ and $2\\\\mathrm{Pt}-\\\\mathrm{g}-\\\\mathrm{C}_3\\\\mathrm{N}_4$ , no significant change in the structure of $2\\\\mathrm{Pt}-10\\\\mathrm{INCN}$ was observed, indicating the excellent stability during the reaction process. Meanwhile, ICP analysis demonstrated no significant Pt leaching occurred on either $2\\\\mathrm{Pt}-10\\\\mathrm{INCN}$ or $2\\\\mathrm{Pt}-\\\\mathrm{In}_2\\\\mathrm{O}_3$ occurred during the reaction, which could be attributed to the strong adsorption of Pt nanoparticles onto $\\\\mathrm{In}_2\\\\mathrm{O}_3$ owing to the presence of Lewis acid sites. However, the $2\\\\mathrm{Pt}-\\\\mathrm{g}-\\\\mathrm{C}_3\\\\mathrm{N}_4$ showed Pt leaching during the reaction process, leading to a decrease in photocatalytic activity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,622,684,637]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,650,927,848]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We developed a $\\\\mathrm{Pt / In_2O_3 / g - C_3N_4}$ multifunctional catalyst by controlling the assembling method. This catalyst exhibited high activity and selectivity to HCOOH during visible-light-driven photocatalytic $\\\\mathrm{CO}_{2}$ reduction owing to the synergetic effects in producing H atoms via water splitting, adsorbing/activating $\\\\mathrm{CO}_{2}$ molecules, and inhibiting photoelectron-hole recombination by accelerating electron transfer and forming heterojunctions. Besides, it also displayed a long lifetime owing to the high structural stability and the strong interaction to inhibit Pt leaching. This work supplied a promising way for designing new catalysts with multiple functions for photocatalytic $\\\\mathrm{CO}_{2}$ reduction at normal pressure and room temperature with a high yield of target products. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,890,722,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflicts of interest \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,920,727,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There are no conflicts to declare. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[1,114,45,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n© CC BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[70,29,179,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,12,926,20]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[882,29,927,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,962,110,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22466 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,962,326,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[606,962,927,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[67,61,284,82]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,91,490,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was supported by NSFC (21761142011, 51572174) and Shanghai Government (18JC1412900, 19YF1436600, 19160712900, 17SG44) as well as Shanghai Engineering Research Center of Green Energy Chemical Engineering. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,166,191,184]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,197,490,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1 K. 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Catal., B, 2013, 130-131, 93-98. \\\",\\\"44 S. Kumar, R. K. Yadav, K. Ram, A. Aguiar, J. Koh and A. J. F. N. Sobral, J. CO $_2$ Util., 2018, 27, 107-114. \\\",\\\"45 Y. Sui, S. Liu, T. Li, Q. Liu, T. Jiang, Y. Guo and J.-L. Luo, J. Catal., 2017, 353, 250-255. \\\",\\\"46 N. Rui, Z. Wang, K. Sun, J. Ye, Q. Ge and C.-j. Liu, Appl. Catal., B, 2017, 218, 488-497. \\\",\\\"47 J. Kim and J. Lee, J. Chem. Phys., 2000, 113, 2856-2865. \\\",\\\"48 G. Gao, Y. Jiao, E. R. Waclawik and A. Du, J. Am. Chem. Soc., 2016, 138, 6292-6297. \\\",\\\"49 D. G. Shchukin, S. K. Poznyak, A. I. Kulak and P. Pichat, J. Photochem. Photobiol., A, 2004, 162, 423-430. \\\",\\\"50 M. Tasbihi, F. Fresno, U. Simon, I. J. Villar-Garcia, V. Pérez-Dieste, C. Escudero and V. A. de la Peña O'Shea, Appl. Catal., B, 2018, 239, 68-76. \\\",\\\"51 Y.-C. Chen, Y.-C. Pu and Y.-J. Hsu, J. Phys. Chem. C, 2012, 116, 2967-2975. \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[3,114,43,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access Article. Published on 11 June 2020. Downloaded on 6/25/2020 9:03:13 AM. \\n(CC) BY-NC This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[67,28,115,42]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[831,11,927,21]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View Article Online \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[816,28,927,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Advances \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,962,391,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This journal is © The Royal Society of Chemistry 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[670,962,873,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RSC Adv., 2020, 10, 22460-22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[885,962,927,973]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1039/d0ra03959d"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Energy and Power Science"},"sha256":{"kind":"string","value":"8b7844e12e7736ab9b30632896027d537a28e46db408f9fa07a7e65f9f1bd8bf"},"title":{"kind":"string","value":"Selective CO<sub>2</sub> reduction to HCOOH on a Pt/In<sub>2</sub>O<sub>3</sub>/g-C<sub>3</sub>N<sub>4</sub> multifunctional visible-photocatalyst"}}},{"rowIdx":158,"cells":{"abstract":{"kind":"string","value":"This paper focuses on the construction of the Jacobian matrix required in tomographic reconstruction algorithms. In microwave tomography, computing the forward solutions during the iterative reconstruction process impacts the accuracy and computational efficiency. Towards this end, we have applied the discrete dipole approximation for the forward solutions with significant time savings. However, while we have discovered that the imaging problem configuration can dramatically impact the computation time required for the forward solver, it can be equally beneficial in constructing the Jacobian matrix calculated in iterative image reconstruction algorithms. Key to this implementation, we propose to use the same simulation grid for both the forward and imaging domain discretizations for the discrete dipole approximation solutions and report in detail the theoretical aspects for this localization. In this way, the computational cost of the nodal adjoint method decreases by several orders of magnitude. Our investigations show that this expansion is a significant enhancement compared to previous implementations and results in a rapid calculation of the Jacobian matrix with a high level of accuracy. The discrete dipole approximation and the newly efficient Jacobian matrices are effectively implemented to produce quantitative images of the simplified breast phantom from the microwave imaging system."},"author":{"kind":"string","value":"Paul Meaney|Andreas Fhager|Samar Hosseinzadegan|Shireen Geimer|Mikael Persson"},"content_list":{"kind":"list like","value":[{"bbox":"[58,120,100,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Letter ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,129,835,203]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Expansion of the Nodal-Adjoint Method for Simple and Efficient Computation of the 2D Tomographic Imaging Jacobian Matrix ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[62,219,882,236]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Samar Hosseinzadegan ${ \\bf 1 } _ { \\mathbb { D } }$ , Andreas Fhager ${ \\bf 1 } _ { \\mathbb { D } }$ , Mikael Persson 1, Shireen Geimer ${ \\mathfrak { 2 } } _ { \\mathbb { O } }$ and Paul Meaney 2,\\* ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,259,939,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Electrical Engineering Department, Chalmers University of Technology, 41296 Gothenburg, Sweden; samar.hosseinzadegan@gmail.com (S.H.); andreas.fhager@chalmers.se (A.F.); mikael.persson@chalmers.se (M.P.) 2 Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA; shireen.geimer@dartmouth.edu Correspondence: paul.m.meaney@dartmouth.edu ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,340,941,569]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: This paper focuses on the construction of the Jacobian matrix required in tomographic reconstruction algorithms. In microwave tomography, computing the forward solutions during the iterative reconstruction process impacts the accuracy and computational efficiency. Towards this end, we have applied the discrete dipole approximation for the forward solutions with significant time savings. However, while we have discovered that the imaging problem configuration can dramatically impact the computation time required for the forward solver, it can be equally beneficial in constructing the Jacobian matrix calculated in iterative image reconstruction algorithms. Key to this implementation, we propose to use the same simulation grid for both the forward and imaging domain discretizations for the discrete dipole approximation solutions and report in detail the theoretical aspects for this localization. In this way, the computational cost of the nodal adjoint method decreases by several orders of magnitude. Our investigations show that this expansion is a significant enhancement compared to previous implementations and results in a rapid calculation of the Jacobian matrix with a high level of accuracy. The discrete dipole approximation and the newly efficient Jacobian matrices are effectively implemented to produce quantitative images of the simplified breast phantom from the microwave imaging system. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,585,939,614]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: nodal adjoint method; Jacobian matrix; discrete dipole approximation; computational efficiency; microwave tomography; breast imaging ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,658,248,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Academic Editor: Andrea Randazzo Received: 3 December 2020 Accepted: 19 January 2021 Published: 22 January 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,728,258,782]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,659,394,674]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,678,941,812]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Microwave imaging is an emerging technology that is beginning to see increased clinical use for a number of applications. These include breast cancer imaging [1–4], stroke diagnosis [5,6], bone imaging [7] and others. For these applications, there is usually a significant endogenous contrast that can be exploited for imaging. For breast cancer imaging, there is a substantial property contrast between benign and malignant tissue [8–10]; for stroke diagnosis, there is a large contrast between blood and normal brain tissue [11]; for bone, there is a significant correlation between the dielectric properties and bone density [7]. In addition, the dielectric properties can be exploited to recover functional information such as temperature monitoring during thermal therapy [12,13] due to their temperature dependence [14]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,813,941,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The most widely applied area for microwave imaging has been in the area of breast cancer imaging. The three most prominent microwave imaging techniques include radar, holography and tomography or inverse problems. Radar approaches can be either in a backscatter or transmission mode, where broadband signals are transmitted and received by either the same antenna or others in an array. The signals are time shifted so as to focus the composite signals at a particular pixel in the field of view and the sum of these components is recorded. This procedure is repeated for all points in the domain until an image is produced. The work by Fear and Stuchly [4] is a good example of the reflection-based technique which has been used in simulation, phantom and limited patient exams. The Craddock group at the University of Bristol has produced good results with their transmission-based system which has been used in clinical trials [1,15]. Microwave holography generally assumes that the broadcast signal and those transmitted through and reflected back from the target are spherical waves which can be decomposed into a superposition of plane waves through a Fourier transform [16]. Each of these can be back propagated to the target and re-transformed into the spatial domain for target identification and characterization. These algorithms are effective in both 2D and 3D. The most prominent effort in this area is by the Nikolova group at McMaster University which has implemented a system that has advanced to phantom studies [17]. For the tomographic approach, numerous groups have produced simulation studies [18–21] on both classic conical structures and with data from actual MR exams [22]. Several approaches have advanced to phantom and animal studies [12,23–26] and there have been several patient studies by the Dartmouth College group—particularly in breast cancer neoadjuvant chemotherapy monitoring [2]. This paper focuses entirely on the tomography approaches since these are the ones that require construction of a Jacobian matrix as part of their image reconstruction process. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,54,257,97]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"三 sensors","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[58,794,154,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"cc + BY ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[687,967,936,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://www.mdpi.com/journal/sensors ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[62,966,396,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729. https://doi.org/10.3390/s21030729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[865,61,939,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MDPI ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,499,147,521]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"\u0001-\u0003\u0001\u0004\u0005\u0006\u0007\b \u0001-\u0003\u0004\u0005\u0006\u0007 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,825,265,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright: $^ ©$ 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,530,257,640]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Citation: Hosseinzadegan, S.; Fhager, A.; Persson, M.; Geimer, S.; Meaney, P. Expansion of the Nodal-Adjoint Method for Simple and Efficient Computation of the 2D Tomographic Imaging Jacobian Matrix. Sensors 2021, 21, 729. https:// doi.org/10.3390/s21030729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,110,941,379]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,381,941,618]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the consistent complaints about microwave tomography is the long computation times. This is due primarily to heavy resources needed for the multiple forward solution calculations at each iteration. These times have generally ranged from several minutes for some 2D implementations [27] to many hours and even days for larger 3D reconstructions that often require parallelized multi-processors and graphical processing units (GPUs) to accelerate the computation speed [18,23,24]. In fact, the EMTensor group is exploring massively parallel, cloud computing to solve the computational issues for their portable and computationally expensive system [28]. These concerns have been somewhat ignored because there are such significant challenges in just recovering a diagnostically relevant image. Problems have most often revolved around the issues of convergence to local minima [29], the need for a priori information by some systems [21,30], and the amount of measurement data necessary for reconstructing viable images and the associated hardware requirements to meet this need [31]. In most cases, it was generally assumed that the computational issues could be addressed later—especially since computer power has consistently improved by factors of two or so every 18 months for several decades now according to Moore’s Law [32]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,620,941,812]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"While the forward solution computation costs are the most substantial, there are other aspects of these formulations which also contribute to the slow overall computation. One critical component of most microwave tomographic imaging techniques, and for that matter most inverse problems, is the Jacobian matrix [33]. While not called this exact term in many microwave formulations, the net result is similar for all techniques. In essence, the terms of the Jacobian are the change in the field registered by the jth receiver due to a small change in the permittivity at a single node in the parameter reconstruction mesh while illuminated by the ith transmitter [34]. These gradient terms provide direction to the iteration process during Newton-like reconstruction processes. The overall size of the matrix is $\\left( N _ { t } \\times N _ { r } \\right) \\times N _ { p } ,$ , where $N _ { t } , N _ { r } ,$ and $N _ { p }$ are the number of transmitters, number of receivers per each transmitter, and the number of parameter values being reconstructed, respectively. In this sense, the matrix can be quite large and its formation can impose a significant impact on the overall computation times. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,813,941,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cui et al. [35] introduced a Green’s function with an integral formulation technique to effectively form the Jacobian matrix which is subsequently incorporated into a distorted Born approximation inverse solution. The technique has been shown to work well with low contrast and small scatter problems when the starting property distribution estimate is that of the surrounding background. This approach is subsequently utilized by Shea et al. [18] and further by Karadima et al. [23]. Zakaria et al. [36] used the finite element contrast source inversion method for microwave imaging and reported in detail on the gradients of the cost function. Van den Berg and Kleinman [37] also devised a contrast source inversion method to solve the inverse problem. While this did not explicitly compute a Jacobian matrix, it does compute the gradients of the cost function which are in the form of Frechet derivatives, called the Polak–Ribiere conjugate gradient directions. This approach is further used by Gilmore et al. [25] which expands upon this concept by adding a multiplicative regularization. The contrast source inversion technique is also used by Rubaek et al. [38] which expands the concept to a log-transformed version, similarly to that used in Meaney et al. [39]. The conversion of the complex Jacobian terms to the log-transformed counterpart involves only minor algebraic operations. Joachimowicz et al. utilizes an iterative variation scheme derived from a classical Newton procedure [40]. The solution was derived for the 2D TM situation and the computation of the Jacobian matrix is a Green’s function formulation applied to a Method of Moments technique for the forward solution. Efforts by Souvorov et al. [34] utilized an iterative Fourier inversion method where the forward solution was based on integral equations. The Jacobian matrix formulation was quite similar to that of Cui et al. [35]. Later efforts by Bindu and Semenov [41] utilized the distorted Born approximation with an FDTD forward solution and similar Jacobian formulation. In none of these cases did the groups actually call their matrices the Jacobian matrix. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,178,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,112,941,380]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,382,941,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"More recently, the discrete dipole approximation (DDA) has been introduced as a means of dramatically reducing the forward solution computation time and the associated memory requirements [42]. This has the potential to reduce the forward solution time of a 2D imaging problem by an order of magnitude or more. Interestingly, the uniform grid configuration informed our understanding of the Jacobian formulation to the point where its construction is now reduced to a low number of vector–vector multiplications. In a more rigorous analysis, this new derivation originates from the nodal adjoint technique introduced by Fang et al. [43]. The net result is that each element of the matrix is created by the multiplication of two complex numbers and a pre-computed scalar term. The adjoint method is an exact method for computing the Jacobian matrix and relies largely on the principle of reciprocity. It is widely used in multiple imaging modalities including optical coherence tomography and electrical impedance tomography in addition to microwave imaging [44–48]. This approach is quite general for the 2D problem and can be readily extrapolated to the 3D situation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,592,941,769]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The paper focuses on the calculation of the Jacobian matrix as an expansion of the nodal adjoint technique with respect to its accuracy and computational cost. A comparison between Jacobian matrices formed via the finite element-type (FE) and the discrete dipole approximation-based (DDA) tomographic image reconstruction algorithms is performed. Our goal is to retain the efficiency embedded in the DDA forward solver and does not allow the Jacobian matrix formation to undermine the capabilities of the fast forward solver. In this study, we present an approach which utilizes the DDA forward solution configuration with the nodal adjoint formulation of the Jacobian matrix allowing us to preserve both performance and accuracy. The accuracy of the Jacobian matrix is investigated with respect to our FE-based version. Additionally, experimental data acquired using the microwave breast imaging system at Chalmers University of Technology is used to image a tissue-like phantom to validate our algorithm. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,771,941,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The following sections describe the mathematical underpinnings of the method and show examples of Jacobian matrix construction in comparison to an existing finite elementbased formulation together with reconstructed images employing the described technique. The paper is organized in the following format: Section 2 describes the nodal adjoint method used for calculation of the Jacobian matrices of the FE and the DDA forward solvers together with investigations of their computational costs from a mathematical point of view; Section 3 shows simulated numerical results from the Jacobian matrices of the FE and DDA solvers, the computation times for these methods as well an image reconstruction validation by phantom experiment; Section 4 discusses the results and concludes the study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,178,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,114,366,127]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,131,941,266]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Beginning with the finite element representation of the dual mesh-based nodal adjoint method derivation of the Jacobian matrix [43], Figure 1 shows the overlapping forward solution mesh (red) and the parameter mesh (blue). For the 2D case, all of the forward solution and parameter mesh elements are triangles. This discussion is readily extended to the 3D case by replacing the triangles with tetrahedrons and expanding the forward solution from this scalar problem to the necessary 3D vector forward distributions. In previous implementations, the size of the forward solution mesh elements was noticeably smaller than that for the parameter mesh because the former’s size is dictated by the sampling requirements to achieve an accurate forward solution [49]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,279,828,473]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Overlapping forward solution and parameter meshes corresponding to the nodes and elements. \"]","image_footnote":"[]","img_path":"images/0232/617643bf3bff7efa310a7126ee77b77da7bd5eda428a75aab548cb1c3ee49f0d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,505,942,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this case, a single term of the Jacobian associated with the sth source antenna, the $r$ th receive antenna and the τth parameter mesh node can be written as follows: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[394,545,821,581]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0743/98d4ff600c01aac3eb7d754e63f66a8ea9f280a8cdaff40db5f31a783056ad59.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nJ ( ( s , r ) , \\tau ) = - \\sum _ { n \\in \\Omega _ { \\tau } } \\sum _ { e \\in \\Omega _ { n } } \\frac { 1 } { j \\omega \\mu _ { 0 } | J _ { r } | } \\frac { A _ { e } } { M } \\phi _ { \\tau } ( \\vec { p } _ { n } ) E _ { s } ( \\vec { p } _ { n } ) E _ { r } ( \\vec { p } _ { n } )\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[278,590,941,816]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $E _ { s } ( \\vec { p } _ { n } )$ and $E _ { r } ( \\vec { p } _ { n } )$ are the electric field values due to sources from both antennas $s$ and $r$ at the nodal location ${ \\vec { p } } _ { n } ,$ and $\\phi _ { \\tau } ( \\vec { p } _ { n } )$ is the parameter mesh basis function (In this situation, we utilize linear basis functions over each triangular element where its value is 1 at the designated node and transitions linearly to zero at the other two nodes and along the edges between these two nodes) due to node $\\tau$ in the parameter mesh and evaluated at node $n$ in the forward solution mesh. $\\Omega _ { n }$ is the region composed of forward solution elements immediately associated with node $n$ (i.e., for the region where the forward solution basis function for node $n$ is non-zero) (Figure 2). $e$ is one of the forward solution elements within $\\Omega _ { n } , A _ { e }$ is the area of element $e$ and $M$ is the number of vertices in a triangle (3). $\\omega$ is the angular frequency, $\\mu _ { 0 }$ is the free space magnetic permeability, $J _ { r }$ is the amplitude of a signal transmitted by the receive antenna $r ,$ and $j$ is the imaginary unit. $\\textstyle \\sum _ { e \\in \\Omega _ { n } } ( \\quad )$ is essentially a numerical integration of the associated terms over element e. $\\Omega _ { \\tau }$ is the region composed of parameter elements immediately associated with node $\\tau$ (i.e., for the region where the parameter basis function for node $\\tau$ is non-zero) (Figure 3). It should be noted that forward solution node $n$ must lie within $\\Omega _ { \\tau }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,178,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,110,757,343]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. Forward solution mesh nodes; example of node $n$ and corresponding region $\\\\Omega _ { n }$ is sketched. \"]","image_footnote":"[]","img_path":"images/0031/285a663cb1469770353bf204a47d9acab8c090f09cb952c154976e1d7b158cf3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[280,379,747,609]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Parameter mesh nodes; example of node $\\\\tau$ and corresponding region $\\\\Omega _ { \\\\tau }$ is sketched. \"]","image_footnote":"[]","img_path":"images/0667/a5b3b0611039041e66ca8cfb1938f27fdb0a8691f26aac8504ffa3873391a230.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,642,941,701]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As can be seen from Figure 2, $\\phi _ { \\tau }$ is non-zero for all seven forward solution nodes in $\\Omega _ { n }$ . Therefore, these summations in Equation (1) need to be performed explicitly. However, an interesting observation is made if both the forward solution and parameter meshes overlap exactly (Figure 4). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,702,942,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this case, there are six parameter mesh elements surrounding node $\\tau$ and only seven forward solution mesh nodes within $\\Omega _ { \\tau }$ . In fact, for the integration (summations) which is performed over just the six $\\tau$ -associated elements, the terms are only non-zero for node $\\tau$ and zero for all the surrounding ones (Again, this is true for the linear basis functions used in this derivation). In this case, the inner summation can be reduced: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[337,785,880,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0270/2d1e28635bbc52c9fa5b3cb080921bf42436541c93ab6bb61878940321939670.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\frac { 1 } { j \\omega \\mu _ { 0 } | J _ { r } | } \\frac { 1 } { M } \\sum _ { e \\in \\Omega _ { n } } A _ { e } \\phi _ { \\tau } ( \\vec { p } _ { n } ) E _ { s } ( \\vec { p } _ { n } ) E _ { r } ( \\vec { p } _ { n } ) = \\frac { 1 } { j \\omega \\mu _ { 0 } | J _ { r } | } E _ { s } ( \\vec { p } _ { \\tau } ) E _ { r } ( \\vec { p } _ { \\tau } ) \\sum _ { e \\in \\Omega _ { n } } \\frac { A _ { e } } { M } \\sum _ { e \\in \\mathcal { S } _ { s } } B _ { e } ( \\vec { p } _ { \\tau } ) B _ { e } ( \\vec { p } _ { n } )\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[277,831,941,862]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the situation where the mesh is effectively uniform, the new summation becomes a constant, where $A$ is the sum of the area in $\\Omega _ { \\tau }$ . This ultimately reduces the Jacobian term to ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[465,871,751,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0778/97a71f35063e59cb8ecccabe38ee57d35ef06a79ade49e29927eb49bf6c424c5.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nJ ( ( s , r ) , \\tau ) = \\frac { - 1 } { j \\omega \\mu _ { 0 } \\vert J _ { r } \\vert } \\frac { A } { M } E _ { s } ( \\vec { p } _ { n } ) E _ { r } ( \\vec { p } _ { n } )\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[277,112,941,204]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This means that each term in the Jacobian is reduced to a simple multiplication of the two forward solutions due to sources from antennas $s$ and $r$ at node $\\tau$ and also multiplied by a constant, $\\frac { 1 } { j \\omega \\mu _ { 0 } | J _ { r } | } \\frac { A } { M }$ . It should be noted that for an entire row of the Jacobian matrix (i.e., where $s$ and $r$ do not change), each element of the matrix is a similar multiplication at different nodes of the mesh. This implies that an entire row of the Jacobian can be computed as a vector–vector multiplication of the two field distributions times a constant: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,215,704,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0971/9be2b9eca2764f99049628d81ab886e9b74b739eddf683ad3e647b2362049c24.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\overline { { J } } ( s , r ) = \\frac { - 1 } { j \\omega \\mu _ { 0 } \\lvert J _ { r } \\rvert } \\frac { A } { M } \\vec { E } _ { s } \\vec { E } _ { r }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[278,275,697,507]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Forward solution mesh and parameter mesh overlap exactly. \"]","image_footnote":"[]","img_path":"images/0993/d30d536fcb55f2cd584cd152d1d6dfe765fab5b9ccea61285a213fc1a0f553f9.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,541,941,720]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thus, computation of the entire Jacobian matrix can be reduced to $n _ { s } \\times n _ { r }$ vector– vector $( n _ { p } \\log )$ multiplications where $n _ { s }$ and $n _ { r }$ are the number of transmitting antennas and the number of receiving antennas per each transmitter, and $n _ { p }$ is the number of nodes in the parameter mesh. In comparison, the computation for a single element of the Jacobian matrix using the nodal adjoint method is the product of two $n _ { f }$ long vectors and a corresponding diagonal matrix, where $n _ { f }$ is the number of nodes in the forward solution mesh. This amounts to $2 \\times n _ { f }$ computations for a single element and $2 \\times n _ { f } \\times n _ { p }$ computations for a complete row. Therefore, the new approach has a factor of $2 \\times n _ { f }$ fewer computations—corresponding to several orders of magnitude faster construction. This is a general relationship and it can be easily demonstrated that it holds for other geometric configurations such as rectangular grids used in finite difference time domain and the discrete dipole approximation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,732,356,745]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,749,939,763]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. Comparison of Jacobian Matrix Row Distributions with That of Known Reconstruction Algorithm ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,766,942,856]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 5 shows a schematic diagram of a typical 2D imaging system arrangement. In this case, the monopole antennas are positioned on a $1 5 . 2 \\mathrm { c m }$ diameter circle, with antenna #1 being the lowest centered one and the subsequent ones ordered in a clockwise configuration. Each antenna broadcasts a signal for which the complementary 15 antennas act as receivers. This process is repeated for each antenna transmitting individually to produce a total of 240 measurements (16 transmitters $\\times 1 5$ receivers per transmitter). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[280,110,675,349]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. Schematic representation of imaging domain together with the antenna array.# 5 # 13 \"]","image_footnote":"[]","img_path":"images/0637/3ecaabba8a41783783c0e2bdacdb03b4976a4d7f95cb689833f9b16a22900083.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[277,391,941,466]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 6a shows the imaging zone for the discrete dipole approximation (DDA)\u000fr,b = 22 method where the circular imaging zone is approximated by a subset of the uniform gridσb = 1(S/m) used for computing the forward solution. In this case, the complete grid is comprised of $6 4 \\times 6 4$ squares for a total forward solution zone ofAntenna # 1 $2 5 \\times 2 5 \\mathrm { c m } ^ { 2 }$ and each single cell is a $3 . 9 \\mathrm { m m }$ square. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[285,482,937,634]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 6. Representation of imagining domain with respect to the meshes used for forward solutionsFigure 6. Representation of imagining domain with respect to the meshes used for forward solutions (a,b) and property reconstruction (a,c(a,b) and property reconstruction (a,c). \"]","image_footnote":"[]","img_path":"images/0052/9e6a51908f95844d3ffc5ec9ee07ce8db2a91d1e4a8a26bfbdb17905008334fb.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,684,941,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"diameters of 14.5 cm. It should be noted that for the forward solution, the region outside ofThe imaging zone is a step-wise circle consisting of 1012 squares and 1085 vertices meshes is represented using the boundary element method com(i.e., the number of unknowns) with an effective diameter of $1 4 . 0 \\mathrm { c m }$ the hom. Figure $^ { 6 \\mathrm { b } , \\mathrm { c } }$ eous medi show the and having outer boundaries extending to infinity [50]. The fine mesh (forward solution) has 3corresponding finite element (FE) meshes used in our FE-based reconstruction algorithm. nodes and 7804 triangular elements while the coarse one (reconstruction) has 559 nodes and 1As with the DDA approach, the antennas are configured on a circle concentric with the elements. The average node spacing for these two meshes is 2.25 mm and 6.08 mm, respectively.centre of the imaging zone. The meshes for the dual mesh approach (one for the forward Figure 7 shows the plots of several rows of the Jacobian matrix using the DDA algorithmsolution and one for the property reconstruction) are both inside the antenna array with the 1085 nodediameters of $1 4 . 5 ~ \\mathrm { c m }$ esponding to different transmit and receive antenna pairs at 1300 MHz a. It should be noted that for the forward solution, the region outhomogeneous bath properties of erb = 22 and σb = 1 (S/m). These calculations all assume that thiside of the meshes is represented using the boundary element method comprised of the the first iteration of a reconstruction problem where the starting distribution of the imaging zonhomogeneous medium and having outer boundaries extending to infinity [50]. The fine homogeneous utilizing the known values of the bath.mesh (forward solution) has 3903 nodes and 7804 triangular elements while the coarse one In this case, the complex values are transformed into their effective log magnitude and ph(reconstruction) has 559 nodes and 1044 elements. The average node spacing for these two values viameshes is $2 . 2 5 \\mathrm { m m }$ nsfo and $6 . 0 8 \\mathrm { m m }$ elationships d, respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,864,941,922]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ibutions. The different cases include: (a) transmitting at antenna #1 and receiving at anteFigure 7 shows the plots of several rows of the Jacobian matrix using the DDA #8, (b) transmitting at antenna #5 and receiving at antenna #13, and (c) transmitting at antennaalgorithm on the 1085 node grid corresponding to different transmit and receive antenna and recepairs at $1 3 0 0 \\mathrm { M H z }$ enna #12, respectively. For the magnitud and homogeneous bath properties of $\\epsilon _ { r b } = 2 2$ here and $\\sigma _ { b } = 1 \\mathrm { ( S / m ) }$ yellow . These red zone extending straight between each of the associated antennas and decreasing rapidly calculations all assume that this is the first iteration of a reconstruction problem where the starting distribution of the imaging zone is homogeneous utilizing the known values of the bath. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[277,112,939,142]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,151,870,624]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 7. Plots of the effective log magnitude (left) and phase (right) distributions for various rows of Jacobian matrix $( \\\\mathbf { m } ^ { 2 } )$ , corresponding to multiple transmitter/receiver pairs, for the discrete dipole approximation (DDA)-based algorithm. The distributions are presented on the DDA grid. Note that the plotting algorithm smoothed the imaging zone shape with triangles around the sharp edges of the reconstruction grid. \"]","image_footnote":"[]","img_path":"images/0093/1007f0c78139fdc7adcc3e23f88fa44d61b29392056ce74004db0d075770197c.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,715,941,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this case, the complex values are transformed into their effective log magnitude and phase values via their transformation relationships described in Meaney et al. [39] for viewing their distributions. The different cases include: (a) transmitting at antenna #1 and receiving at antenna #8, (b) transmitting at antenna #5 and receiving at antenna #13, and (c) transmitting at antenna $\\# 6$ and receiving at antenna #12, respectively. For the magnitude plots, there is a cigar-like yellow and red zone extending straight between each of the associated antennas and decreasing rapidly and oscillating about zero in the orthogonal direction to both sides with respect to the main axis of the band. Given that each matrix term is the change in the field measured at the receiver with respect to a change in the properties at a pixel for a signal broadcast at a transmitter, these distributions effectively represent sensitivity maps for the given transmit/receive pair antennas. It is important to note that these distributions are reciprocal—i.e., the distribution for transmitting from antenna $A$ to $B$ is the same as that for transmitting from $B$ to $A$ . Reciprocity is a key feature in exploiting the adjoint technique. The corresponding phase plots show a similar but wider main band extending between the associated antennas. Extending outwards in the orthogonal direction from this main band, the phase values increase from negative values and then oscillate about zero outwards while diminishing in amplitude. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,112,941,156]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,159,941,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 8 shows the corresponding distributions for the FE-based algorithm plotted on the associated 559 node mesh. The overall effective magnitude and phase distributions are quite similar. The overall scaling is slightly different because the individual values of the Jacobian matrix terms are with respect to the effective grid area immediately surrounding each pixel in the imaging zone. For the FE-based arrangement, the area is $9 6 . 0 \\mathrm { m m } ^ { 2 }$ while that for our uniform grid/DDA configuration, it is $6 0 . { \\overset { - } { 8 } } \\operatorname* { m m } ^ { 2 }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,256,870,732]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 8. Plots of the effective log magnitude (left) and phase (right) distributions for various rows of Jacobian matrix $( \\\\mathbf { m } ^ { 2 } )$ , corresponding to multiple transmitter/receiver pairs, for the finite element (FE)-based algorithm. The distributions are presented on the coarse FE-mesh. \"]","image_footnote":"[]","img_path":"images/0728/90946d47402f824485a464f987aec2dadec6b23611acc374f713f28a56de0bc8.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,793,941,838]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Other than this scaling factor, the results are essentially identical. Figure 9 shows the maps of each row of a FE-based Jacobian matrix divided by the associated DDA rows (both effective log magnitudes and phases). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[899,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[277,104,860,582]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 9. Plots of the effective log magnitude (left) and phase (right) distributions for ratios of Jacobian matrices calculated with DDA and FE-based schemes. The distributions are presented on the DDA grid. \"]","image_footnote":"[]","img_path":"images/0772/190a2df3d62cdc11fd7323bfd2b5d62525a9bc6d3e1df63d8e036240efa69f89.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,642,941,837]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In these cases, the FE-based distributions were first mapped to the DDA-based grid using a linear interpolation and divided pixel-by-pixel by the DDA distributions. The results are nearly uniform distributions across the domain except for large and isolated perturbations along arcs outside of and following the trajectory of the main bands within both the associated magnitude and phase distributions. The two distributions differ by a scaling factor which is related to the fact that the local area in the imaging zone is different because the number of nodes is different for each implementation. This area term has an immediate impact as can be seen in Equation (1). These jumps are caused by instances where the values in the DDA-based distributions are near zero (along the loci of points where the distributions cross zero) while the mapped version of the FE-based distribution is slightly altered spatially (still crossing zero), resulting in these disruptions. In spite of these aberrations, which are minor, the overall uniform distributions confirm the excellent match between the Jacobian calculations for the two methods. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,848,438,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Computation Time ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,868,941,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the computation time, we only considered the recurring steps at each iteration. For instance, the computation time for the weighting factors that only needed to be calculated once and stored in memory was not counted. For the FE-based approach, the code was written in FORTRAN77 and was compiled with gfortran (v. 7.5.0) and running on a single 4-core Xeon E3-1270 3.60 GHz processor with hyperthreading enabled and 32 GBytes of DDR4 2133 MHz RAM running the Ubuntu $1 8 . 0 4 \\ \\mathrm { L T S } )$ operating system. For the DDA-based algorithm, the software code was written in MATLAB (v. R2019b MathWorks, Inc., Natick, MA, USA) and ran on the same machine. The average time (averaged over 20 iterations) for computing the FE-based Jacobian matrix was $1 . 0 8 s$ . The corresponding time for the DDA-based code was 0.0055 s. It is important to note that the sizes of these two matrices are different. While the number of rows for each is the same (16 transmit antennas $\\times \\ 1 5$ receive antennas per each transmitter), the number of nodes in the field of view (i.e., the number of columns of the matrix) is different. For the FE-based scheme, the number of columns was 559 while that for the DDA-base method was 1085. Even with this considerable difference, the new DDA-based approach was substantially faster. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,112,941,277]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,290,477,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. Experimental Validation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[280,307,941,367]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The 2D DDA forward solver and the corresponding Jacobian matrix are embedded in the log-magnitude and phase format reconstruction algorithm. The fundamental aspects of the reconstruction algorithm and the 2D DDA were previously investigated by the authors [27,42,51,52] and are employed for this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,368,941,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The microwave breast imaging system at Chalmers University of Technology [53] is comprised of an imaging tank filled with a coupling medium, i.e., mixture of glycerin and water (80:20 ratio) and a surrounding circular antenna array comprised of 16 monopole antennas. The lossy mixture is a tissue mimicking medium and resembles the breast tissue for purposes of imaging. The $4 \\mathrm { c m }$ diameter cylindrical phantom filled with 84:16 glycerin–water mixture is positioned in front of antennas #6 and #7, shown in Figure 10. The scattering parameters of the system were measured via the Vector Network Analyzer (Rohde & Schwarz ZNBT8) connected to the antenna array, and are provided as the measurement data to the reconstruction algorithm in form of two sets of 240 (16 transmitter $\\times \\ 1 5$ receiver per transmitter) measurements (magnitude and phase parts of the electric fields). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[289,535,675,765]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 10. The photograph of the measurement setup for the case that a cylindrical inclusion is positioned close to antennas #6 and #7. \"]","image_footnote":"[]","img_path":"images/0096/0a05596500d5690e6d83c2c8178a5a172435c688590d0bdc0425a8e0e82bac01.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,814,941,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At $1 5 0 0 ~ \\mathrm { M H z }$ , the dielectric properties for the 80:20 water–glycerin mixture used in the imaging tank was measured such that the relative permittivity $\\epsilon _ { r , b a t h } = 2 0 . 9$ and conductivity $\\sigma _ { b a t h } = 1 . 3 5 \\ : ( \\mathrm { S / m } )$ . The corresponding values for the 84:16 water–glycerin mixture used in the cylindrical phantom (object) are $\\epsilon _ { r , o b j } = 1 6 . 9 $ , $\\sigma _ { o b j } = 1 . 1 5 \\ : ( \\mathrm { S / m } )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,875,939,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 11 shows the reconstructed relative permittivity and conductivity images as a function of iteration number. The circular object is visible in both permittivity and conductivity images in all iterations at an off-centered position (a circle is drawn to show the exact location of the object). The sequence of images illustrates how the algorithm recovers the object in the first few iterations and then gradually refines it. We observe that the reconstructed permittivity images are more accurately recovered compared to those of the conductivity, especially the conductivity images have more artefacts surrounding the phantom position while the permittivity images are not as affected by the artefacts and are smoother. This observation is in line with previous investigations assessing image quality [24,54]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,178,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[277,112,941,203]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,217,939,488]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 11. Images of reconstructed relative permittivity (top row) and conductivity $( S / \\\\mathrm m )$ (bottom row) at $1 5 0 0 \\\\mathrm { M H z }$ as a function of iteration number. \"]","image_footnote":"[]","img_path":"images/0455/6668a78e05d8a9514be1d9bbe979510b93904fccd5725ef459dd273d6b5c238f.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[277,532,941,638]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To confirm the convergence of the reconstruction algorithm, we compare the field calculations with the actual measured data. The field projections refer to the calibrated data as the measured data for the homogeneous imaging tank (without the phantom) subtracted from the inhomogeneous measured data (containing the phantom). Figure 12 shows the computed magnitude and phase projections due to a single transmitter at selected iterations compared with that of the actual measured data. The projections are of similar shapes as the measured data at all iterations and monotonically converge towards them. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[137,658,865,839]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 12. Comparison of calculated magnitude and phase projections of the signals transmitted from Antenna 1 for multiple iterations as a function of receiver number. The actual measurement projection is also shown. \"]","image_footnote":"[]","img_path":"images/1022/c1db2236c780aacbeafc8a5456042bbe36d2d3de799265b55f9058666890dc2d.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,112,942,172]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 13 shows the error of the optimization process for image reconstruction. The relative error (normalized to the first iteration) decreases monotonically with increasing iterations. In this case, the error decreased from 1 to 0.135 in 18 iterations. The stopping criterion is met when the decrease in error from one iteration to the next is less than $1 \\times 1 0 ^ { - 3 }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[282,187,561,302]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 13. Computed relative L2 norm error of projections for the experimental study as a function of number of iterations. \"]","image_footnote":"[]","img_path":"images/0452/afd8da8afce4abd478ee2d93394a4253486aa693567052692305c80ff0c1421c.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[280,349,515,363]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Discussion and Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[280,367,941,606]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For microwave tomographic type imaging algorithms, construction of the Jacobian matrix contributes significantly to the overall computation time. It is computed at each reconstruction iteration, so its time impact is important. Previous imaging techniques have employed the adjoint method which exploits reciprocity to dramatically reduce the computation time. For those implementations, the reconstruction algorithm was finite element based, such that computing the Jacobian meant performing numerous integrations over the various triangular elements and sub-elements within the imaging zone just to calculate a single value within the matrix. The net consequence was that the time was still substantial. In this formulation, we exploit the observation that the distributions of rows of the Jacobian produce effective sensitivity maps with respect to the pair of transmitting and receiving antennas. Inspection of the adjoint-based algorithms used to produce the matrix shows that when the parameter mesh overlaps exactly with the forward solution mesh, the net effect is that the sensitivity distributions are simplified to simple multiplications of the field vectors due to sources at both the transmit and receive antennas. This allows each row of the matrix to be computed as a simple vector–vector product of the two forward solutions which is a dramatically smaller computation task than before. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,607,941,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It should be noted that this approach could be adapted to situations where the forward solution mesh is not identical to the parameter reconstruction mesh. In those situations, the rows of the Jacobian could be computed using this approach as if with the assumption that the two meshes are the same. Subsequently, this distribution could then be mapped from the one mesh to the other utilizing a simple matrix-vector multiplication. While this would involve extra computational steps compared to this preferred implementation, it would most likely be more efficient than existing methods for computing the Jacobian matrix. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,712,941,831]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For many algorithms, the computation time for constructing the Jacobian matrix usually consumes the second most amount of time behind that for computing the forward solutions. However, with the advent of the discrete dipole approximation approaches, the forward solution times are reduced dramatically—to the point where the times for constructing the Jacobian matrix may become comparable. In keeping with reducing the overall time, it is imperative that this task not be ignored. Our new treatment allows the Jacobian matrix computation to be substantially reduced and has a direct impact on the overall image reconstruction time without sacrificing accuracy. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,832,941,876]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The reconstructed images from the experimental study confirm that the simple and efficient calculation of the Jacobian matrices from our new approach and the DDA forward solutions produce high quality images in a highly efficient manner. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[278,114,941,211]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author Contributions: The following summarizes the author contributions: conceptualization, S.H. and P.M.; methodology, S.H., P.M. and A.F.; software, S.H., S.G., and P.M.; validation, S.H., S.G., P.M., and A.F.; formal analysis, S.H., P.M., and A.F.; investigation, S.H., P.M., and A.F.; resources, A.F. and M.P.; writing–original draft preparation, S.H. and P.M.; writing–review and editing, S.H., S.G., P.M. and A.F.; visualization, S.H., S.G. and P.M.; supervision, P.M., A.F.; project administration, A.F. and M.P.; funding acquisition, P.M. and M.P. All authors have read and agreed to the published version of the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,218,939,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding: This work was sponsored by NIH grant # R01-CA240760 and a Chalmers Foundation Excellence grant. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,253,704,267]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflicts of Interest: The authors declare no conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,281,389,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abbreviations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[280,300,655,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The following abbreviations are used in this manuscript: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,325,551,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DDA Discrete Dipole Approximation FE Finite Element FDTD Finite-Difference Time-Domain ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,381,144,394]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,398,941,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. 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[CrossRef] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,178,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,112,941,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,179,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 of 16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,114,944,321]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,61,178,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensors 2021, 21, 729 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[894,61,939,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 of 16 ","text_format":null,"text_level":null,"type":"discarded"}],"string":"[\n {\n \"bbox\": \"[58,120,100,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Letter \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,129,835,203]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Expansion of the Nodal-Adjoint Method for Simple and Efficient Computation of the 2D Tomographic Imaging Jacobian Matrix \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[62,219,882,236]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Samar Hosseinzadegan ${ \\\\bf 1 } _ { \\\\mathbb { D } }$ , Andreas Fhager ${ \\\\bf 1 } _ { \\\\mathbb { D } }$ , Mikael Persson 1, Shireen Geimer ${ \\\\mathfrak { 2 } } _ { \\\\mathbb { O } }$ and Paul Meaney 2,\\\\* \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,259,939,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Electrical Engineering Department, Chalmers University of Technology, 41296 Gothenburg, Sweden; samar.hosseinzadegan@gmail.com (S.H.); andreas.fhager@chalmers.se (A.F.); mikael.persson@chalmers.se (M.P.) 2 Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA; shireen.geimer@dartmouth.edu Correspondence: paul.m.meaney@dartmouth.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,340,941,569]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: This paper focuses on the construction of the Jacobian matrix required in tomographic reconstruction algorithms. In microwave tomography, computing the forward solutions during the iterative reconstruction process impacts the accuracy and computational efficiency. Towards this end, we have applied the discrete dipole approximation for the forward solutions with significant time savings. However, while we have discovered that the imaging problem configuration can dramatically impact the computation time required for the forward solver, it can be equally beneficial in constructing the Jacobian matrix calculated in iterative image reconstruction algorithms. Key to this implementation, we propose to use the same simulation grid for both the forward and imaging domain discretizations for the discrete dipole approximation solutions and report in detail the theoretical aspects for this localization. In this way, the computational cost of the nodal adjoint method decreases by several orders of magnitude. Our investigations show that this expansion is a significant enhancement compared to previous implementations and results in a rapid calculation of the Jacobian matrix with a high level of accuracy. The discrete dipole approximation and the newly efficient Jacobian matrices are effectively implemented to produce quantitative images of the simplified breast phantom from the microwave imaging system. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,585,939,614]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: nodal adjoint method; Jacobian matrix; discrete dipole approximation; computational efficiency; microwave tomography; breast imaging \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,658,248,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Academic Editor: Andrea Randazzo Received: 3 December 2020 Accepted: 19 January 2021 Published: 22 January 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,728,258,782]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,659,394,674]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,678,941,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Microwave imaging is an emerging technology that is beginning to see increased clinical use for a number of applications. These include breast cancer imaging [1–4], stroke diagnosis [5,6], bone imaging [7] and others. For these applications, there is usually a significant endogenous contrast that can be exploited for imaging. For breast cancer imaging, there is a substantial property contrast between benign and malignant tissue [8–10]; for stroke diagnosis, there is a large contrast between blood and normal brain tissue [11]; for bone, there is a significant correlation between the dielectric properties and bone density [7]. In addition, the dielectric properties can be exploited to recover functional information such as temperature monitoring during thermal therapy [12,13] due to their temperature dependence [14]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,813,941,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The most widely applied area for microwave imaging has been in the area of breast cancer imaging. The three most prominent microwave imaging techniques include radar, holography and tomography or inverse problems. Radar approaches can be either in a backscatter or transmission mode, where broadband signals are transmitted and received by either the same antenna or others in an array. The signals are time shifted so as to focus the composite signals at a particular pixel in the field of view and the sum of these components is recorded. This procedure is repeated for all points in the domain until an image is produced. The work by Fear and Stuchly [4] is a good example of the reflection-based technique which has been used in simulation, phantom and limited patient exams. The Craddock group at the University of Bristol has produced good results with their transmission-based system which has been used in clinical trials [1,15]. Microwave holography generally assumes that the broadcast signal and those transmitted through and reflected back from the target are spherical waves which can be decomposed into a superposition of plane waves through a Fourier transform [16]. Each of these can be back propagated to the target and re-transformed into the spatial domain for target identification and characterization. These algorithms are effective in both 2D and 3D. The most prominent effort in this area is by the Nikolova group at McMaster University which has implemented a system that has advanced to phantom studies [17]. For the tomographic approach, numerous groups have produced simulation studies [18–21] on both classic conical structures and with data from actual MR exams [22]. Several approaches have advanced to phantom and animal studies [12,23–26] and there have been several patient studies by the Dartmouth College group—particularly in breast cancer neoadjuvant chemotherapy monitoring [2]. This paper focuses entirely on the tomography approaches since these are the ones that require construction of a Jacobian matrix as part of their image reconstruction process. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,54,257,97]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"三 sensors\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[58,794,154,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"cc + BY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[687,967,936,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://www.mdpi.com/journal/sensors \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[62,966,396,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729. https://doi.org/10.3390/s21030729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[865,61,939,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MDPI \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,499,147,521]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\\u0001-\\u0003\\u0001\\u0004\\u0005\\u0006\\u0007\\b \\u0001-\\u0003\\u0004\\u0005\\u0006\\u0007 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,825,265,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright: $^ ©$ 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,530,257,640]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Citation: Hosseinzadegan, S.; Fhager, A.; Persson, M.; Geimer, S.; Meaney, P. Expansion of the Nodal-Adjoint Method for Simple and Efficient Computation of the 2D Tomographic Imaging Jacobian Matrix. Sensors 2021, 21, 729. https:// doi.org/10.3390/s21030729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,110,941,379]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,381,941,618]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the consistent complaints about microwave tomography is the long computation times. This is due primarily to heavy resources needed for the multiple forward solution calculations at each iteration. These times have generally ranged from several minutes for some 2D implementations [27] to many hours and even days for larger 3D reconstructions that often require parallelized multi-processors and graphical processing units (GPUs) to accelerate the computation speed [18,23,24]. In fact, the EMTensor group is exploring massively parallel, cloud computing to solve the computational issues for their portable and computationally expensive system [28]. These concerns have been somewhat ignored because there are such significant challenges in just recovering a diagnostically relevant image. Problems have most often revolved around the issues of convergence to local minima [29], the need for a priori information by some systems [21,30], and the amount of measurement data necessary for reconstructing viable images and the associated hardware requirements to meet this need [31]. In most cases, it was generally assumed that the computational issues could be addressed later—especially since computer power has consistently improved by factors of two or so every 18 months for several decades now according to Moore’s Law [32]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,620,941,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"While the forward solution computation costs are the most substantial, there are other aspects of these formulations which also contribute to the slow overall computation. One critical component of most microwave tomographic imaging techniques, and for that matter most inverse problems, is the Jacobian matrix [33]. While not called this exact term in many microwave formulations, the net result is similar for all techniques. In essence, the terms of the Jacobian are the change in the field registered by the jth receiver due to a small change in the permittivity at a single node in the parameter reconstruction mesh while illuminated by the ith transmitter [34]. These gradient terms provide direction to the iteration process during Newton-like reconstruction processes. The overall size of the matrix is $\\\\left( N _ { t } \\\\times N _ { r } \\\\right) \\\\times N _ { p } ,$ , where $N _ { t } , N _ { r } ,$ and $N _ { p }$ are the number of transmitters, number of receivers per each transmitter, and the number of parameter values being reconstructed, respectively. In this sense, the matrix can be quite large and its formation can impose a significant impact on the overall computation times. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,813,941,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cui et al. [35] introduced a Green’s function with an integral formulation technique to effectively form the Jacobian matrix which is subsequently incorporated into a distorted Born approximation inverse solution. The technique has been shown to work well with low contrast and small scatter problems when the starting property distribution estimate is that of the surrounding background. This approach is subsequently utilized by Shea et al. [18] and further by Karadima et al. [23]. Zakaria et al. [36] used the finite element contrast source inversion method for microwave imaging and reported in detail on the gradients of the cost function. Van den Berg and Kleinman [37] also devised a contrast source inversion method to solve the inverse problem. While this did not explicitly compute a Jacobian matrix, it does compute the gradients of the cost function which are in the form of Frechet derivatives, called the Polak–Ribiere conjugate gradient directions. This approach is further used by Gilmore et al. [25] which expands upon this concept by adding a multiplicative regularization. The contrast source inversion technique is also used by Rubaek et al. [38] which expands the concept to a log-transformed version, similarly to that used in Meaney et al. [39]. The conversion of the complex Jacobian terms to the log-transformed counterpart involves only minor algebraic operations. Joachimowicz et al. utilizes an iterative variation scheme derived from a classical Newton procedure [40]. The solution was derived for the 2D TM situation and the computation of the Jacobian matrix is a Green’s function formulation applied to a Method of Moments technique for the forward solution. Efforts by Souvorov et al. [34] utilized an iterative Fourier inversion method where the forward solution was based on integral equations. The Jacobian matrix formulation was quite similar to that of Cui et al. [35]. Later efforts by Bindu and Semenov [41] utilized the distorted Born approximation with an FDTD forward solution and similar Jacobian formulation. In none of these cases did the groups actually call their matrices the Jacobian matrix. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,178,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,112,941,380]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,382,941,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"More recently, the discrete dipole approximation (DDA) has been introduced as a means of dramatically reducing the forward solution computation time and the associated memory requirements [42]. This has the potential to reduce the forward solution time of a 2D imaging problem by an order of magnitude or more. Interestingly, the uniform grid configuration informed our understanding of the Jacobian formulation to the point where its construction is now reduced to a low number of vector–vector multiplications. In a more rigorous analysis, this new derivation originates from the nodal adjoint technique introduced by Fang et al. [43]. The net result is that each element of the matrix is created by the multiplication of two complex numbers and a pre-computed scalar term. The adjoint method is an exact method for computing the Jacobian matrix and relies largely on the principle of reciprocity. It is widely used in multiple imaging modalities including optical coherence tomography and electrical impedance tomography in addition to microwave imaging [44–48]. This approach is quite general for the 2D problem and can be readily extrapolated to the 3D situation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,592,941,769]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The paper focuses on the calculation of the Jacobian matrix as an expansion of the nodal adjoint technique with respect to its accuracy and computational cost. A comparison between Jacobian matrices formed via the finite element-type (FE) and the discrete dipole approximation-based (DDA) tomographic image reconstruction algorithms is performed. Our goal is to retain the efficiency embedded in the DDA forward solver and does not allow the Jacobian matrix formation to undermine the capabilities of the fast forward solver. In this study, we present an approach which utilizes the DDA forward solution configuration with the nodal adjoint formulation of the Jacobian matrix allowing us to preserve both performance and accuracy. The accuracy of the Jacobian matrix is investigated with respect to our FE-based version. Additionally, experimental data acquired using the microwave breast imaging system at Chalmers University of Technology is used to image a tissue-like phantom to validate our algorithm. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,771,941,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The following sections describe the mathematical underpinnings of the method and show examples of Jacobian matrix construction in comparison to an existing finite elementbased formulation together with reconstructed images employing the described technique. The paper is organized in the following format: Section 2 describes the nodal adjoint method used for calculation of the Jacobian matrices of the FE and the DDA forward solvers together with investigations of their computational costs from a mathematical point of view; Section 3 shows simulated numerical results from the Jacobian matrices of the FE and DDA solvers, the computation times for these methods as well an image reconstruction validation by phantom experiment; Section 4 discusses the results and concludes the study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,178,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,114,366,127]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,131,941,266]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Beginning with the finite element representation of the dual mesh-based nodal adjoint method derivation of the Jacobian matrix [43], Figure 1 shows the overlapping forward solution mesh (red) and the parameter mesh (blue). For the 2D case, all of the forward solution and parameter mesh elements are triangles. This discussion is readily extended to the 3D case by replacing the triangles with tetrahedrons and expanding the forward solution from this scalar problem to the necessary 3D vector forward distributions. In previous implementations, the size of the forward solution mesh elements was noticeably smaller than that for the parameter mesh because the former’s size is dictated by the sampling requirements to achieve an accurate forward solution [49]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,279,828,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Overlapping forward solution and parameter meshes corresponding to the nodes and elements. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0232/617643bf3bff7efa310a7126ee77b77da7bd5eda428a75aab548cb1c3ee49f0d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,505,942,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this case, a single term of the Jacobian associated with the sth source antenna, the $r$ th receive antenna and the τth parameter mesh node can be written as follows: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[394,545,821,581]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0743/98d4ff600c01aac3eb7d754e63f66a8ea9f280a8cdaff40db5f31a783056ad59.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nJ ( ( s , r ) , \\\\tau ) = - \\\\sum _ { n \\\\in \\\\Omega _ { \\\\tau } } \\\\sum _ { e \\\\in \\\\Omega _ { n } } \\\\frac { 1 } { j \\\\omega \\\\mu _ { 0 } | J _ { r } | } \\\\frac { A _ { e } } { M } \\\\phi _ { \\\\tau } ( \\\\vec { p } _ { n } ) E _ { s } ( \\\\vec { p } _ { n } ) E _ { r } ( \\\\vec { p } _ { n } )\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[278,590,941,816]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $E _ { s } ( \\\\vec { p } _ { n } )$ and $E _ { r } ( \\\\vec { p } _ { n } )$ are the electric field values due to sources from both antennas $s$ and $r$ at the nodal location ${ \\\\vec { p } } _ { n } ,$ and $\\\\phi _ { \\\\tau } ( \\\\vec { p } _ { n } )$ is the parameter mesh basis function (In this situation, we utilize linear basis functions over each triangular element where its value is 1 at the designated node and transitions linearly to zero at the other two nodes and along the edges between these two nodes) due to node $\\\\tau$ in the parameter mesh and evaluated at node $n$ in the forward solution mesh. $\\\\Omega _ { n }$ is the region composed of forward solution elements immediately associated with node $n$ (i.e., for the region where the forward solution basis function for node $n$ is non-zero) (Figure 2). $e$ is one of the forward solution elements within $\\\\Omega _ { n } , A _ { e }$ is the area of element $e$ and $M$ is the number of vertices in a triangle (3). $\\\\omega$ is the angular frequency, $\\\\mu _ { 0 }$ is the free space magnetic permeability, $J _ { r }$ is the amplitude of a signal transmitted by the receive antenna $r ,$ and $j$ is the imaginary unit. $\\\\textstyle \\\\sum _ { e \\\\in \\\\Omega _ { n } } ( \\\\quad )$ is essentially a numerical integration of the associated terms over element e. $\\\\Omega _ { \\\\tau }$ is the region composed of parameter elements immediately associated with node $\\\\tau$ (i.e., for the region where the parameter basis function for node $\\\\tau$ is non-zero) (Figure 3). It should be noted that forward solution node $n$ must lie within $\\\\Omega _ { \\\\tau }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,178,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,110,757,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. Forward solution mesh nodes; example of node $n$ and corresponding region $\\\\\\\\Omega _ { n }$ is sketched. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0031/285a663cb1469770353bf204a47d9acab8c090f09cb952c154976e1d7b158cf3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[280,379,747,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Parameter mesh nodes; example of node $\\\\\\\\tau$ and corresponding region $\\\\\\\\Omega _ { \\\\\\\\tau }$ is sketched. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0667/a5b3b0611039041e66ca8cfb1938f27fdb0a8691f26aac8504ffa3873391a230.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,642,941,701]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As can be seen from Figure 2, $\\\\phi _ { \\\\tau }$ is non-zero for all seven forward solution nodes in $\\\\Omega _ { n }$ . Therefore, these summations in Equation (1) need to be performed explicitly. However, an interesting observation is made if both the forward solution and parameter meshes overlap exactly (Figure 4). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,702,942,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this case, there are six parameter mesh elements surrounding node $\\\\tau$ and only seven forward solution mesh nodes within $\\\\Omega _ { \\\\tau }$ . In fact, for the integration (summations) which is performed over just the six $\\\\tau$ -associated elements, the terms are only non-zero for node $\\\\tau$ and zero for all the surrounding ones (Again, this is true for the linear basis functions used in this derivation). In this case, the inner summation can be reduced: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,785,880,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0270/2d1e28635bbc52c9fa5b3cb080921bf42436541c93ab6bb61878940321939670.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\frac { 1 } { j \\\\omega \\\\mu _ { 0 } | J _ { r } | } \\\\frac { 1 } { M } \\\\sum _ { e \\\\in \\\\Omega _ { n } } A _ { e } \\\\phi _ { \\\\tau } ( \\\\vec { p } _ { n } ) E _ { s } ( \\\\vec { p } _ { n } ) E _ { r } ( \\\\vec { p } _ { n } ) = \\\\frac { 1 } { j \\\\omega \\\\mu _ { 0 } | J _ { r } | } E _ { s } ( \\\\vec { p } _ { \\\\tau } ) E _ { r } ( \\\\vec { p } _ { \\\\tau } ) \\\\sum _ { e \\\\in \\\\Omega _ { n } } \\\\frac { A _ { e } } { M } \\\\sum _ { e \\\\in \\\\mathcal { S } _ { s } } B _ { e } ( \\\\vec { p } _ { \\\\tau } ) B _ { e } ( \\\\vec { p } _ { n } )\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[277,831,941,862]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the situation where the mesh is effectively uniform, the new summation becomes a constant, where $A$ is the sum of the area in $\\\\Omega _ { \\\\tau }$ . This ultimately reduces the Jacobian term to \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[465,871,751,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0778/97a71f35063e59cb8ecccabe38ee57d35ef06a79ade49e29927eb49bf6c424c5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nJ ( ( s , r ) , \\\\tau ) = \\\\frac { - 1 } { j \\\\omega \\\\mu _ { 0 } \\\\vert J _ { r } \\\\vert } \\\\frac { A } { M } E _ { s } ( \\\\vec { p } _ { n } ) E _ { r } ( \\\\vec { p } _ { n } )\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[277,112,941,204]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This means that each term in the Jacobian is reduced to a simple multiplication of the two forward solutions due to sources from antennas $s$ and $r$ at node $\\\\tau$ and also multiplied by a constant, $\\\\frac { 1 } { j \\\\omega \\\\mu _ { 0 } | J _ { r } | } \\\\frac { A } { M }$ . It should be noted that for an entire row of the Jacobian matrix (i.e., where $s$ and $r$ do not change), each element of the matrix is a similar multiplication at different nodes of the mesh. This implies that an entire row of the Jacobian can be computed as a vector–vector multiplication of the two field distributions times a constant: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,215,704,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0971/9be2b9eca2764f99049628d81ab886e9b74b739eddf683ad3e647b2362049c24.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\overline { { J } } ( s , r ) = \\\\frac { - 1 } { j \\\\omega \\\\mu _ { 0 } \\\\lvert J _ { r } \\\\rvert } \\\\frac { A } { M } \\\\vec { E } _ { s } \\\\vec { E } _ { r }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[278,275,697,507]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Forward solution mesh and parameter mesh overlap exactly. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0993/d30d536fcb55f2cd584cd152d1d6dfe765fab5b9ccea61285a213fc1a0f553f9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,541,941,720]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thus, computation of the entire Jacobian matrix can be reduced to $n _ { s } \\\\times n _ { r }$ vector– vector $( n _ { p } \\\\log )$ multiplications where $n _ { s }$ and $n _ { r }$ are the number of transmitting antennas and the number of receiving antennas per each transmitter, and $n _ { p }$ is the number of nodes in the parameter mesh. In comparison, the computation for a single element of the Jacobian matrix using the nodal adjoint method is the product of two $n _ { f }$ long vectors and a corresponding diagonal matrix, where $n _ { f }$ is the number of nodes in the forward solution mesh. This amounts to $2 \\\\times n _ { f }$ computations for a single element and $2 \\\\times n _ { f } \\\\times n _ { p }$ computations for a complete row. Therefore, the new approach has a factor of $2 \\\\times n _ { f }$ fewer computations—corresponding to several orders of magnitude faster construction. This is a general relationship and it can be easily demonstrated that it holds for other geometric configurations such as rectangular grids used in finite difference time domain and the discrete dipole approximation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,732,356,745]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,749,939,763]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. Comparison of Jacobian Matrix Row Distributions with That of Known Reconstruction Algorithm \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,766,942,856]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 5 shows a schematic diagram of a typical 2D imaging system arrangement. In this case, the monopole antennas are positioned on a $1 5 . 2 \\\\mathrm { c m }$ diameter circle, with antenna #1 being the lowest centered one and the subsequent ones ordered in a clockwise configuration. Each antenna broadcasts a signal for which the complementary 15 antennas act as receivers. This process is repeated for each antenna transmitting individually to produce a total of 240 measurements (16 transmitters $\\\\times 1 5$ receivers per transmitter). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[280,110,675,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. Schematic representation of imaging domain together with the antenna array.# 5 # 13 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0637/3ecaabba8a41783783c0e2bdacdb03b4976a4d7f95cb689833f9b16a22900083.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[277,391,941,466]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 6a shows the imaging zone for the discrete dipole approximation (DDA)\\u000fr,b = 22 method where the circular imaging zone is approximated by a subset of the uniform gridσb = 1(S/m) used for computing the forward solution. In this case, the complete grid is comprised of $6 4 \\\\times 6 4$ squares for a total forward solution zone ofAntenna # 1 $2 5 \\\\times 2 5 \\\\mathrm { c m } ^ { 2 }$ and each single cell is a $3 . 9 \\\\mathrm { m m }$ square. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[285,482,937,634]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 6. Representation of imagining domain with respect to the meshes used for forward solutionsFigure 6. Representation of imagining domain with respect to the meshes used for forward solutions (a,b) and property reconstruction (a,c(a,b) and property reconstruction (a,c). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0052/9e6a51908f95844d3ffc5ec9ee07ce8db2a91d1e4a8a26bfbdb17905008334fb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,684,941,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"diameters of 14.5 cm. It should be noted that for the forward solution, the region outside ofThe imaging zone is a step-wise circle consisting of 1012 squares and 1085 vertices meshes is represented using the boundary element method com(i.e., the number of unknowns) with an effective diameter of $1 4 . 0 \\\\mathrm { c m }$ the hom. Figure $^ { 6 \\\\mathrm { b } , \\\\mathrm { c } }$ eous medi show the and having outer boundaries extending to infinity [50]. The fine mesh (forward solution) has 3corresponding finite element (FE) meshes used in our FE-based reconstruction algorithm. nodes and 7804 triangular elements while the coarse one (reconstruction) has 559 nodes and 1As with the DDA approach, the antennas are configured on a circle concentric with the elements. The average node spacing for these two meshes is 2.25 mm and 6.08 mm, respectively.centre of the imaging zone. The meshes for the dual mesh approach (one for the forward Figure 7 shows the plots of several rows of the Jacobian matrix using the DDA algorithmsolution and one for the property reconstruction) are both inside the antenna array with the 1085 nodediameters of $1 4 . 5 ~ \\\\mathrm { c m }$ esponding to different transmit and receive antenna pairs at 1300 MHz a. It should be noted that for the forward solution, the region outhomogeneous bath properties of erb = 22 and σb = 1 (S/m). These calculations all assume that thiside of the meshes is represented using the boundary element method comprised of the the first iteration of a reconstruction problem where the starting distribution of the imaging zonhomogeneous medium and having outer boundaries extending to infinity [50]. The fine homogeneous utilizing the known values of the bath.mesh (forward solution) has 3903 nodes and 7804 triangular elements while the coarse one In this case, the complex values are transformed into their effective log magnitude and ph(reconstruction) has 559 nodes and 1044 elements. The average node spacing for these two values viameshes is $2 . 2 5 \\\\mathrm { m m }$ nsfo and $6 . 0 8 \\\\mathrm { m m }$ elationships d, respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,864,941,922]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ibutions. The different cases include: (a) transmitting at antenna #1 and receiving at anteFigure 7 shows the plots of several rows of the Jacobian matrix using the DDA #8, (b) transmitting at antenna #5 and receiving at antenna #13, and (c) transmitting at antennaalgorithm on the 1085 node grid corresponding to different transmit and receive antenna and recepairs at $1 3 0 0 \\\\mathrm { M H z }$ enna #12, respectively. For the magnitud and homogeneous bath properties of $\\\\epsilon _ { r b } = 2 2$ here and $\\\\sigma _ { b } = 1 \\\\mathrm { ( S / m ) }$ yellow . These red zone extending straight between each of the associated antennas and decreasing rapidly calculations all assume that this is the first iteration of a reconstruction problem where the starting distribution of the imaging zone is homogeneous utilizing the known values of the bath. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[277,112,939,142]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,151,870,624]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 7. Plots of the effective log magnitude (left) and phase (right) distributions for various rows of Jacobian matrix $( \\\\\\\\mathbf { m } ^ { 2 } )$ , corresponding to multiple transmitter/receiver pairs, for the discrete dipole approximation (DDA)-based algorithm. The distributions are presented on the DDA grid. Note that the plotting algorithm smoothed the imaging zone shape with triangles around the sharp edges of the reconstruction grid. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0093/1007f0c78139fdc7adcc3e23f88fa44d61b29392056ce74004db0d075770197c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,715,941,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this case, the complex values are transformed into their effective log magnitude and phase values via their transformation relationships described in Meaney et al. [39] for viewing their distributions. The different cases include: (a) transmitting at antenna #1 and receiving at antenna #8, (b) transmitting at antenna #5 and receiving at antenna #13, and (c) transmitting at antenna $\\\\# 6$ and receiving at antenna #12, respectively. For the magnitude plots, there is a cigar-like yellow and red zone extending straight between each of the associated antennas and decreasing rapidly and oscillating about zero in the orthogonal direction to both sides with respect to the main axis of the band. Given that each matrix term is the change in the field measured at the receiver with respect to a change in the properties at a pixel for a signal broadcast at a transmitter, these distributions effectively represent sensitivity maps for the given transmit/receive pair antennas. It is important to note that these distributions are reciprocal—i.e., the distribution for transmitting from antenna $A$ to $B$ is the same as that for transmitting from $B$ to $A$ . Reciprocity is a key feature in exploiting the adjoint technique. The corresponding phase plots show a similar but wider main band extending between the associated antennas. Extending outwards in the orthogonal direction from this main band, the phase values increase from negative values and then oscillate about zero outwards while diminishing in amplitude. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,112,941,156]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,159,941,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 8 shows the corresponding distributions for the FE-based algorithm plotted on the associated 559 node mesh. The overall effective magnitude and phase distributions are quite similar. The overall scaling is slightly different because the individual values of the Jacobian matrix terms are with respect to the effective grid area immediately surrounding each pixel in the imaging zone. For the FE-based arrangement, the area is $9 6 . 0 \\\\mathrm { m m } ^ { 2 }$ while that for our uniform grid/DDA configuration, it is $6 0 . { \\\\overset { - } { 8 } } \\\\operatorname* { m m } ^ { 2 }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,256,870,732]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 8. Plots of the effective log magnitude (left) and phase (right) distributions for various rows of Jacobian matrix $( \\\\\\\\mathbf { m } ^ { 2 } )$ , corresponding to multiple transmitter/receiver pairs, for the finite element (FE)-based algorithm. The distributions are presented on the coarse FE-mesh. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0728/90946d47402f824485a464f987aec2dadec6b23611acc374f713f28a56de0bc8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,793,941,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Other than this scaling factor, the results are essentially identical. Figure 9 shows the maps of each row of a FE-based Jacobian matrix divided by the associated DDA rows (both effective log magnitudes and phases). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[899,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[277,104,860,582]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 9. Plots of the effective log magnitude (left) and phase (right) distributions for ratios of Jacobian matrices calculated with DDA and FE-based schemes. The distributions are presented on the DDA grid. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0772/190a2df3d62cdc11fd7323bfd2b5d62525a9bc6d3e1df63d8e036240efa69f89.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,642,941,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In these cases, the FE-based distributions were first mapped to the DDA-based grid using a linear interpolation and divided pixel-by-pixel by the DDA distributions. The results are nearly uniform distributions across the domain except for large and isolated perturbations along arcs outside of and following the trajectory of the main bands within both the associated magnitude and phase distributions. The two distributions differ by a scaling factor which is related to the fact that the local area in the imaging zone is different because the number of nodes is different for each implementation. This area term has an immediate impact as can be seen in Equation (1). These jumps are caused by instances where the values in the DDA-based distributions are near zero (along the loci of points where the distributions cross zero) while the mapped version of the FE-based distribution is slightly altered spatially (still crossing zero), resulting in these disruptions. In spite of these aberrations, which are minor, the overall uniform distributions confirm the excellent match between the Jacobian calculations for the two methods. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,848,438,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Computation Time \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,868,941,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the computation time, we only considered the recurring steps at each iteration. For instance, the computation time for the weighting factors that only needed to be calculated once and stored in memory was not counted. For the FE-based approach, the code was written in FORTRAN77 and was compiled with gfortran (v. 7.5.0) and running on a single 4-core Xeon E3-1270 3.60 GHz processor with hyperthreading enabled and 32 GBytes of DDR4 2133 MHz RAM running the Ubuntu $1 8 . 0 4 \\\\ \\\\mathrm { L T S } )$ operating system. For the DDA-based algorithm, the software code was written in MATLAB (v. R2019b MathWorks, Inc., Natick, MA, USA) and ran on the same machine. The average time (averaged over 20 iterations) for computing the FE-based Jacobian matrix was $1 . 0 8 s$ . The corresponding time for the DDA-based code was 0.0055 s. It is important to note that the sizes of these two matrices are different. While the number of rows for each is the same (16 transmit antennas $\\\\times \\\\ 1 5$ receive antennas per each transmitter), the number of nodes in the field of view (i.e., the number of columns of the matrix) is different. For the FE-based scheme, the number of columns was 559 while that for the DDA-base method was 1085. Even with this considerable difference, the new DDA-based approach was substantially faster. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[894,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,112,941,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,290,477,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. Experimental Validation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,307,941,367]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The 2D DDA forward solver and the corresponding Jacobian matrix are embedded in the log-magnitude and phase format reconstruction algorithm. The fundamental aspects of the reconstruction algorithm and the 2D DDA were previously investigated by the authors [27,42,51,52] and are employed for this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,368,941,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The microwave breast imaging system at Chalmers University of Technology [53] is comprised of an imaging tank filled with a coupling medium, i.e., mixture of glycerin and water (80:20 ratio) and a surrounding circular antenna array comprised of 16 monopole antennas. The lossy mixture is a tissue mimicking medium and resembles the breast tissue for purposes of imaging. The $4 \\\\mathrm { c m }$ diameter cylindrical phantom filled with 84:16 glycerin–water mixture is positioned in front of antennas #6 and #7, shown in Figure 10. The scattering parameters of the system were measured via the Vector Network Analyzer (Rohde & Schwarz ZNBT8) connected to the antenna array, and are provided as the measurement data to the reconstruction algorithm in form of two sets of 240 (16 transmitter $\\\\times \\\\ 1 5$ receiver per transmitter) measurements (magnitude and phase parts of the electric fields). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[289,535,675,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 10. The photograph of the measurement setup for the case that a cylindrical inclusion is positioned close to antennas #6 and #7. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0096/0a05596500d5690e6d83c2c8178a5a172435c688590d0bdc0425a8e0e82bac01.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,814,941,873]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At $1 5 0 0 ~ \\\\mathrm { M H z }$ , the dielectric properties for the 80:20 water–glycerin mixture used in the imaging tank was measured such that the relative permittivity $\\\\epsilon _ { r , b a t h } = 2 0 . 9$ and conductivity $\\\\sigma _ { b a t h } = 1 . 3 5 \\\\ : ( \\\\mathrm { S / m } )$ . The corresponding values for the 84:16 water–glycerin mixture used in the cylindrical phantom (object) are $\\\\epsilon _ { r , o b j } = 1 6 . 9 $ , $\\\\sigma _ { o b j } = 1 . 1 5 \\\\ : ( \\\\mathrm { S / m } )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,875,939,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 11 shows the reconstructed relative permittivity and conductivity images as a function of iteration number. The circular object is visible in both permittivity and conductivity images in all iterations at an off-centered position (a circle is drawn to show the exact location of the object). The sequence of images illustrates how the algorithm recovers the object in the first few iterations and then gradually refines it. We observe that the reconstructed permittivity images are more accurately recovered compared to those of the conductivity, especially the conductivity images have more artefacts surrounding the phantom position while the permittivity images are not as affected by the artefacts and are smoother. This observation is in line with previous investigations assessing image quality [24,54]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,178,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[894,61,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[277,112,941,203]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,217,939,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 11. Images of reconstructed relative permittivity (top row) and conductivity $( S / \\\\\\\\mathrm m )$ (bottom row) at $1 5 0 0 \\\\\\\\mathrm { M H z }$ as a function of iteration number. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0455/6668a78e05d8a9514be1d9bbe979510b93904fccd5725ef459dd273d6b5c238f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[277,532,941,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To confirm the convergence of the reconstruction algorithm, we compare the field calculations with the actual measured data. The field projections refer to the calibrated data as the measured data for the homogeneous imaging tank (without the phantom) subtracted from the inhomogeneous measured data (containing the phantom). Figure 12 shows the computed magnitude and phase projections due to a single transmitter at selected iterations compared with that of the actual measured data. The projections are of similar shapes as the measured data at all iterations and monotonically converge towards them. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[137,658,865,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 12. Comparison of calculated magnitude and phase projections of the signals transmitted from Antenna 1 for multiple iterations as a function of receiver number. The actual measurement projection is also shown. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1022/c1db2236c780aacbeafc8a5456042bbe36d2d3de799265b55f9058666890dc2d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[894,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,112,942,172]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 13 shows the error of the optimization process for image reconstruction. The relative error (normalized to the first iteration) decreases monotonically with increasing iterations. In this case, the error decreased from 1 to 0.135 in 18 iterations. The stopping criterion is met when the decrease in error from one iteration to the next is less than $1 \\\\times 1 0 ^ { - 3 }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[282,187,561,302]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 13. Computed relative L2 norm error of projections for the experimental study as a function of number of iterations. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0452/afd8da8afce4abd478ee2d93394a4253486aa693567052692305c80ff0c1421c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[280,349,515,363]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Discussion and Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,367,941,606]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For microwave tomographic type imaging algorithms, construction of the Jacobian matrix contributes significantly to the overall computation time. It is computed at each reconstruction iteration, so its time impact is important. Previous imaging techniques have employed the adjoint method which exploits reciprocity to dramatically reduce the computation time. For those implementations, the reconstruction algorithm was finite element based, such that computing the Jacobian meant performing numerous integrations over the various triangular elements and sub-elements within the imaging zone just to calculate a single value within the matrix. The net consequence was that the time was still substantial. In this formulation, we exploit the observation that the distributions of rows of the Jacobian produce effective sensitivity maps with respect to the pair of transmitting and receiving antennas. Inspection of the adjoint-based algorithms used to produce the matrix shows that when the parameter mesh overlaps exactly with the forward solution mesh, the net effect is that the sensitivity distributions are simplified to simple multiplications of the field vectors due to sources at both the transmit and receive antennas. This allows each row of the matrix to be computed as a simple vector–vector product of the two forward solutions which is a dramatically smaller computation task than before. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,607,941,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It should be noted that this approach could be adapted to situations where the forward solution mesh is not identical to the parameter reconstruction mesh. In those situations, the rows of the Jacobian could be computed using this approach as if with the assumption that the two meshes are the same. Subsequently, this distribution could then be mapped from the one mesh to the other utilizing a simple matrix-vector multiplication. While this would involve extra computational steps compared to this preferred implementation, it would most likely be more efficient than existing methods for computing the Jacobian matrix. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,712,941,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For many algorithms, the computation time for constructing the Jacobian matrix usually consumes the second most amount of time behind that for computing the forward solutions. However, with the advent of the discrete dipole approximation approaches, the forward solution times are reduced dramatically—to the point where the times for constructing the Jacobian matrix may become comparable. In keeping with reducing the overall time, it is imperative that this task not be ignored. Our new treatment allows the Jacobian matrix computation to be substantially reduced and has a direct impact on the overall image reconstruction time without sacrificing accuracy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,832,941,876]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The reconstructed images from the experimental study confirm that the simple and efficient calculation of the Jacobian matrices from our new approach and the DDA forward solutions produce high quality images in a highly efficient manner. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,61,179,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensors 2021, 21, 729 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[894,61,939,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 of 16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[278,114,941,211]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author Contributions: The following summarizes the author contributions: conceptualization, S.H. and P.M.; methodology, S.H., P.M. and A.F.; software, S.H., S.G., and P.M.; validation, S.H., S.G., P.M., and A.F.; formal analysis, S.H., P.M., and A.F.; investigation, S.H., P.M., and A.F.; resources, A.F. and M.P.; writing–original draft preparation, S.H. and P.M.; writing–review and editing, S.H., S.G., P.M. and A.F.; visualization, S.H., S.G. and P.M.; supervision, P.M., A.F.; project administration, A.F. and M.P.; funding acquisition, P.M. and M.P. All authors have read and agreed to the published version of the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,218,939,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding: This work was sponsored by NIH grant # R01-CA240760 and a Chalmers Foundation Excellence grant. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,253,704,267]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflicts of Interest: The authors declare no conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,281,389,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abbreviations \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,300,655,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The following abbreviations are used in this manuscript: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,325,551,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DDA Discrete Dipole Approximation FE Finite Element FDTD Finite-Difference Time-Domain \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,381,144,394]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,398,941,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. 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Methods This study used Korea Workers' Compensation Insurance data, | and the sample comprised workers who claimed compensation for wrTBI from 2010 to 2019. The annual incidence of wrTBI was calculated as the rate per 100,000 workers. Time trends over the 10-year | and 15.5/100,000, respectively. The incidence of mild TBI among workers was higher in 2010, but moderate-to-severe TBI was higher after 2011. Conclusions Our findings highlight the need for providing | period were assessed using Poisson regression. Results The mean incidence of wrTBI was 28.4/100,000. Regarding the incidence rate of wrTBI by severity, mild TBI and moderate-to-severe TBI were 12.9/100,000 | information on mild TBI to workers as part of occupational safety and health education."},"author":{"kind":"string","value":"Bae, Suk Won|Lee, Min-Yong"},"content_list":{"kind":"list like","value":[{"bbox":"[83,89,140,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[135,113,859,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Incidence of Traumatic Brain Injury by Severity Among Work-Related Injured Workers From 2010 to 2019 ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[162,170,832,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An Analysis of Workers' Compensation Insurance Data in Korea ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[332,205,657,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Suk Won Bae, PhD and Min-Yong Lee, MD ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,246,486,400]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objective: This study aimed to investigate the status of work-related traumatic brain injury (wrTBI) in Korea between 2010 and 2019. Methods: This study used Korea Workers' Compensation Insurance data, and the sample comprised workers who claimed compensation for wrTBI from 2010 to 2019. The annual incidence of wrTBI was calculated as the rate per 100,000 workers. Time trends over the 10-year period were assessed using Poisson regression. Results: The mean incidence of wrTBI was 28.4/100,000. Regarding the incidence rate of wrTBI by severity, mild TBI and moderate-to-severe TBI were 12.9/100,000 and 15.5/100,000, respectively. The incidence of mild TBI among workers was higher in 2010, but moderate-to-severe TBI was higher after 2011. Conclusions: Our findings highlight the need for providing information on mild TBI to workers as part of occupational safety and health education. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,407,440,434]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: traumatic brain injury, incidence, worker's compensation, epidemiology, occupational injuries ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,434,484,562]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Traumatic brain injury (TBI) is an acute brain injury resulting from an external physical force to the head leading to short- or long-term physical and psychological problems. $^{1,2}$ Each year, approximately 69 million new cases of TBI are reported worldwide, $^{3,4}$ and almost $37\\%$ of all injury-related deaths in Europe are caused by TBI. $^{5}$ In 2017, approximately 248,000 cases of TBI were reported in Korea, among which the mortality rate among those older than 80 years was 120.6 per 100,000. $^{6}$ According to the World Health Organization, TBI has remained a significant public health problem and a leading cause of mortality and disability worldwide as of 2020. $^{7-9}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,562,484,588]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the United States and Europe, work-related TBI (wrTBI) accounts for less than $10\\%$ of all TBIs, but it still warrants much ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,603,484,635]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From the Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, South Korea (Dr Bae, Dr Lee); and Rehabilitation Medicine Center, Korea Workers' Compensation and Welfare Service Incheon Hospital, Incheon, South Korea (Dr Lee). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,635,482,654]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding sources: This work was supported by the Korea Workers' Compensation and Welfare Service, grant number 0720185002. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,654,482,675]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lee and Bae have no relationships/conditions/circumstances that present potential conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,675,482,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The JOEM editorial board and planners have no financial interest related to this research. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,686,482,736]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ethical considerations and disclosures: This study was exempted from ethics approval by the institutional review board of Seoul National University Hospital (IRB No. E-2108-150-1246) because the data in the Korea Workers' Compensation and Welfare Service were anonymized and de-identified. Accordingly, informed consent was also waived. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,736,482,797]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author contributions: S.W.B. conceived and planned the study, performed the analysis, wrote the original draft with input from all authors, visualized the results, validated the study, and contributed to the interpretation of the results. M.-Y.L. conceived and planned the study, validated the study, contributed to the interpretation of the results, and supervised the entire process. Both authors read and approved the final manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,797,482,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplemental digital contents are available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.joem.org). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,828,482,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Address correspondence to: Min-Yong Lee, MD, Department of Rehabilitation Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, South Korea (roado10@gmail.com). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,859,482,929]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC BY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. DOI: 10.1097/JOM.000000000002556 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[525,253,679,268]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Learning Objectives ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[527,278,910,381]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- To identify differences in the risk factors of work related TBI. \",\"- To identify the important implications for industrial accident prevention strategies and appropriate rehabilitation systems for work related TBI. \",\"- To ascertain the severity and understand the burden and trend of work related TBI by injury severity during a decade (2010–2019) using data from the Korea Workers' Compensation Insurance claims. \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[506,392,926,494]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"concern. $^{10-13}$ WrTBI is one of the most disabling occupational injuries and can change the injured workers' lives due to subsequent job loss and sustained disability. It may also lead to significant economic burden in terms of medical expenses and wage losses. $^{8,10,14,15}$ According to the literature published in 2019, it was reported that the incidence of wrTBI is on the rise despite the decline in work-related injuries. $^{16}$ This finding suggests that efforts to prevent wrTBI are insufficient and that there is a need for increased awareness of wrTBI. $^{3}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,494,928,673]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Clinical features of TBIs are classified according to the severity (ie, mild, moderate, and severe).17 Moderate-to-severe TBI can be life-threatening and cause permanent physical or mental disability, making it difficult to return to work.8,18 Meanwhile, mild TBI, which comprises the majority of TBIs $(70\\% -90\\%)$ 19 is often overlooked because it is not fatal and does not cause severe disability. In most patients with mild TBI, acute symptoms (eg, headache, dizziness, cognitive difficulty) resolve in days to weeks after the injury; however, a subgroup of them may develop persistent neuropsychiatric symptoms up to 3 months after the injury, called post-concussion syndrome.20 Patients with post-concussion syndrome can experience difficulties in daily living and in returning to work.3,8,18,21 However, individuals with mild TBIs are often difficult to identify and are therefore left untreated. Thus, the actual burden of wrTBI may be much higher.7,8,22,23 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,673,928,751]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Therefore, identifying differences in the risk factors and severity of wrTBI may have important implications for industrial accident prevention strategies and appropriate rehabilitation systems. However, although there have been some studies regarding the incidence and mortality of TBI in Korea, to the best of our knowledge, there has been no published report on the epidemiology of wrTBI.[6,24] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,751,928,814]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study aimed to investigate the status of wrTBI with a focus on its severity in Korea and discuss the burden and trend of wrTBI by injury severity during a decade (2010-2019) using data from the Korea Workers' Compensation Insurance (WCI) claims—a large-scale source of administrative data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[606,822,830,836]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MATERIALS AND METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,852,609,865]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data Source ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,867,926,932]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study used Korea WCI data. In Korea, the Industrial Accident Insurance Act was introduced in 1964, and WCI coverage was expanded to all businesses or workplaces that employ workers, with some exceptions. When an industrial accident occurs, the respective employer is supposed to report it to the Korea Ministry of Employment and Labor. Compensation ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[234,40,760,58]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CME AVAILABLE FOR THIS ARTICLE AT ACOEM.ORG ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[66,947,400,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOEM $\\cdot$ Volume 64, Number 9, September 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[900,948,926,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"731 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[66,89,486,168]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is then provided to concerned workers with work-related injuries by the Korea Workers' Compensation and Welfare Service (KCOMWEL). The KCOMWEL manages the WCI data, which include information on workplaces at the time of industrial accidents, injuries, medical care, and compensations. Therefore, we obtained the anonymized data from 2010 to 2019 from the KCOMWEL for this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,182,207,196]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Study Population ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[66,198,486,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The population of this study consisted of workers who claimed compensation for wrTBI from January 1, 2010, to December 31, 2019. Patients with the following TBI diagnostic codes as main or sub-diagnoses were extracted by using the eighth Korean Standard Classification of Diseases based on the International Classification of Diseases, $10^{\\mathrm{th}}$ revision: concussion (S06.0), cranial fracture ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,89,929,205]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(S02.0, S02.1, S02.7, S02.8, S02.9, S07.1, and T90.2), and intracranial injury (S06.1-S06.9 and T90.5). The subjects of this study were defined and selected by priority in the order of intracranial injury, cranial fracture, and concussion among the three TBI diagnostic categories. The diagnoses and priorities according to the diagnostic codes are shown in Supplementary Table 1, http://links.lww.com/JOM/B190. In this study, concussion was classified under mild TBI, whereas cranial fracture and intracranial injury were considered moderate-to-severe TBIs.[6,25-27] Finally, a total of 48,166 patients were included in this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,232,587,245]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Variables ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,248,929,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The variables used in this study included the demographic characteristics, work-related injury characteristics, claim duration, and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[71,317,929,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0747/59eb1245dac1df60ca16001b34ac70a513e1dbf317f330dbecc9c56906e597a7.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":"<table><tr><td>Characteristic</td><td colspan=\"2\">Total (n = 48,166)</td><td colspan=\"2\">Mild (n = 21,842)</td><td colspan=\"2\">Moderate-to-Severe (n = 26,324)</td><td>P*</td></tr><tr><td>Age at injury, yrs</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>50.6</td><td>13.1</td><td>49.9</td><td>13.2</td><td>51.2</td><td>13.1</td><td><0.001</td></tr><tr><td>Median (IQR)</td><td>52</td><td>43–60</td><td>52</td><td>42–59</td><td>53</td><td>44–60</td><td></td></tr><tr><td>Age group, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td><30</td><td>4063</td><td>8.4</td><td>2047</td><td>9.4</td><td>2016</td><td>7.7</td><td></td></tr><tr><td>30–39</td><td>5266</td><td>10.9</td><td>2489</td><td>11.4</td><td>2777</td><td>10.6</td><td></td></tr><tr><td>40–49</td><td>10,262</td><td>21.3</td><td>4690</td><td>21.5</td><td>5572</td><td>21.2</td><td></td></tr><tr><td>50–59</td><td>16,031</td><td>33.3</td><td>7388</td><td>33.8</td><td>8643</td><td>32.8</td><td></td></tr><tr><td>≥60</td><td>12,544</td><td>26.0</td><td>5228</td><td>23.9</td><td>7316</td><td>27.8</td><td></td></tr><tr><td>Sex, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Male</td><td>41,588</td><td>86.3</td><td>17,328</td><td>79.3</td><td>24,260</td><td>92.2</td><td></td></tr><tr><td>Female</td><td>6578</td><td>13.7</td><td>4514</td><td>20.7</td><td>2064</td><td>7.8</td><td></td></tr><tr><td>Work-related injury type, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Injury</td><td>46,222</td><td>96.0</td><td>20,840</td><td>95.4</td><td>25,382</td><td>96.4</td><td></td></tr><tr><td>Commuting injury</td><td>1944</td><td>4.0</td><td>1002</td><td>4.6</td><td>942</td><td>3.6</td><td></td></tr><tr><td>Occupation, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Managers</td><td>3606</td><td>7.5</td><td>1393</td><td>6.4</td><td>2213</td><td>8.4</td><td></td></tr><tr><td>Professionals/related workers</td><td>2407</td><td>5.0</td><td>1224</td><td>5.6</td><td>1183</td><td>4.5</td><td></td></tr><tr><td>Clerks</td><td>1298</td><td>2.7</td><td>663</td><td>3.0</td><td>635</td><td>2.4</td><td></td></tr><tr><td>Service workers</td><td>2189</td><td>4.5</td><td>1374</td><td>6.3</td><td>815</td><td>3.1</td><td></td></tr><tr><td>Sales workers</td><td>469</td><td>1.0</td><td>266</td><td>1.2</td><td>203</td><td>0.8</td><td></td></tr><tr><td>Skilled agricultural, forestry/fishery workers</td><td>944</td><td>2.0</td><td>478</td><td>2.2</td><td>466</td><td>1.8</td><td></td></tr><tr><td>Craft/related trades workers</td><td>11,865</td><td>24.6</td><td>4837</td><td>22.2</td><td>7028</td><td>26.7</td><td></td></tr><tr><td>Equipment/machine operating/assembling workers</td><td>4679</td><td>9.7</td><td>2168</td><td>9.9</td><td>2511</td><td>9.5</td><td></td></tr><tr><td>Elementary workers</td><td>20,709</td><td>43.0</td><td>9439</td><td>43.2</td><td>11,270</td><td>42.8</td><td></td></tr><tr><td>Industry, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Agriculture/forestry/fishing</td><td>1384</td><td>2.9</td><td>729</td><td>3.3</td><td>655</td><td>2.5</td><td></td></tr><tr><td>Mining/quarrying</td><td>172</td><td>0.4</td><td>68</td><td>0.3</td><td>104</td><td>0.4</td><td></td></tr><tr><td>Manufacturing</td><td>9467</td><td>19.7</td><td>3665</td><td>16.8</td><td>5802</td><td>22.0</td><td></td></tr><tr><td>Electricity/gas/steam/air conditioning supply</td><td>41</td><td>0.1</td><td>11</td><td>0.1</td><td>30</td><td>0.1</td><td></td></tr><tr><td>Water supply/sewage/waste management/materials recovery</td><td>10</td><td>0.0</td><td>3</td><td>0.0</td><td>7</td><td>0.0</td><td></td></tr><tr><td>Construction</td><td>19,120</td><td>39.7</td><td>7977</td><td>36.5</td><td>11,143</td><td>42.3</td><td></td></tr><tr><td>Wholesale/retail trade</td><td>2</td><td>0.0</td><td>0</td><td>0.0</td><td>2</td><td>0.0</td><td></td></tr><tr><td>Transportation/storage</td><td>3029</td><td>6.3</td><td>1644</td><td>7.5</td><td>1385</td><td>5.3</td><td></td></tr><tr><td>Accommodation/food service activities</td><td>3584</td><td>7.5</td><td>1872</td><td>8.6</td><td>1712</td><td>6.5</td><td></td></tr><tr><td>Information/communication</td><td>218</td><td>0.5</td><td>104</td><td>0.5</td><td>114</td><td>0.4</td><td></td></tr><tr><td>Financial/insurance activities</td><td>209</td><td>0.4</td><td>113</td><td>0.5</td><td>96</td><td>0.4</td><td></td></tr><tr><td>Real estate activities</td><td>104</td><td>0.2</td><td>49</td><td>0.2</td><td>55</td><td>0.2</td><td></td></tr><tr><td>Professional/scientific/technical activities</td><td>285</td><td>0.6</td><td>125</td><td>0.6</td><td>160</td><td>0.6</td><td></td></tr><tr><td>Business facilities management/business support services/rental and leasing activities</td><td>5003</td><td>10.4</td><td>2361</td><td>10.8</td><td>2642</td><td>10.0</td><td></td></tr><tr><td>Public administration/defense/compulsory social security</td><td>636</td><td>1.3</td><td>405</td><td>1.9</td><td>231</td><td>0.9</td><td></td></tr><tr><td>Education</td><td>374</td><td>0.8</td><td>255</td><td>1.2</td><td>119</td><td>0.5</td><td></td></tr><tr><td>Human health/social work activities</td><td>1155</td><td>2.4</td><td>798</td><td>3.7</td><td>357</td><td>1.4</td><td></td></tr><tr><td>Arts/sports/recreation related services</td><td>520</td><td>1.1</td><td>262</td><td>1.2</td><td>258</td><td>1.0</td><td></td></tr><tr><td>Membership organizations/repair/other personal services</td><td>2661</td><td>5.5</td><td>1310</td><td>6.0</td><td>1351</td><td>5.1</td><td></td></tr><tr><td>Activities of households as employers/undifferentiated goods-and services-producing activities of households for own use</td><td>172</td><td>0.4</td><td>78</td><td>0.4</td><td>94</td><td>0.4</td><td></td></tr><tr><td>Activities of extraterritorial organizations/bodies</td><td>20</td><td>0.0</td><td>13</td><td>0.1</td><td>7</td><td>0.0</td><td></td></tr></table>","table_caption":"[\"TABLE 1. Preinjury Demographic Characteristics of Claimants With Work-Related Traumatic Brain Injury Stratified by Severity in Korea From 2010 to 2019 \"]","table_footnote":"[\"* $P$ value from chi-squared test (categorical variables) or $t$ test (continuous variable). \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[71,42,148,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bae and Lee ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[595,40,928,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOEM Volume 64, Number 9, September 2022 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,948,95,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"732 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[147,948,928,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[66,89,482,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"claim cost of the injured workers. Ages were classified into $< 30$ , 30-39, 40-49, 50-59, and $\\geq 60$ years. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,116,482,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Work-related injury types were classified into injury, disease, and commuting injury. Occupations were classified according to the seventh Korean Standard Classification of Occupations based on the International Standard Classification of Occupations. Industries were classified according to the $10^{\\text{th}}$ Korean Standard Industrial Classification based on the International Standard Industrial Classification. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,191,484,308]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Time lost from work was estimated for workers receiving the cost of income replacement. The duration of work disability was defined as the number of days treated for a work-related injury. The total cost per claim refers to the total cost paid to a worker for an industrial accident. The cost of medical and similar services refers to medical care benefits and medical service fees, medication costs, medical care expenses, and nursing expenses. The cost of income replacement refers to the amount paid to workers with a work-related injury while they are unable to work due to medical treatment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,317,217,331]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Statistical Analyses ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[66,332,482,396]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The mean, standard deviation (SD), median, and interquartile range (IQR) of continuous variables for the subjects and the severity classification were calculated using the $t$ test. The frequency distribution of the categorical variables for comparison by severity was determined using the chi-squared test. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[66,396,484,512]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The annual incidence of wrTBI was calculated as the rate per 100,000 workers by dividing the number of workers diagnosed with TBI by the total number of workers. Time trends over the 10-year period were assessed using Poisson regression. In addition, the incidence rate of wrTBI as stratified by the industry classification was calculated as the mean incidence rate over the past decade. Risk ratios (RRs) and $95\\%$ confidence intervals (CIs) for moderate-to-severe TBI compared with mild TBI were calculated. The statistical analyses were performed using SAS statistical package version 9.4 (SAS Institute, Cary, NC). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[239,533,311,546]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[66,548,486,626]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From 2010 to 2019, a total of 48,166 workers claimed compensation for wrTBI, including 21,842 (45.3%) for mild TBI and 26,324 (54.7%) for moderate-to-severe TBI (Supplementary Table 2, http:// links.lww.com/JOM/B190). This table accounted for approximately 5% of all claims during this study period. The mean incidence of wrTBI was 28.4/100,000. In terms of the incidence rate of wrTBI by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,89,926,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"severity, mild TBI and moderate-to-severe TBI were 12.9/100,000 and 15.5/100,000, respectively (RR, 1.21; 95% CI, 1.19-1.22). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,116,928,294]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table 1 shows the preindustrial accident demographic characteristics of workers with wrTBI. The mean age at the time of the work-related injury was 50.6 years, and the mean age with moderate-to-severe TBI was 1.3 years older than those with mild TBI $(P < 0.001)$ . WrTBI most commonly occurred in those aged 50-59 years, with more than half of the cases occurring in those aged $\\geq 50$ years $(P < 0.001)$ . Males and injury in terms of work-related injury type accounted for the majority of wrTBI cases $(P < 0.001$ and $P < 0.001$ , respectively). In terms of occupation, wrTBI was most common in elementary workers $(43.0\\%)$ and craft/related trades workers $(24.6\\%)$ . As for industries, wrTBI most commonly occurred in construction $(39.7\\%)$ , followed by manufacturing $(19.7\\%)$ and business facilities management/business support services/rental and leasing activities $(10.4\\%)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,294,928,384]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 1 shows the wrTBI trend over 10 years. The incidence of workers with mild TBI decreased until 2016 and then increased in 2017 ( $P \\leq 0.001$ ). The incidence of moderate-to-severe TBI among workers continued to decrease from 17.6/100,000 (95% CI, 16.9-18.2) in 2010 to 14.5/100,000 (95% CI, 13.9-15.0) in 2019 ( $P = 0.001$ ). The incidence of mild TBI among workers was higher in 2010, but moderate-to-severe TBI was higher after 2011. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,383,928,524]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table 2 shows the incidence of wrTBI among all workers by industry. The incidence of wrTBI among all workers was the highest in construction (112.9/100,000), and lowest in wholesale/retail trade (0.0/100,000). The incidence rates of mild TBI and moderate-to-severe TBI were highest in construction, followed by manufacturing and business facilities management/business support services/rental and leasing activities. The industry with the highest incidence of moderate-to-severe TBI compared with mild TBI was electricity/gas/steam/air conditioning supply (RR, 2.73; $95\\%$ CI, 1.59-4.67), whereas the industry with the lowest rate of wrTBI was the human health/social work activities industry (RR, 0.45; $95\\%$ CI, 0.41-0.49). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,523,928,626]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table 3 shows the characteristics of compensation claims for wrTBI. Of all workers with wrTBI, $86.4\\%$ experienced time lost from work, with a higher proportion among those with mild TBI than those with moderate-to-severe TBI $(P < 0.001)$ . The total duration of compensated medical care was 262.2 days, but it was longer for those with moderate-to-severe TBI at 358.2 days $(P < 0.001)$ . The total cost per claim, medical and like services, and income replacement for moderate-to-severe TBI workers were nearly four times higher ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[222,654,777,911]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 1. Incidence of work-related traumatic brain injury in all workers in Korea from 2010 to 2019. \"]","image_footnote":"[]","img_path":"images/0845/b592100af90e228d896fa61515b7b0306c7cad3691da925d39846583b8f58c23.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[66,42,400,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOEM $\\cdot$ Volume 64, Number 9, September 2022 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[667,42,928,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Incidence of Work-Related TBI by Severity ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[66,948,847,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[900,948,926,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"733 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[68,129,931,451]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0783/9fc79954b9a5c11225980d19c5f5dec97458614c3c8eb16188e7611037362a6c.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Industry Sector</td><td colspan=\"4\">All Workers (rate per 100,000)*</td></tr><tr><td>Total</td><td>Mild</td><td>Moderate-to-Severe</td><td>RR (95% CI)†</td></tr><tr><td>Agriculture/forestry/fishing</td><td>8.2</td><td>4.3</td><td>3.9</td><td>0.90 (0.83–0.97)</td></tr><tr><td>Mining/quarrying</td><td>1.0</td><td>0.4</td><td>0.6</td><td>1.53 (1.23–1.91)</td></tr><tr><td>Manufacturing</td><td>55.9</td><td>21.6</td><td>34.3</td><td>1.58 (1.54–1.63)</td></tr><tr><td>Electricity/gas/steam/air conditioning supply</td><td>0.2</td><td>0.1</td><td>0.2</td><td>2.73 (1.59–4.67)</td></tr><tr><td>Water supply/sewage/waste management/materials recovery</td><td>0.1</td><td>0.0</td><td>0.0</td><td>2.33 (0.83–6.54)</td></tr><tr><td>Construction</td><td>112.9</td><td>47.1</td><td>65.8</td><td>1.40 (1.37–1.43)</td></tr><tr><td>Wholesale/retail trade</td><td>0.0</td><td>0.0</td><td>0.0</td><td>NA</td></tr><tr><td>Transportation/storage</td><td>17.9</td><td>9.7</td><td>8.2</td><td>0.84 (0.80–0.89)</td></tr><tr><td>Accommodation/food service activities</td><td>21.2</td><td>11.1</td><td>10.1</td><td>0.91 (0.87–0.96)</td></tr><tr><td>Information/communication</td><td>1.3</td><td>0.6</td><td>0.7</td><td>1.10 (0.91–1.32)</td></tr><tr><td>Financial/insurance activities</td><td>1.2</td><td>0.7</td><td>0.6</td><td>0.85 (0.70–1.03)</td></tr><tr><td>Real estate activities</td><td>0.6</td><td>0.3</td><td>0.3</td><td>1.12 (0.85–1.47)</td></tr><tr><td>Professional/scientific/technical activities</td><td>1.7</td><td>0.7</td><td>0.9</td><td>1.28 (1.08–1.51)</td></tr><tr><td>Business facilities management/business support services/rental and leasing activities</td><td>29.5</td><td>13.9</td><td>15.6</td><td>1.12 (1.08–1.16)</td></tr><tr><td>Public administration/defense/compulsory social security</td><td>3.8</td><td>2.4</td><td>1.4</td><td>0.57 (0.51–0.64)</td></tr><tr><td>Education</td><td>2.2</td><td>1.5</td><td>0.7</td><td>0.47 (0.40–0.55)</td></tr><tr><td>Human health/social work activities</td><td>6.8</td><td>4.7</td><td>2.1</td><td>0.45 (0.41–0.49)</td></tr><tr><td>Arts/sports/recreation related services</td><td>3.1</td><td>1.5</td><td>1.5</td><td>0.98 (0.87–1.11)</td></tr><tr><td>Membership organizations/repair/other personal services</td><td>15.7</td><td>7.7</td><td>8.0</td><td>1.03 (0.98–1.09)</td></tr><tr><td>Activities of households as employers/undifferentiated goods- and services-producing activities of households for own use</td><td>1.0</td><td>0.5</td><td>0.6</td><td>1.21 (0.97–1.49)</td></tr><tr><td>Activities of extraterritorial organizations/bodies</td><td>0.1</td><td>0.1</td><td>0.0</td><td>0.54 (0.27–1.06)</td></tr><tr><td>Total</td><td>28.4</td><td>12.9</td><td>15.5</td><td>1.21 (1.19–1.22)</td></tr></table>","table_caption":"[\"TABLE 2. Incidence Rate of Work-Related Traumatic Brain Injury by Industry Sector and Severity Among All Workers in Korea From 2010 to 2019 \"]","table_footnote":"[\"*Rates are presented as an average over the 10-year period. \",\"†Moderate-to-severe TBI to mild TBI risk ratio. \",\"NA, not applicable; RR, risk ratio. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[66,503,489,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"than for workers with mild TBI. In addition, the mean mortality rate of wrTBI was 2.8/100,000, which was mostly associated with moderate-to-severe TBI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[224,553,330,566]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[66,567,489,634]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This is the first epidemiologic study of wrTBI in Korea to consider the severity of the TBI in its analysis. From Korea WCI data spanning 10 years (2010-2019), we estimated the incidence rate of wrTBI by severity and industry sector and reported differences by severity in terms of demographic and claims characteristics. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,503,929,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There were some differences in should be hyphenated demographic characteristics depending on severity, but the overall tendency was similar in both mild and moderate-to-severe groups. Table 1 shows that wrTBI occurred mostly in older workers, males, manual workers, and the construction industry. This result is consistent with the results of previous studies regarding wrTBI. $^{1,3,8-10,21,28,29}$ Different tasks at work and employment characteristics according to sex may have contributed to the higher incidence of wrTBI in males. $^{8,9}$ For older workers, decreased concentration and falls due to lack of balance and flexibility may have been the main causes of wrTBI. $^{28}$ In addition, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,673,931,886]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0944/6821d06d301eb2b972020d0839b29277fcaa3b5b6e236744b13904847dea4b5b.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Claims</td><td colspan=\"2\">Total</td><td colspan=\"2\">Mild</td><td colspan=\"2\">Moderate-to-Severe</td><td>P*</td></tr><tr><td>All claimants, n</td><td>48,166</td><td></td><td>21,842</td><td></td><td>26,324</td><td></td><td></td></tr><tr><td>Time lost from work, n (%)</td><td>41,591</td><td>86.4</td><td>19,502</td><td>89.3</td><td>22,089</td><td>83.9</td><td><0.001</td></tr><tr><td>Inpatient hospital stay, n (%)</td><td>43,936</td><td>91.2</td><td>19,182</td><td>87.8</td><td>24,754</td><td>94.0</td><td><0.001</td></tr><tr><td>Duration of work disability</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD) number of days</td><td>262.2</td><td>397.4</td><td>146.5</td><td>190.9</td><td>358.2</td><td>488.2</td><td><0.001</td></tr><tr><td>Median (IQR) number of days</td><td>148</td><td>53–299</td><td>94</td><td>43–188</td><td>212</td><td>81–446</td><td></td></tr><tr><td>Claim costs paid (million KRW)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD) total cost per claim</td><td>59.26</td><td>110.90</td><td>21.87</td><td>44.20</td><td>90.29</td><td>136.97</td><td><0.001</td></tr><tr><td>Mean (SD) cost of medical and like services</td><td>22.17</td><td>69.92</td><td>6.97</td><td>21.95</td><td>34.62</td><td>90.43</td><td><0.001</td></tr><tr><td>Mean (SD) cost of income replacement</td><td>14.45</td><td>21.15</td><td>8.58</td><td>12.38</td><td>19.32</td><td>25.28</td><td><0.001</td></tr><tr><td>Time-loss claims,†n</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Claim costs paid (million KRW)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD) total cost per claim</td><td>60.11</td><td>112.63</td><td>24.02</td><td>45.69</td><td>91.97</td><td>140.99</td><td><0.001</td></tr><tr><td>Mean (SD) cost of medical and like services</td><td>25.10</td><td>70.28</td><td>7.67</td><td>23.11</td><td>40.48</td><td>91.24</td><td><0.001</td></tr><tr><td>Mean (SD) cost of income replacement</td><td>16.74</td><td>21.90</td><td>9.61</td><td>12.72</td><td>23.03</td><td>26.00</td><td><0.001</td></tr><tr><td>Mortality rate‡</td><td>2.8</td><td></td><td>0.0</td><td></td><td>2.7</td><td></td><td></td></tr></table>","table_caption":"[\"TABLE 3. Claims Characteristics of Work-Related Traumatic Brain Injury by Severity in Korea From 2010 to 2019 \"]","table_footnote":"[\"* $P$ value from chi-squared test (categorical variables) or t test (continuous variable). \",\"$\\\\dagger$ Analyses restricted to claimants with $>0$ claim cost paid lost from work. \",\"${}^{2}$ Rates are presented as an average over the 10-year period (rate per 100,000). \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[71,42,150,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bae and Lee ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[595,40,928,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOEM Volume 64, Number 9, September 2022 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[71,948,95,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"734 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[148,948,929,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[66,90,482,115]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"manual labor may be associated with more frequent exposure to risky work environments.[9] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,116,484,446]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study is one of the few to explore the trend of wrTBI. We identified that the mean incidence of wrTBI was 28.4/100,000 workers per year. It was in Australia where the mean incidence of wrTBI was 19.8/100,000 workers per year,[9] and it was lower in Canada, where it was 33.1/100,000 workers per year.[14] Based on the incidence of Korea TBI reported in Oh et al.'s study,[6] wrTBI is confirmed to comprise approximately $5\\%$ of all TBI in Korea. This is consistent with the trends of wrTBI incidence rates in the United States and Europe, where wrTBI accounted for less than $10\\%$ of all TBI cases.[10-13] Figure 1 shows that the number of workers with a diagnosis of wrTBI decreased until 2016 but increased in trend in 2017. Similarly, the incidence of mild wrTBI among workers initially decreased, and then increased again from 2017, whereas the incidence of moderate-to-severe TBI among workers continued to decrease for the past 10 years. The trend of industrial accidents announced by the Korea Ministry of Employment and Labor was similar to the results of this study. This is presumably due to the result of policies for improving access to workers' compensation insurance.[30] Since 2018, the employer confirmation system has been abolished, allowing workers to file an industrial accident claim without confirmation from the employer. In addition, the number of work accidents may have increased since injuries incurred during commuting were also approved as work-related injuries.[31] Traffic accidents are the most common cause of work-related mild TBI,[10,21,29,32] and this may be related to the increase in the incidence of mild TBI due to traffic accidents occurring while commuting to and from work. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,447,484,649]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The incidence of moderate-to-severe TBI was higher than that of mild TBI during the observation period except for the first observation year, which is consistent with the results of Brolin et al.'s study. Considering that $70\\%$ to $90\\%$ of TBI cases are classified as mild TBI, these results are interesting. Mild wrTBI incidence rate is likely underestimated since patients with mild TBI often do not seek medical help. Even if a patient needs clinical care, most of them recover within days to weeks after a traumatic incident. However, because it can take a few weeks to receive approval for an industrial accident, considerable cases of mild wrTBI are unlikely to lead to an industrial accident claim. In addition, for mild TBI, the symptoms can be underreported due to the vagueness or workers' lack of awareness of the symptoms. Thus, in some cases, mild wrTBI may not even be diagnosed. Therefore, it is necessary to emphasize the symptoms of mild TBI (ie, concussion) during occupational safety and health education sessions conducted for workers in Korea. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,650,484,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study showed differences by severity in the distribution and proportion of wrTBI by industry. Moderate-to-severe wrTBIs commonly occurred in construction, manufacturing, and business facilities management/business support services/rental and leasing activities associated with manual labor or hazardous working conditions. Mild wrTBIs occurred in financial and insurance activities, public administration/defense/compulsory social security, and service industries. In particular, the incidence of both mild and moderate-to-severe TBI was much higher in the construction industry compared with other industries. Considering that construction workers are at high risk of serious and fatal injuries,[29] and that previous studies have also identified the construction industry as a major contributor to the wrTBI-related industry sector,[10,34] it is necessary to review risk factors and the mechanisms of injuries in this specific industry.[28] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,829,484,930]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The results of our study showed significant work disability and economic burdens of wrTBI. Injured workers with moderate-to-severe TBI had a longer duration of work disability and higher expense claims than those with mild TBI. However, the proportion of those who experienced time lost from work was higher in subjects with mild TBI than moderate-to-severe TBI. Although acute symptoms after mild TBI improve in days to weeks, approximately $15\\%$ of mild TBI patients suffer from persistent neuropsychiatric symptoms (eg, headache, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,90,928,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"dizziness, cognitive dysfunction, depression, anxiety), which impact their decision regarding whether to return to work beyond 1 year.[35,36] In Korea, the return-to-work program (functional capacity evaluation, work conditioning, and work hardening) is only provided by the KCOMWEL,[37] and mainly focuses on physical issues. However, the results of this study suggest that, aside from physical problems, neuropsychiatric problems should also be considered when assessing return to work in patients with mild wrTBI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,191,928,294]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The strengths of this study are as follows: First, because the WCI data used in this study was nationally representative, our results can be considered as representative of work-related injuries in Korea. Second, to the best of our knowledge, this is the first study to investigate the trend of wrTBI by severity among work-related injury workers in Korea for a duration of 10 years. Third, our study can be seen as wide scale because we were able to provide information on the wrTBI incidence of workers across 21 industries. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,294,928,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However, this study also has several limitations. First, the amount of compensation may not be accurate for injured workers whose compensation claims have not been completed or if compensation for an industrial accident has not been closed. For example, if a worker killed an industrial accident in October 2019 and the resulting compensation was not yet closed, the included compensation amount might only be for 3 months. Second, the age- and sex-standardized incidence of wrTBI could not be calculated because the number of injured workers by age group and sex could not be identified due to restricted access to the statistical data. Third, further studies regarding factors affecting the incidence of wrTBI are needed. Although our study investigated the industry-stratified incidence of wrTBI, further studies that consider gender, mechanism of injury, injured workers' employment status, and workplace size are needed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,485,607,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,501,928,667]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This study provides useful information on the epidemiology of wrTBI concerning its severity during a decade (2010-2019) in Korea. The incidence of wrTBI in Korea decreased until 2016 and then increased in trend from 2017. The incidence of moderate-to-severe TBI was higher than that of mild TBI during the observation period except for the first observation year. Injured workers with moderate-to-severe TBI had a longer duration of work disability and higher expense claims than those with mild TBI. However, the proportion of those who experienced time lost from work was higher in subjects with mild TBI than moderate-to-severe TBI. Our findings highlight the need for providing information to workers on mild TBI in occupational safety and health education and may serve as the basis for further wrTBI research. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[626,682,809,696]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,696,928,737]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors would like to thank the Korea Workers' Compensation and Welfare Service for making this study possible and providing the data from the Korea workers' compensation insurance claims. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[667,751,768,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[515,769,928,930]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Brolin K, Lanner D, Halldin P. Work-related traumatic brain injury in the construction industry in Sweden and Germany. Saf Sci. 2021;136:105147. \",\"2. Carroll LJ, Cassidy JD, Holm L, Kraus J, Coronado VG, WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004; (43 Suppl):113-125. \",\"3. Toccalino D, Colantonio A, Chan V. Update on the epidemiology of work-related traumatic brain injury: a systematic review and meta-analysis. Occup Environ Med. 2021;78:769-776. \",\"4. Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018;1-18. \",\"5. Zelinkova V, Brazinova A, Taylor MS, et al. Location of traumatic brain injury-related deaths: epidemiological analysis of 11 European countries. Brain Inj. 2019;33:830-835. \"]","page_idx":"4","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[66,42,400,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOEM $\\cdot$ Volume 64, Number 9, September 2022 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[667,42,926,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Incidence of Work-Related TBI by Severity ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[66,948,847,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[900,948,926,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"735 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[71,89,486,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"6. Kim HK, Leigh JH, Lee YS, et al. Decreasing incidence and mortality in traumatic brain injury in Korea, 2008-2017: a population-based longitudinal study. Int J Environ Res Public Health. 2020;17:6197. \",\"7. Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22:341-353. \",\"8. Chang VC, Guerriero EN, Colantonio A. Epidemiology of work-related traumatic brain injury: A systematic review. Am J Ind Med. 2015;58:353-377. \",\"9. Chang VC, Ruseckaite R, Collie A, Colantonio A. Examining the epidemiology of work-related traumatic brain injury through a sex/gender lens: analysis of workers' compensation claims in Victoria, Australia. Occup Environ Med. 2014;71:695-703. \",\"10. Kim H, Colantonio A, Chipman M. Traumatic brain injury occurring at work. NeuroRehabilitation. 2006;21:269-278. \",\"11. Wei C, Roesler J, Kinde M. Nonfatal work-related traumatic brain injury in Minnesota, 1999-2008. Minn Med. 2012;95:55-59. \",\"12. Harrison J, Helps Y, Henley G. Hospital separations due to traumatic brain injury, Australia 2004-05. *Inj Res Stat Ser.* 2008;45:ePub. \",\"13. Baldo V, Marcolongo A, Floreani A, et al. Epidemiological aspect of traumatic brain injury in Northeast Italy. Eur J Epidemiol. 2003;18:1059-1063. \",\"14. Colantonio A, Mroczek D, Patel J, Lewko J, Fergenbaum J, Brison R. Examining occupational traumatic brain injury in Ontario. Can J Public Health. 2010;101:S58-S62. \",\"15. Kristman VL, Cote P, Hogg-Johnson S, et al. The burden of work disability associated with mild traumatic brain injury in Ontario compensated workers: a prospective cohort study. Open Occup Health Saf J. 2010;2:1-8. \",\"16. Sharma B, Nowrouzi-Kia B, Mollayeva T, et al. Work-related traumatic brain injury: a brief report on workers perspective on job and health and safety training, supervision, and injury preventability. *Work*. 2019;62:319-325. \",\"17. Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT, Workshop Scientific Team and Advisory Panel Members. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008;25:719-738. \",\"18. Whiteneck GG, Cuthbert JP, Corrigan JD, Bogner JA. Risk of negative outcomes after traumatic brain injury: a statewide population-based survey. J Head Trauma Rehabil. 2016;31:E43-E54. \",\"19. Levin HS, Diaz-Arrastia RR. Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol 2015;14:506-517. \",\"20. Carroll L, Cassidy JD, Peloso P, et al. Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004;36:84-105. \",\"21. Chang VH, Lombard LA, Greher MR. Mild traumatic brain injury in the occupational setting. PMR. 2011;3:S387-S395. \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[511,89,929,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"22. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21:375-378. \",\"23. Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9:231-236. \",\"24. Choi DH, Song KJ, Shin SD, Ro YS, Hong KJ, Park JH. Epidemiology and outcomes of sports-related traumatic brain injury in children. J Korean Med Sci. 2019;34:e290. \",\"25. Mateu NC. Traumatic brain injury in Denmark 2008-2012. Scand J Public Health. 2020;48:331-337. \",\"26. Madsen T, Erlangsen A, Orlovska S, Mofaddy R, Nordentoft M, Benros ME. Association between traumatic brain injury and risk of suicide. JAMA. 2018; 320:580-588. \",\"27. Choi Y, Kim EY, Sun J, et al. Incidence of depression after traumatic brain injury: a nationwide longitudinal study of 2.2 million adults. J Neurotrauma. 2022;39:390-397. \",\"28. Paci M, Infante-Rivard C, Marcoux J. Traumatic brain injury in the workplace. Can J Neurol Sci. 2017;44:518-524. \",\"29. Colantonio A, McVittie D, Lewko J, Yin J. Traumatic brain injuries in the construction industry. Brain Inj. 2009;23:873-878. \",\"30. Ministry of Employment and Labor. Analysis of Occupational Accidents; 2019. Seoul, South Korea: Ministry of Employment and Labor; 2021. \",\"31. Bae SW, Lee MY, Park SW, Lee G, Leigh JH. Satisfying medical and rehabilitation needs positively influences returning to work after a work-related injury: an analysis of national panel data from 2018 to 2019. BMC Public Health. 2021;21:2017. \",\"32. Dunne J, Quifones-Ossa GA, Still EG, et al. The epidemiology of traumatic brain injury due to traffic accidents in Latin America: a narrative review. J Neurosci Rural Pract 2020;11:287-290. \",\"33. Iverson GL, Lange RT, Brooks BL, Rennison VL. \\\"Good old days\\\" bias following mild traumatic brain injury. Clin Neuropsychol. 2010;24:17-37. \",\"34. Konda S, Reichard A, Tiesman HM, Hendricks S. Non-fatal work-related traumatic brain injuries treated in US hospital emergency departments, 1998-2007. *Inj Prev*. 2015;21:115-120. \",\"35. Schretlen DJ, Shapiro AM. A quantitative review of the effects of traumatic brain injury on cognitive functioning. Int Rev Psychiatry. 2003;15:341-349. \",\"36. Alexander MP. Mild traumatic brain injury: pathophysiology, natural history, and clinical management. *Neurology*. 1995;45:1253-1260. \",\"37. Bae SW. Effect of professional certification on employees' return-to-work rate after occupational injuries in Korea: focusing on vulnerable groups. Environ Health Prev Med 2021;26:6. \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[71,42,150,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bae and Lee ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[595,42,928,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOEM $\\cdot$ Volume 64, Number 9, September 2022 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[71,948,95,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"736 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[148,948,928,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[83,89,140,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[135,113,859,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Incidence of Traumatic Brain Injury by Severity Among Work-Related Injured Workers From 2010 to 2019 \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[162,170,832,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An Analysis of Workers' Compensation Insurance Data in Korea \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[332,205,657,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Suk Won Bae, PhD and Min-Yong Lee, MD \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,246,486,400]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objective: This study aimed to investigate the status of work-related traumatic brain injury (wrTBI) in Korea between 2010 and 2019. Methods: This study used Korea Workers' Compensation Insurance data, and the sample comprised workers who claimed compensation for wrTBI from 2010 to 2019. The annual incidence of wrTBI was calculated as the rate per 100,000 workers. Time trends over the 10-year period were assessed using Poisson regression. Results: The mean incidence of wrTBI was 28.4/100,000. Regarding the incidence rate of wrTBI by severity, mild TBI and moderate-to-severe TBI were 12.9/100,000 and 15.5/100,000, respectively. The incidence of mild TBI among workers was higher in 2010, but moderate-to-severe TBI was higher after 2011. Conclusions: Our findings highlight the need for providing information on mild TBI to workers as part of occupational safety and health education. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,407,440,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: traumatic brain injury, incidence, worker's compensation, epidemiology, occupational injuries \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,434,484,562]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Traumatic brain injury (TBI) is an acute brain injury resulting from an external physical force to the head leading to short- or long-term physical and psychological problems. $^{1,2}$ Each year, approximately 69 million new cases of TBI are reported worldwide, $^{3,4}$ and almost $37\\\\%$ of all injury-related deaths in Europe are caused by TBI. $^{5}$ In 2017, approximately 248,000 cases of TBI were reported in Korea, among which the mortality rate among those older than 80 years was 120.6 per 100,000. $^{6}$ According to the World Health Organization, TBI has remained a significant public health problem and a leading cause of mortality and disability worldwide as of 2020. $^{7-9}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,562,484,588]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the United States and Europe, work-related TBI (wrTBI) accounts for less than $10\\\\%$ of all TBIs, but it still warrants much \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,603,484,635]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From the Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, South Korea (Dr Bae, Dr Lee); and Rehabilitation Medicine Center, Korea Workers' Compensation and Welfare Service Incheon Hospital, Incheon, South Korea (Dr Lee). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,635,482,654]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding sources: This work was supported by the Korea Workers' Compensation and Welfare Service, grant number 0720185002. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,654,482,675]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lee and Bae have no relationships/conditions/circumstances that present potential conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,675,482,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The JOEM editorial board and planners have no financial interest related to this research. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,686,482,736]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ethical considerations and disclosures: This study was exempted from ethics approval by the institutional review board of Seoul National University Hospital (IRB No. E-2108-150-1246) because the data in the Korea Workers' Compensation and Welfare Service were anonymized and de-identified. Accordingly, informed consent was also waived. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,736,482,797]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author contributions: S.W.B. conceived and planned the study, performed the analysis, wrote the original draft with input from all authors, visualized the results, validated the study, and contributed to the interpretation of the results. M.-Y.L. conceived and planned the study, validated the study, contributed to the interpretation of the results, and supervised the entire process. Both authors read and approved the final manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,797,482,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplemental digital contents are available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.joem.org). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,828,482,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Address correspondence to: Min-Yong Lee, MD, Department of Rehabilitation Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, South Korea (roado10@gmail.com). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,859,482,929]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC BY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. DOI: 10.1097/JOM.000000000002556 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[525,253,679,268]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Learning Objectives \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[527,278,910,381]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- To identify differences in the risk factors of work related TBI. \\\",\\\"- To identify the important implications for industrial accident prevention strategies and appropriate rehabilitation systems for work related TBI. \\\",\\\"- To ascertain the severity and understand the burden and trend of work related TBI by injury severity during a decade (2010–2019) using data from the Korea Workers' Compensation Insurance claims. \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[506,392,926,494]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"concern. $^{10-13}$ WrTBI is one of the most disabling occupational injuries and can change the injured workers' lives due to subsequent job loss and sustained disability. It may also lead to significant economic burden in terms of medical expenses and wage losses. $^{8,10,14,15}$ According to the literature published in 2019, it was reported that the incidence of wrTBI is on the rise despite the decline in work-related injuries. $^{16}$ This finding suggests that efforts to prevent wrTBI are insufficient and that there is a need for increased awareness of wrTBI. $^{3}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,494,928,673]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Clinical features of TBIs are classified according to the severity (ie, mild, moderate, and severe).17 Moderate-to-severe TBI can be life-threatening and cause permanent physical or mental disability, making it difficult to return to work.8,18 Meanwhile, mild TBI, which comprises the majority of TBIs $(70\\\\% -90\\\\%)$ 19 is often overlooked because it is not fatal and does not cause severe disability. In most patients with mild TBI, acute symptoms (eg, headache, dizziness, cognitive difficulty) resolve in days to weeks after the injury; however, a subgroup of them may develop persistent neuropsychiatric symptoms up to 3 months after the injury, called post-concussion syndrome.20 Patients with post-concussion syndrome can experience difficulties in daily living and in returning to work.3,8,18,21 However, individuals with mild TBIs are often difficult to identify and are therefore left untreated. Thus, the actual burden of wrTBI may be much higher.7,8,22,23 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,673,928,751]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Therefore, identifying differences in the risk factors and severity of wrTBI may have important implications for industrial accident prevention strategies and appropriate rehabilitation systems. However, although there have been some studies regarding the incidence and mortality of TBI in Korea, to the best of our knowledge, there has been no published report on the epidemiology of wrTBI.[6,24] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,751,928,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study aimed to investigate the status of wrTBI with a focus on its severity in Korea and discuss the burden and trend of wrTBI by injury severity during a decade (2010-2019) using data from the Korea Workers' Compensation Insurance (WCI) claims—a large-scale source of administrative data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[606,822,830,836]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MATERIALS AND METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,852,609,865]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data Source \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,867,926,932]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study used Korea WCI data. In Korea, the Industrial Accident Insurance Act was introduced in 1964, and WCI coverage was expanded to all businesses or workplaces that employ workers, with some exceptions. When an industrial accident occurs, the respective employer is supposed to report it to the Korea Ministry of Employment and Labor. Compensation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[234,40,760,58]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CME AVAILABLE FOR THIS ARTICLE AT ACOEM.ORG \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[66,947,400,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOEM $\\\\cdot$ Volume 64, Number 9, September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[900,948,926,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"731 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[66,89,486,168]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is then provided to concerned workers with work-related injuries by the Korea Workers' Compensation and Welfare Service (KCOMWEL). The KCOMWEL manages the WCI data, which include information on workplaces at the time of industrial accidents, injuries, medical care, and compensations. Therefore, we obtained the anonymized data from 2010 to 2019 from the KCOMWEL for this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,182,207,196]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Study Population \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,198,486,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The population of this study consisted of workers who claimed compensation for wrTBI from January 1, 2010, to December 31, 2019. Patients with the following TBI diagnostic codes as main or sub-diagnoses were extracted by using the eighth Korean Standard Classification of Diseases based on the International Classification of Diseases, $10^{\\\\mathrm{th}}$ revision: concussion (S06.0), cranial fracture \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,89,929,205]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(S02.0, S02.1, S02.7, S02.8, S02.9, S07.1, and T90.2), and intracranial injury (S06.1-S06.9 and T90.5). The subjects of this study were defined and selected by priority in the order of intracranial injury, cranial fracture, and concussion among the three TBI diagnostic categories. The diagnoses and priorities according to the diagnostic codes are shown in Supplementary Table 1, http://links.lww.com/JOM/B190. In this study, concussion was classified under mild TBI, whereas cranial fracture and intracranial injury were considered moderate-to-severe TBIs.[6,25-27] Finally, a total of 48,166 patients were included in this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,232,587,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Variables \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,248,929,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The variables used in this study included the demographic characteristics, work-related injury characteristics, claim duration, and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[71,317,929,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0747/59eb1245dac1df60ca16001b34ac70a513e1dbf317f330dbecc9c56906e597a7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Characteristic</td><td colspan=\\\"2\\\">Total (n = 48,166)</td><td colspan=\\\"2\\\">Mild (n = 21,842)</td><td colspan=\\\"2\\\">Moderate-to-Severe (n = 26,324)</td><td>P*</td></tr><tr><td>Age at injury, yrs</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>50.6</td><td>13.1</td><td>49.9</td><td>13.2</td><td>51.2</td><td>13.1</td><td><0.001</td></tr><tr><td>Median (IQR)</td><td>52</td><td>43–60</td><td>52</td><td>42–59</td><td>53</td><td>44–60</td><td></td></tr><tr><td>Age group, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td><30</td><td>4063</td><td>8.4</td><td>2047</td><td>9.4</td><td>2016</td><td>7.7</td><td></td></tr><tr><td>30–39</td><td>5266</td><td>10.9</td><td>2489</td><td>11.4</td><td>2777</td><td>10.6</td><td></td></tr><tr><td>40–49</td><td>10,262</td><td>21.3</td><td>4690</td><td>21.5</td><td>5572</td><td>21.2</td><td></td></tr><tr><td>50–59</td><td>16,031</td><td>33.3</td><td>7388</td><td>33.8</td><td>8643</td><td>32.8</td><td></td></tr><tr><td>≥60</td><td>12,544</td><td>26.0</td><td>5228</td><td>23.9</td><td>7316</td><td>27.8</td><td></td></tr><tr><td>Sex, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Male</td><td>41,588</td><td>86.3</td><td>17,328</td><td>79.3</td><td>24,260</td><td>92.2</td><td></td></tr><tr><td>Female</td><td>6578</td><td>13.7</td><td>4514</td><td>20.7</td><td>2064</td><td>7.8</td><td></td></tr><tr><td>Work-related injury type, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Injury</td><td>46,222</td><td>96.0</td><td>20,840</td><td>95.4</td><td>25,382</td><td>96.4</td><td></td></tr><tr><td>Commuting injury</td><td>1944</td><td>4.0</td><td>1002</td><td>4.6</td><td>942</td><td>3.6</td><td></td></tr><tr><td>Occupation, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Managers</td><td>3606</td><td>7.5</td><td>1393</td><td>6.4</td><td>2213</td><td>8.4</td><td></td></tr><tr><td>Professionals/related workers</td><td>2407</td><td>5.0</td><td>1224</td><td>5.6</td><td>1183</td><td>4.5</td><td></td></tr><tr><td>Clerks</td><td>1298</td><td>2.7</td><td>663</td><td>3.0</td><td>635</td><td>2.4</td><td></td></tr><tr><td>Service workers</td><td>2189</td><td>4.5</td><td>1374</td><td>6.3</td><td>815</td><td>3.1</td><td></td></tr><tr><td>Sales workers</td><td>469</td><td>1.0</td><td>266</td><td>1.2</td><td>203</td><td>0.8</td><td></td></tr><tr><td>Skilled agricultural, forestry/fishery workers</td><td>944</td><td>2.0</td><td>478</td><td>2.2</td><td>466</td><td>1.8</td><td></td></tr><tr><td>Craft/related trades workers</td><td>11,865</td><td>24.6</td><td>4837</td><td>22.2</td><td>7028</td><td>26.7</td><td></td></tr><tr><td>Equipment/machine operating/assembling workers</td><td>4679</td><td>9.7</td><td>2168</td><td>9.9</td><td>2511</td><td>9.5</td><td></td></tr><tr><td>Elementary workers</td><td>20,709</td><td>43.0</td><td>9439</td><td>43.2</td><td>11,270</td><td>42.8</td><td></td></tr><tr><td>Industry, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td><0.001</td></tr><tr><td>Agriculture/forestry/fishing</td><td>1384</td><td>2.9</td><td>729</td><td>3.3</td><td>655</td><td>2.5</td><td></td></tr><tr><td>Mining/quarrying</td><td>172</td><td>0.4</td><td>68</td><td>0.3</td><td>104</td><td>0.4</td><td></td></tr><tr><td>Manufacturing</td><td>9467</td><td>19.7</td><td>3665</td><td>16.8</td><td>5802</td><td>22.0</td><td></td></tr><tr><td>Electricity/gas/steam/air conditioning supply</td><td>41</td><td>0.1</td><td>11</td><td>0.1</td><td>30</td><td>0.1</td><td></td></tr><tr><td>Water supply/sewage/waste management/materials recovery</td><td>10</td><td>0.0</td><td>3</td><td>0.0</td><td>7</td><td>0.0</td><td></td></tr><tr><td>Construction</td><td>19,120</td><td>39.7</td><td>7977</td><td>36.5</td><td>11,143</td><td>42.3</td><td></td></tr><tr><td>Wholesale/retail trade</td><td>2</td><td>0.0</td><td>0</td><td>0.0</td><td>2</td><td>0.0</td><td></td></tr><tr><td>Transportation/storage</td><td>3029</td><td>6.3</td><td>1644</td><td>7.5</td><td>1385</td><td>5.3</td><td></td></tr><tr><td>Accommodation/food service activities</td><td>3584</td><td>7.5</td><td>1872</td><td>8.6</td><td>1712</td><td>6.5</td><td></td></tr><tr><td>Information/communication</td><td>218</td><td>0.5</td><td>104</td><td>0.5</td><td>114</td><td>0.4</td><td></td></tr><tr><td>Financial/insurance activities</td><td>209</td><td>0.4</td><td>113</td><td>0.5</td><td>96</td><td>0.4</td><td></td></tr><tr><td>Real estate activities</td><td>104</td><td>0.2</td><td>49</td><td>0.2</td><td>55</td><td>0.2</td><td></td></tr><tr><td>Professional/scientific/technical activities</td><td>285</td><td>0.6</td><td>125</td><td>0.6</td><td>160</td><td>0.6</td><td></td></tr><tr><td>Business facilities management/business support services/rental and leasing activities</td><td>5003</td><td>10.4</td><td>2361</td><td>10.8</td><td>2642</td><td>10.0</td><td></td></tr><tr><td>Public administration/defense/compulsory social security</td><td>636</td><td>1.3</td><td>405</td><td>1.9</td><td>231</td><td>0.9</td><td></td></tr><tr><td>Education</td><td>374</td><td>0.8</td><td>255</td><td>1.2</td><td>119</td><td>0.5</td><td></td></tr><tr><td>Human health/social work activities</td><td>1155</td><td>2.4</td><td>798</td><td>3.7</td><td>357</td><td>1.4</td><td></td></tr><tr><td>Arts/sports/recreation related services</td><td>520</td><td>1.1</td><td>262</td><td>1.2</td><td>258</td><td>1.0</td><td></td></tr><tr><td>Membership organizations/repair/other personal services</td><td>2661</td><td>5.5</td><td>1310</td><td>6.0</td><td>1351</td><td>5.1</td><td></td></tr><tr><td>Activities of households as employers/undifferentiated goods-and services-producing activities of households for own use</td><td>172</td><td>0.4</td><td>78</td><td>0.4</td><td>94</td><td>0.4</td><td></td></tr><tr><td>Activities of extraterritorial organizations/bodies</td><td>20</td><td>0.0</td><td>13</td><td>0.1</td><td>7</td><td>0.0</td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 1. Preinjury Demographic Characteristics of Claimants With Work-Related Traumatic Brain Injury Stratified by Severity in Korea From 2010 to 2019 \\\"]\",\n \"table_footnote\": \"[\\\"* $P$ value from chi-squared test (categorical variables) or $t$ test (continuous variable). \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[71,42,148,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bae and Lee \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[595,40,928,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOEM Volume 64, Number 9, September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,948,95,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"732 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[147,948,928,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[66,89,482,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"claim cost of the injured workers. Ages were classified into $< 30$ , 30-39, 40-49, 50-59, and $\\\\geq 60$ years. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,116,482,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Work-related injury types were classified into injury, disease, and commuting injury. Occupations were classified according to the seventh Korean Standard Classification of Occupations based on the International Standard Classification of Occupations. Industries were classified according to the $10^{\\\\text{th}}$ Korean Standard Industrial Classification based on the International Standard Industrial Classification. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,191,484,308]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Time lost from work was estimated for workers receiving the cost of income replacement. The duration of work disability was defined as the number of days treated for a work-related injury. The total cost per claim refers to the total cost paid to a worker for an industrial accident. The cost of medical and similar services refers to medical care benefits and medical service fees, medication costs, medical care expenses, and nursing expenses. The cost of income replacement refers to the amount paid to workers with a work-related injury while they are unable to work due to medical treatment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,317,217,331]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Statistical Analyses \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,332,482,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The mean, standard deviation (SD), median, and interquartile range (IQR) of continuous variables for the subjects and the severity classification were calculated using the $t$ test. The frequency distribution of the categorical variables for comparison by severity was determined using the chi-squared test. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,396,484,512]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The annual incidence of wrTBI was calculated as the rate per 100,000 workers by dividing the number of workers diagnosed with TBI by the total number of workers. Time trends over the 10-year period were assessed using Poisson regression. In addition, the incidence rate of wrTBI as stratified by the industry classification was calculated as the mean incidence rate over the past decade. Risk ratios (RRs) and $95\\\\%$ confidence intervals (CIs) for moderate-to-severe TBI compared with mild TBI were calculated. The statistical analyses were performed using SAS statistical package version 9.4 (SAS Institute, Cary, NC). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[239,533,311,546]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,548,486,626]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From 2010 to 2019, a total of 48,166 workers claimed compensation for wrTBI, including 21,842 (45.3%) for mild TBI and 26,324 (54.7%) for moderate-to-severe TBI (Supplementary Table 2, http:// links.lww.com/JOM/B190). This table accounted for approximately 5% of all claims during this study period. The mean incidence of wrTBI was 28.4/100,000. In terms of the incidence rate of wrTBI by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,89,926,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"severity, mild TBI and moderate-to-severe TBI were 12.9/100,000 and 15.5/100,000, respectively (RR, 1.21; 95% CI, 1.19-1.22). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,116,928,294]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table 1 shows the preindustrial accident demographic characteristics of workers with wrTBI. The mean age at the time of the work-related injury was 50.6 years, and the mean age with moderate-to-severe TBI was 1.3 years older than those with mild TBI $(P < 0.001)$ . WrTBI most commonly occurred in those aged 50-59 years, with more than half of the cases occurring in those aged $\\\\geq 50$ years $(P < 0.001)$ . Males and injury in terms of work-related injury type accounted for the majority of wrTBI cases $(P < 0.001$ and $P < 0.001$ , respectively). In terms of occupation, wrTBI was most common in elementary workers $(43.0\\\\%)$ and craft/related trades workers $(24.6\\\\%)$ . As for industries, wrTBI most commonly occurred in construction $(39.7\\\\%)$ , followed by manufacturing $(19.7\\\\%)$ and business facilities management/business support services/rental and leasing activities $(10.4\\\\%)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,294,928,384]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 1 shows the wrTBI trend over 10 years. The incidence of workers with mild TBI decreased until 2016 and then increased in 2017 ( $P \\\\leq 0.001$ ). The incidence of moderate-to-severe TBI among workers continued to decrease from 17.6/100,000 (95% CI, 16.9-18.2) in 2010 to 14.5/100,000 (95% CI, 13.9-15.0) in 2019 ( $P = 0.001$ ). The incidence of mild TBI among workers was higher in 2010, but moderate-to-severe TBI was higher after 2011. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,383,928,524]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table 2 shows the incidence of wrTBI among all workers by industry. The incidence of wrTBI among all workers was the highest in construction (112.9/100,000), and lowest in wholesale/retail trade (0.0/100,000). The incidence rates of mild TBI and moderate-to-severe TBI were highest in construction, followed by manufacturing and business facilities management/business support services/rental and leasing activities. The industry with the highest incidence of moderate-to-severe TBI compared with mild TBI was electricity/gas/steam/air conditioning supply (RR, 2.73; $95\\\\%$ CI, 1.59-4.67), whereas the industry with the lowest rate of wrTBI was the human health/social work activities industry (RR, 0.45; $95\\\\%$ CI, 0.41-0.49). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,523,928,626]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table 3 shows the characteristics of compensation claims for wrTBI. Of all workers with wrTBI, $86.4\\\\%$ experienced time lost from work, with a higher proportion among those with mild TBI than those with moderate-to-severe TBI $(P < 0.001)$ . The total duration of compensated medical care was 262.2 days, but it was longer for those with moderate-to-severe TBI at 358.2 days $(P < 0.001)$ . The total cost per claim, medical and like services, and income replacement for moderate-to-severe TBI workers were nearly four times higher \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[222,654,777,911]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 1. Incidence of work-related traumatic brain injury in all workers in Korea from 2010 to 2019. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0845/b592100af90e228d896fa61515b7b0306c7cad3691da925d39846583b8f58c23.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[66,42,400,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOEM $\\\\cdot$ Volume 64, Number 9, September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[667,42,928,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Incidence of Work-Related TBI by Severity \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[66,948,847,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[900,948,926,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"733 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[68,129,931,451]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0783/9fc79954b9a5c11225980d19c5f5dec97458614c3c8eb16188e7611037362a6c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Industry Sector</td><td colspan=\\\"4\\\">All Workers (rate per 100,000)*</td></tr><tr><td>Total</td><td>Mild</td><td>Moderate-to-Severe</td><td>RR (95% CI)†</td></tr><tr><td>Agriculture/forestry/fishing</td><td>8.2</td><td>4.3</td><td>3.9</td><td>0.90 (0.83–0.97)</td></tr><tr><td>Mining/quarrying</td><td>1.0</td><td>0.4</td><td>0.6</td><td>1.53 (1.23–1.91)</td></tr><tr><td>Manufacturing</td><td>55.9</td><td>21.6</td><td>34.3</td><td>1.58 (1.54–1.63)</td></tr><tr><td>Electricity/gas/steam/air conditioning supply</td><td>0.2</td><td>0.1</td><td>0.2</td><td>2.73 (1.59–4.67)</td></tr><tr><td>Water supply/sewage/waste management/materials recovery</td><td>0.1</td><td>0.0</td><td>0.0</td><td>2.33 (0.83–6.54)</td></tr><tr><td>Construction</td><td>112.9</td><td>47.1</td><td>65.8</td><td>1.40 (1.37–1.43)</td></tr><tr><td>Wholesale/retail trade</td><td>0.0</td><td>0.0</td><td>0.0</td><td>NA</td></tr><tr><td>Transportation/storage</td><td>17.9</td><td>9.7</td><td>8.2</td><td>0.84 (0.80–0.89)</td></tr><tr><td>Accommodation/food service activities</td><td>21.2</td><td>11.1</td><td>10.1</td><td>0.91 (0.87–0.96)</td></tr><tr><td>Information/communication</td><td>1.3</td><td>0.6</td><td>0.7</td><td>1.10 (0.91–1.32)</td></tr><tr><td>Financial/insurance activities</td><td>1.2</td><td>0.7</td><td>0.6</td><td>0.85 (0.70–1.03)</td></tr><tr><td>Real estate activities</td><td>0.6</td><td>0.3</td><td>0.3</td><td>1.12 (0.85–1.47)</td></tr><tr><td>Professional/scientific/technical activities</td><td>1.7</td><td>0.7</td><td>0.9</td><td>1.28 (1.08–1.51)</td></tr><tr><td>Business facilities management/business support services/rental and leasing activities</td><td>29.5</td><td>13.9</td><td>15.6</td><td>1.12 (1.08–1.16)</td></tr><tr><td>Public administration/defense/compulsory social security</td><td>3.8</td><td>2.4</td><td>1.4</td><td>0.57 (0.51–0.64)</td></tr><tr><td>Education</td><td>2.2</td><td>1.5</td><td>0.7</td><td>0.47 (0.40–0.55)</td></tr><tr><td>Human health/social work activities</td><td>6.8</td><td>4.7</td><td>2.1</td><td>0.45 (0.41–0.49)</td></tr><tr><td>Arts/sports/recreation related services</td><td>3.1</td><td>1.5</td><td>1.5</td><td>0.98 (0.87–1.11)</td></tr><tr><td>Membership organizations/repair/other personal services</td><td>15.7</td><td>7.7</td><td>8.0</td><td>1.03 (0.98–1.09)</td></tr><tr><td>Activities of households as employers/undifferentiated goods- and services-producing activities of households for own use</td><td>1.0</td><td>0.5</td><td>0.6</td><td>1.21 (0.97–1.49)</td></tr><tr><td>Activities of extraterritorial organizations/bodies</td><td>0.1</td><td>0.1</td><td>0.0</td><td>0.54 (0.27–1.06)</td></tr><tr><td>Total</td><td>28.4</td><td>12.9</td><td>15.5</td><td>1.21 (1.19–1.22)</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 2. Incidence Rate of Work-Related Traumatic Brain Injury by Industry Sector and Severity Among All Workers in Korea From 2010 to 2019 \\\"]\",\n \"table_footnote\": \"[\\\"*Rates are presented as an average over the 10-year period. \\\",\\\"†Moderate-to-severe TBI to mild TBI risk ratio. \\\",\\\"NA, not applicable; RR, risk ratio. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[66,503,489,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"than for workers with mild TBI. In addition, the mean mortality rate of wrTBI was 2.8/100,000, which was mostly associated with moderate-to-severe TBI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[224,553,330,566]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[66,567,489,634]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This is the first epidemiologic study of wrTBI in Korea to consider the severity of the TBI in its analysis. From Korea WCI data spanning 10 years (2010-2019), we estimated the incidence rate of wrTBI by severity and industry sector and reported differences by severity in terms of demographic and claims characteristics. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,503,929,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There were some differences in should be hyphenated demographic characteristics depending on severity, but the overall tendency was similar in both mild and moderate-to-severe groups. Table 1 shows that wrTBI occurred mostly in older workers, males, manual workers, and the construction industry. This result is consistent with the results of previous studies regarding wrTBI. $^{1,3,8-10,21,28,29}$ Different tasks at work and employment characteristics according to sex may have contributed to the higher incidence of wrTBI in males. $^{8,9}$ For older workers, decreased concentration and falls due to lack of balance and flexibility may have been the main causes of wrTBI. $^{28}$ In addition, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,673,931,886]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0944/6821d06d301eb2b972020d0839b29277fcaa3b5b6e236744b13904847dea4b5b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Claims</td><td colspan=\\\"2\\\">Total</td><td colspan=\\\"2\\\">Mild</td><td colspan=\\\"2\\\">Moderate-to-Severe</td><td>P*</td></tr><tr><td>All claimants, n</td><td>48,166</td><td></td><td>21,842</td><td></td><td>26,324</td><td></td><td></td></tr><tr><td>Time lost from work, n (%)</td><td>41,591</td><td>86.4</td><td>19,502</td><td>89.3</td><td>22,089</td><td>83.9</td><td><0.001</td></tr><tr><td>Inpatient hospital stay, n (%)</td><td>43,936</td><td>91.2</td><td>19,182</td><td>87.8</td><td>24,754</td><td>94.0</td><td><0.001</td></tr><tr><td>Duration of work disability</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD) number of days</td><td>262.2</td><td>397.4</td><td>146.5</td><td>190.9</td><td>358.2</td><td>488.2</td><td><0.001</td></tr><tr><td>Median (IQR) number of days</td><td>148</td><td>53–299</td><td>94</td><td>43–188</td><td>212</td><td>81–446</td><td></td></tr><tr><td>Claim costs paid (million KRW)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD) total cost per claim</td><td>59.26</td><td>110.90</td><td>21.87</td><td>44.20</td><td>90.29</td><td>136.97</td><td><0.001</td></tr><tr><td>Mean (SD) cost of medical and like services</td><td>22.17</td><td>69.92</td><td>6.97</td><td>21.95</td><td>34.62</td><td>90.43</td><td><0.001</td></tr><tr><td>Mean (SD) cost of income replacement</td><td>14.45</td><td>21.15</td><td>8.58</td><td>12.38</td><td>19.32</td><td>25.28</td><td><0.001</td></tr><tr><td>Time-loss claims,†n</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Claim costs paid (million KRW)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD) total cost per claim</td><td>60.11</td><td>112.63</td><td>24.02</td><td>45.69</td><td>91.97</td><td>140.99</td><td><0.001</td></tr><tr><td>Mean (SD) cost of medical and like services</td><td>25.10</td><td>70.28</td><td>7.67</td><td>23.11</td><td>40.48</td><td>91.24</td><td><0.001</td></tr><tr><td>Mean (SD) cost of income replacement</td><td>16.74</td><td>21.90</td><td>9.61</td><td>12.72</td><td>23.03</td><td>26.00</td><td><0.001</td></tr><tr><td>Mortality rate‡</td><td>2.8</td><td></td><td>0.0</td><td></td><td>2.7</td><td></td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 3. Claims Characteristics of Work-Related Traumatic Brain Injury by Severity in Korea From 2010 to 2019 \\\"]\",\n \"table_footnote\": \"[\\\"* $P$ value from chi-squared test (categorical variables) or t test (continuous variable). \\\",\\\"$\\\\\\\\dagger$ Analyses restricted to claimants with $>0$ claim cost paid lost from work. \\\",\\\"${}^{2}$ Rates are presented as an average over the 10-year period (rate per 100,000). \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[71,42,150,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bae and Lee \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[595,40,928,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOEM Volume 64, Number 9, September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[71,948,95,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"734 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[148,948,929,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[66,90,482,115]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"manual labor may be associated with more frequent exposure to risky work environments.[9] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,116,484,446]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study is one of the few to explore the trend of wrTBI. We identified that the mean incidence of wrTBI was 28.4/100,000 workers per year. It was in Australia where the mean incidence of wrTBI was 19.8/100,000 workers per year,[9] and it was lower in Canada, where it was 33.1/100,000 workers per year.[14] Based on the incidence of Korea TBI reported in Oh et al.'s study,[6] wrTBI is confirmed to comprise approximately $5\\\\%$ of all TBI in Korea. This is consistent with the trends of wrTBI incidence rates in the United States and Europe, where wrTBI accounted for less than $10\\\\%$ of all TBI cases.[10-13] Figure 1 shows that the number of workers with a diagnosis of wrTBI decreased until 2016 but increased in trend in 2017. Similarly, the incidence of mild wrTBI among workers initially decreased, and then increased again from 2017, whereas the incidence of moderate-to-severe TBI among workers continued to decrease for the past 10 years. The trend of industrial accidents announced by the Korea Ministry of Employment and Labor was similar to the results of this study. This is presumably due to the result of policies for improving access to workers' compensation insurance.[30] Since 2018, the employer confirmation system has been abolished, allowing workers to file an industrial accident claim without confirmation from the employer. In addition, the number of work accidents may have increased since injuries incurred during commuting were also approved as work-related injuries.[31] Traffic accidents are the most common cause of work-related mild TBI,[10,21,29,32] and this may be related to the increase in the incidence of mild TBI due to traffic accidents occurring while commuting to and from work. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,447,484,649]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The incidence of moderate-to-severe TBI was higher than that of mild TBI during the observation period except for the first observation year, which is consistent with the results of Brolin et al.'s study. Considering that $70\\\\%$ to $90\\\\%$ of TBI cases are classified as mild TBI, these results are interesting. Mild wrTBI incidence rate is likely underestimated since patients with mild TBI often do not seek medical help. Even if a patient needs clinical care, most of them recover within days to weeks after a traumatic incident. However, because it can take a few weeks to receive approval for an industrial accident, considerable cases of mild wrTBI are unlikely to lead to an industrial accident claim. In addition, for mild TBI, the symptoms can be underreported due to the vagueness or workers' lack of awareness of the symptoms. Thus, in some cases, mild wrTBI may not even be diagnosed. Therefore, it is necessary to emphasize the symptoms of mild TBI (ie, concussion) during occupational safety and health education sessions conducted for workers in Korea. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,650,484,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study showed differences by severity in the distribution and proportion of wrTBI by industry. Moderate-to-severe wrTBIs commonly occurred in construction, manufacturing, and business facilities management/business support services/rental and leasing activities associated with manual labor or hazardous working conditions. Mild wrTBIs occurred in financial and insurance activities, public administration/defense/compulsory social security, and service industries. In particular, the incidence of both mild and moderate-to-severe TBI was much higher in the construction industry compared with other industries. Considering that construction workers are at high risk of serious and fatal injuries,[29] and that previous studies have also identified the construction industry as a major contributor to the wrTBI-related industry sector,[10,34] it is necessary to review risk factors and the mechanisms of injuries in this specific industry.[28] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,829,484,930]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The results of our study showed significant work disability and economic burdens of wrTBI. Injured workers with moderate-to-severe TBI had a longer duration of work disability and higher expense claims than those with mild TBI. However, the proportion of those who experienced time lost from work was higher in subjects with mild TBI than moderate-to-severe TBI. Although acute symptoms after mild TBI improve in days to weeks, approximately $15\\\\%$ of mild TBI patients suffer from persistent neuropsychiatric symptoms (eg, headache, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,90,928,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"dizziness, cognitive dysfunction, depression, anxiety), which impact their decision regarding whether to return to work beyond 1 year.[35,36] In Korea, the return-to-work program (functional capacity evaluation, work conditioning, and work hardening) is only provided by the KCOMWEL,[37] and mainly focuses on physical issues. However, the results of this study suggest that, aside from physical problems, neuropsychiatric problems should also be considered when assessing return to work in patients with mild wrTBI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,191,928,294]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The strengths of this study are as follows: First, because the WCI data used in this study was nationally representative, our results can be considered as representative of work-related injuries in Korea. Second, to the best of our knowledge, this is the first study to investigate the trend of wrTBI by severity among work-related injury workers in Korea for a duration of 10 years. Third, our study can be seen as wide scale because we were able to provide information on the wrTBI incidence of workers across 21 industries. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,294,928,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However, this study also has several limitations. First, the amount of compensation may not be accurate for injured workers whose compensation claims have not been completed or if compensation for an industrial accident has not been closed. For example, if a worker killed an industrial accident in October 2019 and the resulting compensation was not yet closed, the included compensation amount might only be for 3 months. Second, the age- and sex-standardized incidence of wrTBI could not be calculated because the number of injured workers by age group and sex could not be identified due to restricted access to the statistical data. Third, further studies regarding factors affecting the incidence of wrTBI are needed. Although our study investigated the industry-stratified incidence of wrTBI, further studies that consider gender, mechanism of injury, injured workers' employment status, and workplace size are needed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,485,607,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,501,928,667]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This study provides useful information on the epidemiology of wrTBI concerning its severity during a decade (2010-2019) in Korea. The incidence of wrTBI in Korea decreased until 2016 and then increased in trend from 2017. The incidence of moderate-to-severe TBI was higher than that of mild TBI during the observation period except for the first observation year. Injured workers with moderate-to-severe TBI had a longer duration of work disability and higher expense claims than those with mild TBI. However, the proportion of those who experienced time lost from work was higher in subjects with mild TBI than moderate-to-severe TBI. Our findings highlight the need for providing information to workers on mild TBI in occupational safety and health education and may serve as the basis for further wrTBI research. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[626,682,809,696]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,696,928,737]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors would like to thank the Korea Workers' Compensation and Welfare Service for making this study possible and providing the data from the Korea workers' compensation insurance claims. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[667,751,768,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,769,928,930]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Brain Inj. 2019;33:830-835. \\\"]\",\n \"page_idx\": \"4\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[66,42,400,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOEM $\\\\cdot$ Volume 64, Number 9, September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[667,42,926,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Incidence of Work-Related TBI by Severity \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[66,948,847,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[900,948,926,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"735 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[71,89,486,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"6. Kim HK, Leigh JH, Lee YS, et al. Decreasing incidence and mortality in traumatic brain injury in Korea, 2008-2017: a population-based longitudinal study. 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Hospital separations due to traumatic brain injury, Australia 2004-05. *Inj Res Stat Ser.* 2008;45:ePub. \\\",\\\"13. Baldo V, Marcolongo A, Floreani A, et al. Epidemiological aspect of traumatic brain injury in Northeast Italy. Eur J Epidemiol. 2003;18:1059-1063. \\\",\\\"14. Colantonio A, Mroczek D, Patel J, Lewko J, Fergenbaum J, Brison R. Examining occupational traumatic brain injury in Ontario. Can J Public Health. 2010;101:S58-S62. \\\",\\\"15. Kristman VL, Cote P, Hogg-Johnson S, et al. The burden of work disability associated with mild traumatic brain injury in Ontario compensated workers: a prospective cohort study. Open Occup Health Saf J. 2010;2:1-8. \\\",\\\"16. Sharma B, Nowrouzi-Kia B, Mollayeva T, et al. Work-related traumatic brain injury: a brief report on workers perspective on job and health and safety training, supervision, and injury preventability. *Work*. 2019;62:319-325. \\\",\\\"17. Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT, Workshop Scientific Team and Advisory Panel Members. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008;25:719-738. \\\",\\\"18. Whiteneck GG, Cuthbert JP, Corrigan JD, Bogner JA. Risk of negative outcomes after traumatic brain injury: a statewide population-based survey. J Head Trauma Rehabil. 2016;31:E43-E54. \\\",\\\"19. Levin HS, Diaz-Arrastia RR. Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol 2015;14:506-517. \\\",\\\"20. Carroll L, Cassidy JD, Peloso P, et al. Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004;36:84-105. \\\",\\\"21. Chang VH, Lombard LA, Greher MR. Mild traumatic brain injury in the occupational setting. PMR. 2011;3:S387-S395. \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[511,89,929,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"22. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21:375-378. \\\",\\\"23. Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9:231-236. \\\",\\\"24. Choi DH, Song KJ, Shin SD, Ro YS, Hong KJ, Park JH. Epidemiology and outcomes of sports-related traumatic brain injury in children. J Korean Med Sci. 2019;34:e290. \\\",\\\"25. Mateu NC. Traumatic brain injury in Denmark 2008-2012. Scand J Public Health. 2020;48:331-337. \\\",\\\"26. Madsen T, Erlangsen A, Orlovska S, Mofaddy R, Nordentoft M, Benros ME. Association between traumatic brain injury and risk of suicide. JAMA. 2018; 320:580-588. \\\",\\\"27. Choi Y, Kim EY, Sun J, et al. Incidence of depression after traumatic brain injury: a nationwide longitudinal study of 2.2 million adults. J Neurotrauma. 2022;39:390-397. \\\",\\\"28. Paci M, Infante-Rivard C, Marcoux J. Traumatic brain injury in the workplace. Can J Neurol Sci. 2017;44:518-524. \\\",\\\"29. Colantonio A, McVittie D, Lewko J, Yin J. Traumatic brain injuries in the construction industry. Brain Inj. 2009;23:873-878. \\\",\\\"30. Ministry of Employment and Labor. Analysis of Occupational Accidents; 2019. Seoul, South Korea: Ministry of Employment and Labor; 2021. \\\",\\\"31. Bae SW, Lee MY, Park SW, Lee G, Leigh JH. Satisfying medical and rehabilitation needs positively influences returning to work after a work-related injury: an analysis of national panel data from 2018 to 2019. BMC Public Health. 2021;21:2017. \\\",\\\"32. Dunne J, Quifones-Ossa GA, Still EG, et al. The epidemiology of traumatic brain injury due to traffic accidents in Latin America: a narrative review. J Neurosci Rural Pract 2020;11:287-290. \\\",\\\"33. Iverson GL, Lange RT, Brooks BL, Rennison VL. \\\\\\\"Good old days\\\\\\\" bias following mild traumatic brain injury. Clin Neuropsychol. 2010;24:17-37. \\\",\\\"34. Konda S, Reichard A, Tiesman HM, Hendricks S. Non-fatal work-related traumatic brain injuries treated in US hospital emergency departments, 1998-2007. *Inj Prev*. 2015;21:115-120. \\\",\\\"35. Schretlen DJ, Shapiro AM. A quantitative review of the effects of traumatic brain injury on cognitive functioning. Int Rev Psychiatry. 2003;15:341-349. \\\",\\\"36. Alexander MP. Mild traumatic brain injury: pathophysiology, natural history, and clinical management. *Neurology*. 1995;45:1253-1260. \\\",\\\"37. Bae SW. Effect of professional certification on employees' return-to-work rate after occupational injuries in Korea: focusing on vulnerable groups. Environ Health Prev Med 2021;26:6. \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[71,42,150,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bae and Lee \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[595,42,928,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOEM $\\\\cdot$ Volume 64, Number 9, September 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[71,948,95,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"736 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[148,948,928,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1097/jom.0000000000002556"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"400533ce6996c89d79d512cca864a64fe783bbcada9ced88b84b6504323b6ff2"},"title":{"kind":"string","value":"Incidence of Traumatic Brain Injury by Severity Among Work-Related Injured Workers From 2010 to 2019"}}},{"rowIdx":160,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Shawky El Moursi, Mohamed"},"content_list":{"kind":"list like","value":[{"bbox":"[117,73,872,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Guest Editorial: IEEE Transactions on Power Delivery IEEE Transactions on Power Systems Joint Special Section on Hybrid AC/DC Transmission Grids ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,253,486,537]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HVDC technology has brought many advantages to power transmission. Examples are increased flexibility in operation, expanded power transfer capability and easier interconnection of energy sources. However, HVDC links need to be built along existing AC transmission grids. It has become increasingly evident that the future power transmission systems will become interwoven networks of AC and DC subsystems, i.e., hybrid AC/DC transmission grids. The AC and DC grids have their own characteristics. An AC grid tends to have a large inertia and well-understood responses to disturbances. A DC grid generally has a low tolerance to fault and can respond very fast. When the two grids are interconnected, substantially more complex dynamic and transient interactions can occur. A single AC system fault, for example, may lead to simultaneous commutation failures in multiple converter stations. New phenomena, such as super-synchronous resonance, can also emerge whose mechanisms have not been fully understood. All these characteristics present new challenges to the planning, design and operation of future power transmission systems. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,540,486,674]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In view of this major trend in the evolution of power transmission systems, the IEEE Transactions on Power Delivery and IEEE Transactions on Power Systems have decided to publish this joint special section on the subject, with the objective to promote research, innovation and exchange in the broad field of hybrid AC/DC transmission grids. In this special section, we invited submission of original research and/or review works from both power delivery and power system perspectives. Topics of interest include the following: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[74,675,484,840]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- Methodologies for Planning and Operating Hybrid AC/DC Grids; \",\"- Modelling and Analysis of Electromechanical Dynamics in Hybrid AC/DC Grids; \",\"- Techniques for Monitoring and Control of Dynamic and Transient Stability of Hybrid Grids; \",\"Modelling and Analysis of Electromagnetic Interactions in Hybrid AC/DC Grids; \",\"- Techniques for Detection and Mitigation of (Subsynchronous, Supersynchronous, Harmonic and High Frequency) Resonance and Inter-Converter Oscillations; \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[516,253,929,523]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"- Innovations on the Protection of Hybrid Grids Including AC and DC Fault Ride-Through Techniques; \",\"- High Power Converter Topologies, Design, Protection and Control as Well as HIL Evaluations and Grid Level Integration of Different Converter Technologies; \",\"- Advances in Power Apparatuses Enabling AC/DC Grids (e.g., HVDC circuit breakers); \",\"- Advanced Synchronization Schemes for Enhancing Dynamics Response and Stability; \",\"- Techniques and Apparatus to Enhance Inertia Response of Hybrid AC/DC Grids (such as virtual inertia support and augmentation of different types of energy storage systems); \",\"- Blackout Restoration for Hybrid AC/DC Grids; \",\"- Dynamic Interactions of a Hybrid Grid with Various Energy Sources; \",\"- Cyber-Security for Hybrid AC/DC Grids (e.g., identifying new security threats at converter and system levels, attacks and mitigation techniques). \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[500,525,929,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This Special Section, therefore, welcomed submission of original works from both power delivery and power system perspectives. After receiving the extended abstracts, the guest EIC and editorial board determined which Transaction is a better fit for the work. Authors then submitted full papers to the designated transaction. This Special Section attracted 229 extended abstracts and the review process concluded with inviting 86 and 81 extended abstracts to submit full papers to TPWRS and TPWRD, respectively. Finally, we received 120 papers with a total of 47 valuable papers accepted for publication in the TPWRD and TPWRS. The acceptance rate is $39\\%$ of the submitted full papers and $20\\%$ of the submitted extended abstracts. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[500,720,929,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I would like to express my sincere thanks to the Editor-in-Chief of the IEEE Transactions on Power Delivery, Prof. Wilsun Xu from the University of Alberta, and the Editor-in-Chief of the IEEE Transactions on Power Systems, Prof. Nikolaos Hatziargyriou from National Technical University of Athens for appointing me as Guest Editor in Chief of this Special Section and their great efforts and advice throughout the review process. I would also like to express my sincere gratitude and thanks to the team of Guest Editors for their great efforts and time devoted to this special section. Their valuable expertise and dedication have made it a reality. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,37,466,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IEEE TRANSACTIONS ON POWER SYSTEMS, VOL. 36, NO. 1, JANUARY 2021 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[907,39,930,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"563 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[72,882,382,895]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Digital Object Identifier 10.1109/TPWRS.2020.3041890 ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[193,914,792,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"0885-8950 © 2021 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission. See https://www.ieee.org/publications/rights/index.html for more information. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,79,329,94]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Guest advisors for special section: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,95,493,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Prof. Frede Blabjerg, Villum Investigator, Aalborg University, Denmark. \",\"Prof. Vijay Vittal, Ira A. Fulton Chair Professor, Arizona State University. \"]","page_idx":"1","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[82,156,188,167]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Guest editors: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,170,493,607]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Prof. Nilanjan Ray Chaudhuri, Penn State College of Engineering, USA. \",\"Prof. Xinzhou Dong, Professor, Tsinghua University, China \",\"- Dr. Sébastien Dennetiere, Senior Researcher, RTE Centre National d'Expertise Réseaux, France. \",\"Prof. Johan Enslin, Executive Director, ZGEC at Clemson, Charleston, South Carolina Area, USA. \",\"Prof. Tim Green, Professor, Imperial College London, UK.\",\"Prof. Oriol Gomis-Bellmunt, Professor, Universitat Politècnica de Catalunya, Barcelona, Spain. \",\"Prof. Lennart Harnefors, Senior Principal Scientist ABB & Adjunct Professor of KTH, Sweden. \",\"Prof. Brian K. Johnson, Professor, University of Idaho, Moscow, ID, USA. \",\"Prof. Dragan Jovcic, Chair in Engineering, University of Aberdeen, Aberdeen, UK. \",\"Prof. Federico Milano, Professor, University College Dublin, Dublin, Ireland. \",\"- Dr. Lisa Qi, Senior Principal Scientist, ABB Corporate Research Center, USA. \",\"Prof. Luis Rouco, Professor, Universidad Pontificia Comillas, Madrid, Spain. \",\"- Dr. Ali Mehrizi-Sani, Associate Professor, Washington State University, Pullman, WA, USA. \",\"Prof. Xiongfei Wang, Professor and Research Program Leader, Aalborg University, Denmark. \",\"Prof. Zheng Xu, Professor, Zhejiang University, China. \",\"Prof. Lie Xu, Professor, University of Strathclyde, UK.\"]","page_idx":"1","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[63,608,493,743]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On behalf, of the Guest editorial board, I am deeply thankful and appreciative to the large number of reviewers who have devoted long time and efforts in providing high quality reviews and constructive comments that resulted in a number of high quality publications for this special section. Last, but not least, this special section would not happen without the intellectual contributions and the impressive amount of work of the authors devoted for preparing the work and revising the papers for successful publication. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,744,493,864]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This special section shared between TPWRD and TPWRS includes valuable papers that will benefit the PES community for improving the planning, operational control, system stability, power electronics and protection schemes for Hybrid AC/DC Transmission Grids. Looking into the future, attention is given to the unique feature of hybrid AC/DC grid that emphasizes the strong coupling between apparatus level behaviors with system wide responses. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,864,493,893]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted papers in the Special Section: Hybrid AC/DC Transmission Grids ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,895,481,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IEEE Transactions on Power Delivery (Accepted Papers) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[92,910,493,938]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1) Integrated Multiport DC Power Flow Controller with DC Circuit Breaker ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[528,80,936,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"2) Experimental Investigation of Electrical Stresses on the Main Components of HVDC Circuit Breakers \",\"3) Incorporating DC Grid Protection, Frequency Stability and Reliability Into Offshore DC Grid Planning \",\"4) Static and dynamic evaluation of different architectures for an actual HVDC link project \",\"5) Instantaneous Active Power Integral Differential Protection for Hybrid AC/DC Transmission Systems Based on Fault Variation Component \",\"6) A DC Line Protection Scheme for MMC-Based DC Grids Based on AC/DC Transient Information \",\"7) A Hybrid-Arm Modular Multilevel Converters Topology with DC low voltage operation Capability for Unidirectional HVDC Bulk Power Transmission \",\"8) Transient Voltage and Current Stresses Estimation of MMC-MTDC System via Discrete-time Analysis \",\"9) A Novel DC Fault Ride-Through Method for Wind Farms Connected to the Grid Through Bipolar MMC-HVDC Transmission \",\"10) Analysis and Prevention of Subsequent Commutation Failures Caused by Improper Inverter Control Interactions in HVDC Systems \",\"11) Real-Time Hierarchical Neural Network Based Fault Detection and Isolation for High-Speed Railway System Under Hybrid AC/DC Grid \",\"12) Study on the Parameter Requirements for Resistive - Type Superconducting Fault Current Limiters Combined with Mechanical DC Circuit Breakers in Hybrid AC/DC Transmission Grids \",\"13) A Fault Tolerant Scheme for Integration of Remote Renewable Energy Sources with HVDC System \",\"14) A Novel DC Transmission System Fault Location Technique for Offshore Renewable Energy Harvesting \",\"15) Protection Coordination of AC/DC Intersystem Faults in Hybrid Transmission Grids \",\"16) Augmented Design of DC/DC Modular Multilevel Converter Improving Efficiency and Reducing Number of SMs \",\"17) Equivalent Multiple dq Frame Model of the MMC using Dynamic Phasor Theory in the $\\\\alpha \\\\beta z$ -Frame \",\"18) Preventive and Curative Actions by Meshed Bipolar HVDC-Overlay-Systems \",\"19) A Novel DC Fault Ride Through Control Methodology for Hybrid Modular Multilevel Converters in HVDC Systems \",\"20) Detailed Equivalent and Average Value Models of Hybrid Cascaded Multilevel Converters for Efficient and Accurate EMT-Type Simulation \",\"21) Frequency-Coupling Impedance Model based Analysis of a High Frequency Resonance Incident in an Actual MMC-HVDC System \",\"22) Response Mechanism of DFIG to Transient Voltage Disturbance under Commutation Failure of LCC-HVDC System \"]","page_idx":"1","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[67,40,89,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"564 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[528,39,936,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IEEE TRANSACTIONS ON POWER SYSTEMS, VOL. 36, NO. 1, JANUARY 2021 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[75,79,486,155]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"23) A Novel Traveling Wave Protection Method for DC Transmission Lines Using Current Fitting \",\"24) The Last Circuit Breakers Identification in Hybrid AC/DC Power Grids Based on Improved Tarjan Algorithm \"]","page_idx":"2","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[75,156,471,170]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IEEE Transactions on Power Systems (Accepted Papers) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,171,486,608]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1) Adaptive Droop Control of Multi-Terminal HVDC Network for Frequency Regulation and Power Sharing \",\"2) Hybrid AC/DC Transmission Expansion Planning Considering HVAC to HVDC Conversion Under Renewable Penetration \",\"3) Cybersecurity of Wide Area Monitoring, Protection and Control Systems for HVDC Applications \",\"4) Renewable Integration in Hybrid ac-dc Systems Using Multi-Port Autonomous Reconfigurable Solar Power Plant (MARS) \",\"5) Frequency Response Impact of Integration of HVDC Into a Low Inertia AC Power Grid \",\"6) A Novel Distributed Supplementary Control of Multi-Terminal VSC-HVDC Grids for Rotor Angle Stability Enhancement of AC/DC Systems \",\"7) Coordinated Voltage and Frequency Control in Hybrid AC/MT-HVDC Power Grids for Stability Improvement \",\"8) Coordinated Wide Area Control of Multiple Controllers in a Power System Embedded With HVDC Lines \",\"9) Cost-Based Adaptive Droop Control Strategy for VSCMTDC System \",\"10) Mitigation of Subsynchronous Interaction in Hybrid AC/DC Grid With Renewable Energy Using Faster-Than Real-Time Dynamic Simulation \",\"11) Synchronized Phasor Measurement Unit Based Central Controller for Normal and Contingent Operation of a High Capacity HVDC Macrogrid for the Continental US \",\"12) Optimal Planning and Operation of Multi Frequency HVAC Transmission Systems \"]","page_idx":"2","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[518,79,930,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"13) Model Order Reduction of Multi-Terminal Direct-Current Grid Systems \",\"14) Coordinated Design of Supplementary Controllers in VSCHVDC Multi-Terminal Systems to Damp Electromechanical Oscillations \",\"15) Hybrid AC/DC Network With Parallel LCC-VSC Interlinking Converters \",\"16) Three-Port Small Signal Admittance Based Model of VSCs for Studies of Multiterminal HVDC Hybrid AC/DC Transmission Grids \",\"17) Minimization of ACDC Grid Transmission Loss and DC Voltage Deviation Using Adaptive Droop Control and Improved AC-DC Power Flow Algorithm \",\"18) Switching System's MLE Based Transient Stability Assessment of AC/DC Hybrid System Considering Continuous Commutation Failure \",\"19) Control of Interlinking Converters in Hybrid AC/DC Grids: Network Stability and Scalability \",\"20) Two-Level Combined Control Scheme of VSC-MTDC Integrated Offshore Wind Farms for Onshore System Frequency Support \",\"21) Hierarchical and Robust Scheduling Approach for VSCMTDC Meshed AC/DC Grid With High Share of Wind Power \",\"22) Primary Frequency Support through North American Continental HVDC Interconnections With VSC-MTDC Systems \",\"23) Exploiting the Operational Flexibility of Wind Integrated Hybrid AC/DC Power Systems \"]","page_idx":"2","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[500,532,927,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PROF. MOHAMED SHAWKY EL MOURSI, Guest Editor-in-Chief Electrical Engineering and Computer Science Department Khalifa University of Science and Technology Abu Dhabi, UAE ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[501,593,760,607]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E-mail: mohamed.elmoursi@ku.ac.ae","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,642,255,834]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0284/f28f77e8aa87ca7be03d78fdb6a8ec0066c443040443ccc5468ca463b9a2a7a2.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[277,638,929,698]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Mohamed Shawky El Moursi (Senior Member, IEEE) received the B.Sc. and M.Sc. degrees from Mansoura University, Mansoura, Egypt, in 1997 and 2002, respectively, and the Ph.D. degree from the University of New Brunswick (UNB), Fredericton, NB, Canada, in 2005, all in electrical engineering. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,699,930,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From 2002 to 2005, he was a Research and Teaching Assistant with the Department of Electrical and Computer Engineering, UNB. He joined the Power Electronics Group, McGill University, as a Postdoctoral Fellow. He joined Technology R&D, Wind Power Plant Group, Vestas Wind Systems, Arhus, Denmark. He was with the TRANSCO, UAE, as a Senior Study and Planning Engineer. He is currently a Professor with the Electrical and Computer Engineering Department, Khalifa University of Science and Technology—Masdar Campus and seconded to a Professor Position with the Faculty of Engineering, Mansoura University, Mansoura, Egypt, and currently on leave. He was a Visiting Professor with the Massachusetts Institute of Technology, Cambridge, MA, USA. His research interests include power system, power electronics, FACTS technologies, VSC-","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,835,930,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HVdc systems, microgrid operation and control, and renewable energy systems (wind and PV) integration and interconnections. He is currently an Editor of the IEEE TRANSACTIONS ON POWER DELIVERY and IEEE TRANSACTIONS ON POWER SYSTEMS, an Associate Editor for the IEEE TRANSACTIONS ON POWER ELECTRONICS, IEEE TRANSACTIONS ON SMART GRID, and IET Power Electronics Journals, the Guest Editor of the IEEE TRANSACTIONS ON ENERGY CONVERSION, the Guest Editor-in-Chief for special section between the IEEE TRANSACTIONS ON POWER DELIVERY and IEEE TRANSACTIONS ON POWER SYSTEMS, an Editor of IEEE POWER ENGINEERING LETTERS, the Regional Editor for IET Renewable Power Generation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,37,466,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IEEE TRANSACTIONS ON POWER SYSTEMS, VOL. 36, NO. 1, JANUARY 2021 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[907,39,930,50]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"565 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[117,73,872,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Guest Editorial: IEEE Transactions on Power Delivery IEEE Transactions on Power Systems Joint Special Section on Hybrid AC/DC Transmission Grids \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,253,486,537]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HVDC technology has brought many advantages to power transmission. Examples are increased flexibility in operation, expanded power transfer capability and easier interconnection of energy sources. However, HVDC links need to be built along existing AC transmission grids. It has become increasingly evident that the future power transmission systems will become interwoven networks of AC and DC subsystems, i.e., hybrid AC/DC transmission grids. The AC and DC grids have their own characteristics. An AC grid tends to have a large inertia and well-understood responses to disturbances. A DC grid generally has a low tolerance to fault and can respond very fast. When the two grids are interconnected, substantially more complex dynamic and transient interactions can occur. A single AC system fault, for example, may lead to simultaneous commutation failures in multiple converter stations. New phenomena, such as super-synchronous resonance, can also emerge whose mechanisms have not been fully understood. All these characteristics present new challenges to the planning, design and operation of future power transmission systems. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,540,486,674]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In view of this major trend in the evolution of power transmission systems, the IEEE Transactions on Power Delivery and IEEE Transactions on Power Systems have decided to publish this joint special section on the subject, with the objective to promote research, innovation and exchange in the broad field of hybrid AC/DC transmission grids. In this special section, we invited submission of original research and/or review works from both power delivery and power system perspectives. Topics of interest include the following: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[74,675,484,840]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- Methodologies for Planning and Operating Hybrid AC/DC Grids; \\\",\\\"- Modelling and Analysis of Electromechanical Dynamics in Hybrid AC/DC Grids; \\\",\\\"- Techniques for Monitoring and Control of Dynamic and Transient Stability of Hybrid Grids; \\\",\\\"Modelling and Analysis of Electromagnetic Interactions in Hybrid AC/DC Grids; \\\",\\\"- Techniques for Detection and Mitigation of (Subsynchronous, Supersynchronous, Harmonic and High Frequency) Resonance and Inter-Converter Oscillations; \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[516,253,929,523]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- Innovations on the Protection of Hybrid Grids Including AC and DC Fault Ride-Through Techniques; \\\",\\\"- High Power Converter Topologies, Design, Protection and Control as Well as HIL Evaluations and Grid Level Integration of Different Converter Technologies; \\\",\\\"- Advances in Power Apparatuses Enabling AC/DC Grids (e.g., HVDC circuit breakers); \\\",\\\"- Advanced Synchronization Schemes for Enhancing Dynamics Response and Stability; \\\",\\\"- Techniques and Apparatus to Enhance Inertia Response of Hybrid AC/DC Grids (such as virtual inertia support and augmentation of different types of energy storage systems); \\\",\\\"- Blackout Restoration for Hybrid AC/DC Grids; \\\",\\\"- Dynamic Interactions of a Hybrid Grid with Various Energy Sources; \\\",\\\"- Cyber-Security for Hybrid AC/DC Grids (e.g., identifying new security threats at converter and system levels, attacks and mitigation techniques). \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[500,525,929,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This Special Section, therefore, welcomed submission of original works from both power delivery and power system perspectives. After receiving the extended abstracts, the guest EIC and editorial board determined which Transaction is a better fit for the work. Authors then submitted full papers to the designated transaction. This Special Section attracted 229 extended abstracts and the review process concluded with inviting 86 and 81 extended abstracts to submit full papers to TPWRS and TPWRD, respectively. Finally, we received 120 papers with a total of 47 valuable papers accepted for publication in the TPWRD and TPWRS. The acceptance rate is $39\\\\%$ of the submitted full papers and $20\\\\%$ of the submitted extended abstracts. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[500,720,929,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I would like to express my sincere thanks to the Editor-in-Chief of the IEEE Transactions on Power Delivery, Prof. Wilsun Xu from the University of Alberta, and the Editor-in-Chief of the IEEE Transactions on Power Systems, Prof. Nikolaos Hatziargyriou from National Technical University of Athens for appointing me as Guest Editor in Chief of this Special Section and their great efforts and advice throughout the review process. I would also like to express my sincere gratitude and thanks to the team of Guest Editors for their great efforts and time devoted to this special section. Their valuable expertise and dedication have made it a reality. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,37,466,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IEEE TRANSACTIONS ON POWER SYSTEMS, VOL. 36, NO. 1, JANUARY 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[907,39,930,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"563 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[72,882,382,895]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Digital Object Identifier 10.1109/TPWRS.2020.3041890 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[193,914,792,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"0885-8950 © 2021 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission. See https://www.ieee.org/publications/rights/index.html for more information. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,79,329,94]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Guest advisors for special section: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,95,493,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Prof. Frede Blabjerg, Villum Investigator, Aalborg University, Denmark. \\\",\\\"Prof. Vijay Vittal, Ira A. Fulton Chair Professor, Arizona State University. \\\"]\",\n \"page_idx\": \"1\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[82,156,188,167]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Guest editors: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,170,493,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Prof. Nilanjan Ray Chaudhuri, Penn State College of Engineering, USA. \\\",\\\"Prof. Xinzhou Dong, Professor, Tsinghua University, China \\\",\\\"- Dr. Sébastien Dennetiere, Senior Researcher, RTE Centre National d'Expertise Réseaux, France. \\\",\\\"Prof. Johan Enslin, Executive Director, ZGEC at Clemson, Charleston, South Carolina Area, USA. \\\",\\\"Prof. Tim Green, Professor, Imperial College London, UK.\\\",\\\"Prof. Oriol Gomis-Bellmunt, Professor, Universitat Politècnica de Catalunya, Barcelona, Spain. \\\",\\\"Prof. Lennart Harnefors, Senior Principal Scientist ABB & Adjunct Professor of KTH, Sweden. \\\",\\\"Prof. Brian K. Johnson, Professor, University of Idaho, Moscow, ID, USA. \\\",\\\"Prof. Dragan Jovcic, Chair in Engineering, University of Aberdeen, Aberdeen, UK. \\\",\\\"Prof. Federico Milano, Professor, University College Dublin, Dublin, Ireland. \\\",\\\"- Dr. Lisa Qi, Senior Principal Scientist, ABB Corporate Research Center, USA. \\\",\\\"Prof. Luis Rouco, Professor, Universidad Pontificia Comillas, Madrid, Spain. \\\",\\\"- Dr. Ali Mehrizi-Sani, Associate Professor, Washington State University, Pullman, WA, USA. \\\",\\\"Prof. Xiongfei Wang, Professor and Research Program Leader, Aalborg University, Denmark. \\\",\\\"Prof. Zheng Xu, Professor, Zhejiang University, China. \\\",\\\"Prof. Lie Xu, Professor, University of Strathclyde, UK.\\\"]\",\n \"page_idx\": \"1\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[63,608,493,743]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On behalf, of the Guest editorial board, I am deeply thankful and appreciative to the large number of reviewers who have devoted long time and efforts in providing high quality reviews and constructive comments that resulted in a number of high quality publications for this special section. Last, but not least, this special section would not happen without the intellectual contributions and the impressive amount of work of the authors devoted for preparing the work and revising the papers for successful publication. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,744,493,864]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This special section shared between TPWRD and TPWRS includes valuable papers that will benefit the PES community for improving the planning, operational control, system stability, power electronics and protection schemes for Hybrid AC/DC Transmission Grids. Looking into the future, attention is given to the unique feature of hybrid AC/DC grid that emphasizes the strong coupling between apparatus level behaviors with system wide responses. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,864,493,893]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted papers in the Special Section: Hybrid AC/DC Transmission Grids \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,895,481,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IEEE Transactions on Power Delivery (Accepted Papers) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[92,910,493,938]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1) Integrated Multiport DC Power Flow Controller with DC Circuit Breaker \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[528,80,936,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"2) Experimental Investigation of Electrical Stresses on the Main Components of HVDC Circuit Breakers \\\",\\\"3) Incorporating DC Grid Protection, Frequency Stability and Reliability Into Offshore DC Grid Planning \\\",\\\"4) Static and dynamic evaluation of different architectures for an actual HVDC link project \\\",\\\"5) Instantaneous Active Power Integral Differential Protection for Hybrid AC/DC Transmission Systems Based on Fault Variation Component \\\",\\\"6) A DC Line Protection Scheme for MMC-Based DC Grids Based on AC/DC Transient Information \\\",\\\"7) A Hybrid-Arm Modular Multilevel Converters Topology with DC low voltage operation Capability for Unidirectional HVDC Bulk Power Transmission \\\",\\\"8) Transient Voltage and Current Stresses Estimation of MMC-MTDC System via Discrete-time Analysis \\\",\\\"9) A Novel DC Fault Ride-Through Method for Wind Farms Connected to the Grid Through Bipolar MMC-HVDC Transmission \\\",\\\"10) Analysis and Prevention of Subsequent Commutation Failures Caused by Improper Inverter Control Interactions in HVDC Systems \\\",\\\"11) Real-Time Hierarchical Neural Network Based Fault Detection and Isolation for High-Speed Railway System Under Hybrid AC/DC Grid \\\",\\\"12) Study on the Parameter Requirements for Resistive - Type Superconducting Fault Current Limiters Combined with Mechanical DC Circuit Breakers in Hybrid AC/DC Transmission Grids \\\",\\\"13) A Fault Tolerant Scheme for Integration of Remote Renewable Energy Sources with HVDC System \\\",\\\"14) A Novel DC Transmission System Fault Location Technique for Offshore Renewable Energy Harvesting \\\",\\\"15) Protection Coordination of AC/DC Intersystem Faults in Hybrid Transmission Grids \\\",\\\"16) Augmented Design of DC/DC Modular Multilevel Converter Improving Efficiency and Reducing Number of SMs \\\",\\\"17) Equivalent Multiple dq Frame Model of the MMC using Dynamic Phasor Theory in the $\\\\\\\\alpha \\\\\\\\beta z$ -Frame \\\",\\\"18) Preventive and Curative Actions by Meshed Bipolar HVDC-Overlay-Systems \\\",\\\"19) A Novel DC Fault Ride Through Control Methodology for Hybrid Modular Multilevel Converters in HVDC Systems \\\",\\\"20) Detailed Equivalent and Average Value Models of Hybrid Cascaded Multilevel Converters for Efficient and Accurate EMT-Type Simulation \\\",\\\"21) Frequency-Coupling Impedance Model based Analysis of a High Frequency Resonance Incident in an Actual MMC-HVDC System \\\",\\\"22) Response Mechanism of DFIG to Transient Voltage Disturbance under Commutation Failure of LCC-HVDC System \\\"]\",\n \"page_idx\": \"1\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[67,40,89,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"564 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[528,39,936,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IEEE TRANSACTIONS ON POWER SYSTEMS, VOL. 36, NO. 1, JANUARY 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[75,79,486,155]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"23) A Novel Traveling Wave Protection Method for DC Transmission Lines Using Current Fitting \\\",\\\"24) The Last Circuit Breakers Identification in Hybrid AC/DC Power Grids Based on Improved Tarjan Algorithm \\\"]\",\n \"page_idx\": \"2\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[75,156,471,170]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IEEE Transactions on Power Systems (Accepted Papers) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,171,486,608]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1) Adaptive Droop Control of Multi-Terminal HVDC Network for Frequency Regulation and Power Sharing \\\",\\\"2) Hybrid AC/DC Transmission Expansion Planning Considering HVAC to HVDC Conversion Under Renewable Penetration \\\",\\\"3) Cybersecurity of Wide Area Monitoring, Protection and Control Systems for HVDC Applications \\\",\\\"4) Renewable Integration in Hybrid ac-dc Systems Using Multi-Port Autonomous Reconfigurable Solar Power Plant (MARS) \\\",\\\"5) Frequency Response Impact of Integration of HVDC Into a Low Inertia AC Power Grid \\\",\\\"6) A Novel Distributed Supplementary Control of Multi-Terminal VSC-HVDC Grids for Rotor Angle Stability Enhancement of AC/DC Systems \\\",\\\"7) Coordinated Voltage and Frequency Control in Hybrid AC/MT-HVDC Power Grids for Stability Improvement \\\",\\\"8) Coordinated Wide Area Control of Multiple Controllers in a Power System Embedded With HVDC Lines \\\",\\\"9) Cost-Based Adaptive Droop Control Strategy for VSCMTDC System \\\",\\\"10) Mitigation of Subsynchronous Interaction in Hybrid AC/DC Grid With Renewable Energy Using Faster-Than Real-Time Dynamic Simulation \\\",\\\"11) Synchronized Phasor Measurement Unit Based Central Controller for Normal and Contingent Operation of a High Capacity HVDC Macrogrid for the Continental US \\\",\\\"12) Optimal Planning and Operation of Multi Frequency HVAC Transmission Systems \\\"]\",\n \"page_idx\": \"2\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[518,79,930,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"13) Model Order Reduction of Multi-Terminal Direct-Current Grid Systems \\\",\\\"14) Coordinated Design of Supplementary Controllers in VSCHVDC Multi-Terminal Systems to Damp Electromechanical Oscillations \\\",\\\"15) Hybrid AC/DC Network With Parallel LCC-VSC Interlinking Converters \\\",\\\"16) Three-Port Small Signal Admittance Based Model of VSCs for Studies of Multiterminal HVDC Hybrid AC/DC Transmission Grids \\\",\\\"17) Minimization of ACDC Grid Transmission Loss and DC Voltage Deviation Using Adaptive Droop Control and Improved AC-DC Power Flow Algorithm \\\",\\\"18) Switching System's MLE Based Transient Stability Assessment of AC/DC Hybrid System Considering Continuous Commutation Failure \\\",\\\"19) Control of Interlinking Converters in Hybrid AC/DC Grids: Network Stability and Scalability \\\",\\\"20) Two-Level Combined Control Scheme of VSC-MTDC Integrated Offshore Wind Farms for Onshore System Frequency Support \\\",\\\"21) Hierarchical and Robust Scheduling Approach for VSCMTDC Meshed AC/DC Grid With High Share of Wind Power \\\",\\\"22) Primary Frequency Support through North American Continental HVDC Interconnections With VSC-MTDC Systems \\\",\\\"23) Exploiting the Operational Flexibility of Wind Integrated Hybrid AC/DC Power Systems \\\"]\",\n \"page_idx\": \"2\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[500,532,927,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PROF. MOHAMED SHAWKY EL MOURSI, Guest Editor-in-Chief Electrical Engineering and Computer Science Department Khalifa University of Science and Technology Abu Dhabi, UAE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[501,593,760,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E-mail: mohamed.elmoursi@ku.ac.ae\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,642,255,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0284/f28f77e8aa87ca7be03d78fdb6a8ec0066c443040443ccc5468ca463b9a2a7a2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[277,638,929,698]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Mohamed Shawky El Moursi (Senior Member, IEEE) received the B.Sc. and M.Sc. degrees from Mansoura University, Mansoura, Egypt, in 1997 and 2002, respectively, and the Ph.D. degree from the University of New Brunswick (UNB), Fredericton, NB, Canada, in 2005, all in electrical engineering. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,699,930,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From 2002 to 2005, he was a Research and Teaching Assistant with the Department of Electrical and Computer Engineering, UNB. He joined the Power Electronics Group, McGill University, as a Postdoctoral Fellow. He joined Technology R&D, Wind Power Plant Group, Vestas Wind Systems, Arhus, Denmark. He was with the TRANSCO, UAE, as a Senior Study and Planning Engineer. He is currently a Professor with the Electrical and Computer Engineering Department, Khalifa University of Science and Technology—Masdar Campus and seconded to a Professor Position with the Faculty of Engineering, Mansoura University, Mansoura, Egypt, and currently on leave. He was a Visiting Professor with the Massachusetts Institute of Technology, Cambridge, MA, USA. His research interests include power system, power electronics, FACTS technologies, VSC-\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,835,930,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HVdc systems, microgrid operation and control, and renewable energy systems (wind and PV) integration and interconnections. He is currently an Editor of the IEEE TRANSACTIONS ON POWER DELIVERY and IEEE TRANSACTIONS ON POWER SYSTEMS, an Associate Editor for the IEEE TRANSACTIONS ON POWER ELECTRONICS, IEEE TRANSACTIONS ON SMART GRID, and IET Power Electronics Journals, the Guest Editor of the IEEE TRANSACTIONS ON ENERGY CONVERSION, the Guest Editor-in-Chief for special section between the IEEE TRANSACTIONS ON POWER DELIVERY and IEEE TRANSACTIONS ON POWER SYSTEMS, an Editor of IEEE POWER ENGINEERING LETTERS, the Regional Editor for IET Renewable Power Generation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,37,466,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IEEE TRANSACTIONS ON POWER SYSTEMS, VOL. 36, NO. 1, JANUARY 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[907,39,930,50]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"565 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1109/tpwrs.2020.3041890"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"4e04fd5ad20ea078d0e3fd42cb812b08a8d4891441a985d24d5d7a29e941f268"},"title":{"kind":"string","value":"Guest Editorial: IEEE Transactions on Power Delivery IEEE Transactions on Power Systems Joint Special Section on Hybrid AC/DC Transmission Grids"}}},{"rowIdx":161,"cells":{"abstract":{"kind":"string","value":"Potato is the third most important staple food crop. To address challenges associated with global food security, a hybrid potato breeding system, aimed at converting potato from a tuber-propagated tetraploid crop into a seed-propagated diploid crop through crossing inbred lines, is under development. However, given that most diploid potatoes are self-incompatible, this represents a major obstacle which needs to be addressed in order to develop inbred lines. Here, we report on a self-compatible diploid potato, RH89-039-16 (RH), which can efficiently induce a mating transition from self-incompatibility to self-compatibility, when crossed to self-incompatible lines. We identify the S-locusinhibitor (Sli) gene in RH, capable of interacting with multiple allelic variants of the pistil-specific S-ribonucleases (S-RNases). Further, Sli gene functions like a general S-RNase inhibitor, to impart SC to RH and other self-incompatible potatoes. Discovery of Sli now offers a path forward for the diploid hybrid breeding program."},"author":{"kind":"string","value":"Chunzhi Zhang|Futing Li|Han Guo|Bo Zhang|Fei Tang|Qinggang Liao|Sanwen Huang|Yi Shang|Canhui Li|Die Tang|Huiqin Yang|Jinzhe Zhang|Ling Ma|William J Lucas|Zhen Peng|Yuxin Jia|Dongli Gao|Xuming Luo|Meng Gao"},"content_list":{"kind":"list like","value":[{"bbox":"[68,161,161,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[806,159,828,175]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0134/c6cf4b6a3880d9ed1a2c8a4ac45790012ce86b1443b0b348f109c9c8989bd1c9.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[831,162,922,173]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,189,349,203]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41467-021-24266-7 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[391,187,443,202]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,212,927,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A nonS-locus F-box gene breaks self-incompatibility in diploid potatoes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,290,927,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ling Ma $^{1,7}$ , Chunzhi Zhang $^{2,7}$ , Bo Zhang $^{1,7}$ , Fei Tang $^{1}$ , Futing Li $^{1}$ , Qinggang Liao $^{2}$ , Die Tang $^{2}$ , Zhen Peng $^{3}$ , Yuxin Jia $^{2}$ , Meng Gao $^{1}$ , Han Guo $^{4}$ , Jinzhe Zhang $^{5}$ , Xuming Luo $^{2}$ , Huiqin Yang $^{1}$ , Dongli Gao $^{1}$ , William J. Lucas $^{2,6}$ , Canhui Li $^{1\\boxtimes}$ , Sanwen Huang $^{2\\boxtimes}$ & Yi Shang $^{1\\boxtimes}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,401,690,612]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Potato is the third most important staple food crop. To address challenges associated with global food security, a hybrid potato breeding system, aimed at converting potato from a tuber-propagated tetraploid crop into a seed-propagated diploid crop through crossing inbred lines, is under development. However, given that most diploid potatoes are self-incompatible, this represents a major obstacle which needs to be addressed in order to develop inbred lines. Here, we report on a self-compatible diploid potato, RH89-039-16 (RH), which can efficiently induce a mating transition from self-incompatibility to self-compatibility, when crossed to self-incompatible lines. We identify the S-locusinhibitor (Sli) gene in RH, capable of interacting with multiple allelic variants of the pistil-specific S-ribonucleases (S-RNases). Further, Sli gene functions like a general S-RNase inhibitor, to impart SC to RH and other self-incompatible potatoes. Discovery of Sli now offers a path forward for the diploid hybrid breeding program. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[53,21,539,94]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"nature COMMUNICATIONS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,841,929,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"<sup>1</sup>Key Laboratory for Potato Biology of Yunnan Province, The CAAS-YNNU-YINMORE Joint Academy of Potato Science, Yunnan Normal University, Kunming, China. <sup>2</sup>Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. <sup>3</sup>College of Plant Science and Technology, Beijing University of Agriculture, Beijing, China. <sup>4</sup>Department of Economic Plants and Biotechnology, Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. <sup>5</sup>Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of Ministry of Agriculture, Sino-Dutch Joint Lab of Horticultural Genomics, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China. <sup>6</sup>Department of Plant Biology, College of Biological Sciences, University of California, Davis, CA, USA. <sup>7</sup>These authors contributed equally: Ling Ma, Chunzhi Zhang, Bo Zhang. <sup>8</sup>email: ch2010201@163.com; huangsanwen@caas.cn; shangyi@ynnu.edu.cn ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[68,957,724,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[917,957,927,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[67,61,490,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Potato is consumed as a staple food by approximately 1.3 billion people<sup>1</sup>. Currently, most potato cultivars are tetraploids, carrying four copies of chromosome sets, thereby complicating breeding efforts to introduce new traits. This constitutes a major challenge in terms of expanding potato's contribution to feeding the fast-growing global population, especially under the threat of climate change<sup>2</sup>. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,154,490,329]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A potential pathway to circumvent this impediment of potato breeding is the development of a hybrid potato breeding system $^{3,4}$ , which would convert potato into a diploid seed crop by crossing elite inbred lines. In diploid potato, beneficial alleles can be efficiently introgressed into these inbred lines, thereby shortening the breeding period $^{3,5}$ . Moreover, the hybrid offspring, propagated via true seeds rather than tubers, would facilitate both botanical seed storage and delivery, along with eliminating the risks presently associated with tuber-borne pathogens $^{6}$ . However, given that a majority of diploid potatoes are self-incompatible, this obligate outcrossing mating system poses a major obstacle (another big hurdle is inbreeding depression, including poor vigor and low fertility in potato) to develop diploid inbred lines $^{7-10}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,329,489,583]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Solanaceae, the self-incompatibility (SI) system is gametophytic and controlled by a single polymorphic locus, called S-locus $^{11}$ . This locus encodes two types of determinants: female/pistil S-determinant (a cytotoxic S-ribonuclease, S-RNase) $^{12}$ and male/pollen S-determinant (a set of pollen-specific S-locus F-box proteins, SLFs) $^{13}$ . The S-RNase inhibits the growth of self-pollen tubes by either degrading ribosomal RNA (rRNA) $^{14}$ or disrupting the dynamic equilibrium of the cytoskeleton $^{15}$ . Based on the collaborative non-self recognition system, the S-RNase could be polyubiquitinated and degraded by the interactions with the collective action of 16-20 nonself SLFs that induce compatibility $^{16,17}$ . Otherwise, the S-RNase would not be degraded, as it is not recognized by the self SLFs $^{18}$ . Thus, loss-of-function mutations of S-RNase $^{8,9}$ , and degradation of this protein by the introduction of nonself SLFs $^{19}$ , have been reported to confer self-compatibility (SC) in Solanaceae. However, as genetically modified crops are still widely prohibited and even the acceptance of genome-edited crop is under debate, alternative strategies for addressing SI in the development of diploid inbred lines are preferred. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,584,490,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Previous studies have shown that a dominant locus, S-locus inhibitor (Sli), from a wild diploid potato species, Solanum chacoense Bitt., is responsible for breaking down the stylar incompatible response[7,20-22]. Although Eggers et al. reported the identification of Sli from the wild species in the Solanaceae International Online Meeting[23], the molecular mechanism of Sli was not described. Furthermore, this wild accession produces long stolons and high levels of toxic steroidal glycoalkaloids in tubers[8,24,25], which also limits its breeding potential. Alternatively, RH89-039-16 (RH), a long-day adaptive line derived from S. tuberosum group Tuberosum, is another self-compatible diploid potato that produces tubers[26,27]. Clot et al. has shown that RH also harbors the Sli SC haplotype at the distal end of chromosome $12^{22}$ . However, the molecular basis underlying the SI to SC transition in RH remains unknown, and it is unknown whether RH can transmit heritable SC to self-incompatible diploid potatoes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,797,490,879]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this study, we identify a non-S-locus $F$ -box (NSF) gene in RH. This gene is identical to the Sli gene, and capable of interacting with multiple allelic variants of S-RNases, functioning like a general S-locus inhibitor to introduce SC to both RH and other self-incompatible lines. The discovery of Sli offers a new and effective path for the hybrid diploid potato breeding program. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,902,124,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,916,490,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SC gene colocalizes with a segregation distortion region. As shown in Fig. 1a, self-pollinated RH plants produced fruits, and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,61,927,287]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"their pollen tubes penetrated the style and reached the ovary. To explore the genetic basis underlying the SC phenotype of RH, $\\mathrm{F_1}$ hybrids (PI $225689\\times \\mathrm{RH}$ ) from RH crossed with PI 225689, a self-incompatible diploid line (a/a) from S. tuberosum group Phureja, were evaluated for self-compatibility (Fig. 1a and Supplementary Fig. 1a). Genetic analysis of $\\mathrm{F_1}$ progeny established a $\\sim 1:1$ segregation ratio of SC to SI (131 self-compatible plants versus 107 self-incompatible plants; $\\chi^2 = 2.42 < \\chi^{2}_{0.05} = 3.84$ ), indicating that SC in RH is caused by a single dominant heterozygous gene (A/a) or gametophytic factor. Next, 40 self-compatible and 40 self-incompatible $\\mathrm{F_1}$ individuals were carefully selected for a bulked segregant analysis (BSA), which exhibited a peak associated with SC/SI located at the end of chromosome 12 (58~61 Mb, Fig. 1b). InDel markers were then developed, and a total of 238 self-compatible and self-incompatible $\\mathrm{F_1}$ individuals were used to pinpoint the location of the candidate to an interval between the marker M-1 and M-2 (2.24 Mb, Fig. 1c). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,289,927,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accurate evaluation of self-compatible/incompatible individuals from mapping populations is essential for the fine mapping of the SC gene. Unfortunately, this phenotyping process is labor-intensive and time-consuming, which may explain why the most established SC gene Sli has not been cloned since it was first reported in $1998^{20,21}$ . Interestingly, we observed an extreme segregation distortion (SD), in that only homozygous haplotype A/A or heterozygote A/a, but no homozygous haplotype a/a, was identified in the $\\mathrm{F}_2$ progeny from crossing PI 225689 and RH (A/A:A/a = 3030:2954 ≈ 1:1, $\\chi^2 = 0.97 < \\chi_{0.05}^2 = 3.84$ ). Furthermore, the same SD region was also observed in the $\\mathrm{S}_1$ population of $\\mathrm{RH}^{27,28}$ . Based on these observations, we hypothesized that selfing of heterozygote self-compatible plants (A/a) would result in SD of the progeny, and the absence of homozygous haplotype a/a in the offspring is linked either to lethal genes or to failed double fertilization resulting from the gametophytic SI in potato. Since RH may harbor SLFs that recognize the S-RNase harbored by PI 225689, individuals carrying the homozygous haplotype a/a were detected in the $\\mathrm{F}_1$ population (PI $225689 \\times \\mathrm{RH}$ ). This result suggests that the SD in the $\\mathrm{F}_2$ population and the $\\mathrm{S}_1$ population of RH are caused by the gametophytic SI. Thus, only the pollen harboring the SC gene could penetrate the self-style and fulfil the fertilization to produce progeny, and all the $\\mathrm{F}_2$ progeny would carry the SC gene and exhibit self-compatible phenotype (Fig. 1d). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,649,927,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SC in RH is controlled by a non-S-locus $F$ -box gene. The discovery of the SD in the $\\mathrm{F}_2$ population greatly accelerated the mapping of the SC gene in RH, by removing the laborious phenotyping requirement. In total, $6624\\mathrm{F}_2$ individuals produced from the 131 selfed $\\mathrm{F}_1$ plants were used to narrow down the SC gene to a $64.61\\mathrm{kb}$ interval (Fig. 1c). There were five annotated genes in this region (Fig. 1c), and two of them were expressed in pollen (Supplementary Fig. 1b). Interestingly, sequence variations including a $536\\mathrm{bp}$ insertion at $100\\mathrm{bp}$ upstream of the start codon of PGSC0003DMG400016861, encoding an $F$ -box gene, were observed between RH and PI 225689 (Fig. 1e). In addition, quantitative real-time RT-PCR (qRT-PCR) revealed that this gene was highly expressed in RH pollen, but not in the pollen of PI 225689 (Fig. 1f). Based on these findings, PGSC0003DMG400016861 was considered to be the target gene and was named, hereafter, non-S-locus $F$ -box (NSF) gene. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,863,927,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To confirm the in vivo role of $NSF$ , a 3839 bp DNA sequence, including a 2,100 bp promoter region (Fig. 1g), was cloned from RH and transformed into a self-incompatible diploid potato clone from S. phureja S15-65. A population of 3750 explants was screened, from which 26 transgenic positive lines were selected for further study. Flow cytometry assays revealed that only two of the 26 lines ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[477,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 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The bar is $1\\\\mathrm{cm}$ on the four left images and $500\\\\mu \\\\mathrm{m}$ on the six right images. The arrested pollen tube is identified with the red arrow. The experiments were repeated five times with similar results. b BSA-Seq analysis of the $\\\\mathsf{F}_1$ hybrid population (PI $225689\\\\times \\\\mathsf{RH}$ ). The SNP index $(\\\\Delta)$ of SC and SI pools, prepared from the $\\\\mathsf{F}_1$ progeny, as mapped along the RH genome. The red arrow indicates a peak above the threshold value. c Fine mapping of NSF using $238~\\\\mathsf{F}_1$ and $6,624~\\\\mathsf{F}_2$ individuals. The number in the bracket indicates the number of recombinants with the same genotype. The NSF location is indicated in red. d The pollen elongation cease model is proposed to explain the distorted segregation of the $\\\\mathsf{F}_2$ population. Pollen with 'a' genotype is short of SC gene. Cease of pollen tube elongation resulted in unsuccessful fertilization. Thus, the individuals with 'aa' genotype (indicated in pale grey) cannot be identified in the $\\\\mathsf{F}_2$ population. e Allelic variation of the candidate gene, PGSC0003DMG400016861, between RH (SC) and PI 225689 (SI). The major difference between the two alleles was a 536 bp deletion within the promoter region of the candidate gene. f Expression level of the candidate gene, in the pollen of RH and PI 225689, normalized against an endogenous reference gene ( $StEF1-\\\\alpha$ , elongation factor $1\\\\alpha$ ). Data are presented as means $\\\\pm$ s.d. ( $n = 3$ biological replicates). g Phenotype transition, from SI to SC, after transformation of the candidate gene into a self-incompatible line S15-65. Plants transformed with an empty vector served as a negative control. Note the presence of fruit in L1 and L2 and absence in the vector control. L1/2, two NSF transgenic lines. The bar is $1\\\\mathrm{cm}$ . h Expression level of the candidate gene in the pollen of negative control and two transgenic lines, normalized against $StEF1-\\\\alpha$ . Data are presented as means $\\\\pm$ s.d. ( $n = 3$ biological replicates). \"]","image_footnote":"[]","img_path":"images/0629/14f89e2659cf652ab8663445e74b2eab2cdd24f00c7edabcc4ef55080e6bb7f9.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[67,843,490,938]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"were diploid plants; the others were tetraploid (Supplementary Fig. 2). Consistent with our hypothesis, a phenotype change from SI to SC (Fig. 1g), and high NSF expression in pollen was observed in these two transgenic lines (Fig. 1h). In contrast, the SI phenotype of the plant transformed with an empty vector was not changed (Fig. 1g), suggesting that high expression of NSF in the pollen tissue is required to render SC to RH. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,843,929,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NSF/Sli is efficient in rendering SC to self-incompatible diploid potatoes. The most established method of conferring SC is with the dominant Sli gene $^{22}$ , identified in chc 525-3, a self-compatible clone of the self-incompatible species S. chacoense $^{20}$ . As the Sli gene was also mapped at the distal end of chromosome 12 in S. chacoense $^{21,22}$ , NSF in RH could be identical to the Sli gene in S. chacoense. This possibility was tested by analyzing the collinear ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,23,519,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[830,17,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE 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2 Characteristics of NSF/Sli in rendering SC to self-incompatible diploid potatoes. a Collinearity analysis of the distal ends of chromosome 12 between RH and M6. Orthologous relations between the different syntenic loci are depicted by gray. The NSF gene is identified with the red arrow. b The number of self-compatible diploid potatoes induced by NSF/Sli. Six groups (S. stenotomum, S. gonocalyx, S. tuberosom, S. phureja, S. ajanhui, and S. curtilobum) and two subgroups (tuberosum and andigena) are indicated with different colors. The number represents the accessions that transfer from SI to SC after crossing with RH or E172. c Expression patterns of Sli in different developmental stages of RH flowers. Development of the RH flower was divided into five stages, including four developing stages according to bud size (status of each stage was shown as illustration) and one mature stage. Expression level was normalized to the expression in stage 1. StEF1- $\\\\alpha$ was set as an endogenous reference gene. Data are presented as means $\\\\pm$ s.d. $(n = 3$ biological replicates). d In situ mRNA hybridization of Sli in the stage 4 flower bud and mature stamen. d1 and d4, the stage 4 flower bud (d1) and mature pollen (d4) used in the in situ hybridization assay. d2 and d5, the transverse sections of the stage 4 flower bud (d2) and mature stamen (d5). Bar $200\\\\mu m$ Magnification of the red square in d2 and d5 are presented in d3 and d6, respectively (bar is $20~{\\\\mu\\\\mathrm{m}}$ ). The experiments were repeated three times with similar results. \"]","image_footnote":"[]","img_path":"images/0342/f01d08ccf36eec42d7fcd3a330b4b3d093bf4276bdea674dd43da4827d41fd23.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[704,259,719,267]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"d3 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[704,268,801,332]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[704,333,719,343]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"d6 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[704,343,801,407]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,579,490,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"region at the distal end of chromosome 12 between RH and M6, a self-compatible inbred clone created by seven generations of self-pollination of S. chacoense $^{24,25}$ . A total of 12 collinear genes, including $NSF/Sli$ , and a $120\\mathrm{kb}$ synteny region were identified (Fig. 2a). We further amplified the collinear region, including the 2100 bp promoter and the 1810 bp gene coding sequence, where $NSF/Sli$ is located in $\\mathrm{E}172^{29}$ (a self-compatible $\\mathrm{F}_1$ individual generated by crossing a self-incompatible diploid line E and chc 525-3). The promoter sequences in E172 and M6 are identical to that of RH, but there are five DNA base differences within the $NSF/Sli$ coding region, resulting in two amino acid changes (C214R and Q249R) in M6 (Supplementary Fig. 3). Based on this result, we speculated that $NSF$ is the $Sli$ gene and confers the SC in M6 and E172. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,765,490,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To test whether the Sli gene is an efficient pollen SI-breaker, RH and E172 were used as the Sli gene donor to pollinate 125 self-incompatible diploid lines that belong to six groups (50 S. stenotomum, 37 S. goniocalyx, 25 S. phureja11 S. tuberosom, 1 S. ajanhuiiri, and 1 S. curtilobum lines, Fig. 2b and Supplementary Table 1). After pollination, $110\\mathrm{F}_1$ populations of the 125 crossings exhibited SC, including 43 S. stenotomum, 34 S. goniocalyx, 20 S. phureja, 11 S. tuberosum (7 tuberosum and 4 andigena), 1 S. ajanhuiiri, and 1 S. curtilobum lines (Fig. 2b, Supplementary Table 1). The remaining 15 diploid lines failed to cross with RH or E172 because of different flowering times when compared to that of RH or E172, resulting in unsuccessful pollination. In conclusion, the Sli gene in RH ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,579,927,608]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"can serve as an efficient SI-breaker to produce self-compatible diploid potatoes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,622,927,837]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sli is capable of interacting with a diverse set of S-RNases. Since Sli is specifically expressed in floral organs, and its transcript gradually increases with the development of pollen, reaching its maximum expression in the mature pollens' wall (Fig. 2c, d), Sli may play an essential role in mediating the interactions between pollen and stigma, and function like SLFs to interact with and detoxify the S-RNases during pollen tube elongation, to confer SC to self-incompatible lines. To test this hypothesis, firstly, 14 full-length variants of S-RNases (StS-RNase1-14), sharing an amino acid identity ranging from $39.62\\%$ to $87.38\\%$ , were cloned from diploid potatoes using the method described in Ye et al. (Supplementary Table 2). The phylogenetic analysis determined that StS-RNase1-14 and 35 potato S-RNase alleles obtained from Genebank belong to the class III type RNase (Fig. 3a and Supplementary Table 3). Thus, StS-RNase1-14 were considered as the potential female S-determinants, and used in the following assays. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,837,927,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The motifs located downstream of the F-box domain can confer substrate specificity for ubiquitination $^{30}$ . Phylogenetic analysis of Sli revealed a Phloem Protein 2 (PP2) domain with $\\sim 160$ amino acid residues at its C-terminus (Supplementary Fig. 4). Thus, the C-terminus containing the PP2 domain or the full length of Sli was used in yeast two-hybrid (Y2H) assay to assess the interactions between Sli and the S-RNase variants. As revealed by Y2H, the C-terminal region of Sli interacted with the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[477,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,957,80,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[176,957,831,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[90,61,910,502]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0554/f2d2838e42a556f60730b267d6dd48d8511f549e3e95318b576c1427258ccd8c.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,525,838,709]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3 Wide interactions between Sli and 14 types of potential StS-RNases. a A phylogenetic tree analysis of the potatoes S-RNases. StS-RNase1-14 are 14 types of S-RNases reported in this study (indicated in red), while the other 35 S-RNases were obtained from GenBank. b Yeast two-hybrid (Y2H) analysis of the interactions between 14 potential S-RNases and the PP2 domain of Sli (BD-PP2). The conserved domains of Sli are indicated by rectangles. The interactions between potential S-RNases and the full length of Sli are shown in Supplementary Fig. 6. The F-box protein interaction domain of a SLF gene (RHC01H2G1617) was used as a negative control [BD-StSLF(t)]. WLHA, synthetic dropout media lacking tryptophan, leucine, histidine, and adenine. BD binding domain, AD activation domain. c The firefly luciferase (LUC) complementation imaging assays of the interactions between the S-RNases and the PP2 domain of Sli. LUC signal was captured in the leaf area co-expressing the PP2 domain of Sli and each of the S-RNases (indicated in red), except for S3, S9, S10, and S13. Sn denote each type of the StS-RNase1-14, nLUC the N terminal of LUC protein, cLUC the C terminal of LUC protein. The experiments were repeated three times with similar results. \"]","image_footnote":"[]","img_path":"images/0680/c450ff3a7f65c151ec4e751812c893fe624a52ea24b29d1ba279313fe5faaef9.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[67,850,492,947]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"majority of the StS-RNases, with the exception of StS-RNase3, 9, 10, and 13 (Fig. 3b), while full-length Sli failed to interact with StS-RNase3, 9, 11, 13, and 14 (Supplementary Fig. 5). The in vivo interactions between Sli and the StS-RNase1-14 were further tested using a firefly luciferase (LUC) complementation assay. Here, a fluorescent signal was detected in tobacco leaves coexpressing the N-terminal half of Luc (nLUC) plus the PP2 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,850,929,947]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"domain of Sli fusion protein, together with the C-terminal half of Luc (cLUC) plus each of the StS-RNase1, 2, 4-8, 11, 12, and 14 fusion protein (Fig. 3c). In contrast, the C-terminal region of a male SLF gene, RHC01H2G1617, selected from the 32 pollen-specific $F$ -box genes in chromosome 1 (Supplementary Fig. 6), could only interact with StS-RNase9 (Fig. 3b). This is consistent with the collaborative nonself-recognition model that one SLF ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,23,519,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[830,17,927,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,957,724,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[915,957,927,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[67,61,490,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"generally interacts with limited types of nonself S-RNases, and thus plants need to carry multiple types of SLFs in one S-haplotype to ensure the detoxification of nonself S-RNases, as well as out-crossing in Solanaceae $^{16}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,141,147,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,154,492,439]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The extensive interactions between various StS-RNases and Sli provide insight into the molecular basis of the phenotype transition from SI to SC in diploid potatoes. Support for such a model is presented by the facts that both Sli and SLFs belong to the F-box family of proteins, and that the collaborative nonself recognition model is conserved in Solanaceae[1]. It is very interesting to note that, in RH and M6, the SC arose from the evolution of a non-S-locus F box protein, not the novel SLFs as suggested in the two-step model[1],[3]. Since Sli interacts not only with the self S-RNase in RH, but also with multiple types of the S-RNases to promote out-crossing with other diploids, the appearance of Sli may represent an efficient route to introduce a fixed SC phenotype to S-RNase-based self-incompatible plants (Fig. 4). It is also interesting to note that all the three self-compatible lines (RH, M6, and E172) harbor a 536 bp insertion at the promoter of Sli (Fig. 1e, f). Although several SNP mutations were also identified within this region in self-compatible and self-incompatible lines, the 536 bp fragment is most likely to be involved in activating the expression of Sli in the pollen of self-compatible lines. Testing of this hypothesis would provide insights into the regulatory mechanism, as well as the evolutionary trajectory of the Sli gene. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,61,927,260]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although the Sli gene has been widely used in conferring SC, the fact that Sli cannot interact with all types of S-RNases indicates that the Sli gene cannot be used to confer SC to all the self-incompatible lines. On the other hand, loss-of-function mutations of the S-RNase have been shown to produce a stable SC phenotype in S. pennellii, S. habrochaites, and S. arcanum[18]. These non-GMO inactivating mutations thus provide another efficient method to break the SI of diploids. In our breeding program, we observed a semi-self-compatible diploid, PG6359, due to the low expression of $\\mathrm{S}_{\\mathrm{s}11}$ -RNase in this line[28]. Since Sli is located on Ch12 and S-RNase is on Ch01, usage of SC genes from different sources in breeding can effectively avoid the genetic bottlenecks caused by the deleterious mutations linked to these loci, considering that S-RNase is near the centromere while Sli is near the telomere. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,260,927,329]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In summary, the identification of RH as an efficient SC inducer, the general S-locus inhibitor Sli, as well as the markers associated with the SC/SI phenotype would pave the way for developing the inbred lines and accelerate the hybrid diploid potato breeding. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,347,571,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,359,927,438]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Plant materials. The self-compatible material chc525-3 (Solanum chacoense Bitt.) was kindly provided by Prof. K. Hosaka (Obihiro University of Agriculture and Veterinary Medicine) and we selected E172 from a vigorous self-compatible clone in the selfed progeny of chc525-3 to cross with $\\mathrm{E}^{32}$ . The RH was kindly provided by the Department of Plant Breeding at Wageningen University. The 115 self-incompatible lines and S15-65 were kindly provided by the International Potato Center (CIP). The self-compatible line M6 was kindly provided by the U. S. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[191,461,808,856]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4 A model depicting the evolution of Sli in diploid potatoes. In Solanaceae, a two-step model was proposed to explain the evolution of new SLFs to confer SC to self-incompatible plants, by first interacting with the self S-RNase. Then, the reverse from SC to SI is induced by the loss of ability for these new SLFs to interact with the self S-RNase. The appearance of Sli at the non-S-locus region represents a new strategy, in addition to the loss-of-function (LOF) mutations of S-RNases, to confer SC to self-incompatible lines. The S-haplotypes in RH are StS-RNases2 and 3. Negative regulations of the multiple StS-RNases by the nonself SLFs or Sli are indicated by the barred lines, which constitute the molecular basis to impart SC to RH and other self-incompatible potatoes. SI self-incompatibility, SC self-compatibility, S1-S14 14 types of S-RNases identified from self-incompatible diploid potatoes, Ch chromosome. \"]","image_footnote":"[]","img_path":"images/0741/1792ae6d99d1dacffc516cdf27dca72ab066fd58a101a27e43aebbd44dd1d248.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[70,17,166,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[477,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,957,80,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[176,957,831,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[67,62,490,118]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Department of Agriculture (USDA). All of the diploid lines were grown normally in a controlled glasshouse with a $16\\mathrm{h}$ photoperiod and $25^{\\circ}\\mathrm{C}$ day/18°C night temperatures. Self-incompatible PI 225689 was crossed with RH to produce the self-compatible $\\mathbf{F}_1$ individuals that were later selfed to obtain the $6624~\\mathrm{F}_2$ population for the map-based cloning of Sli. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,135,490,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SC/SI phenotyping. Mature pollen of the $\\mathrm{F_1}$ hybrids from RH crossed with PI 225689 (PI $225689\\times \\mathrm{RH}$ ) or RH/E172 crossed with the 125 self-incompatible lines was freshly collected and used to pollinate stigmas of the same plant at the blooming stage. Three clones were used to test the SC/SI phenotype for each genotype. This pollination process was repeated at least 30 times for each clone. If all the three clones failed to set berries, this genotype was termed as SI type, while if all the three clones had more than two berries, they were regarded as SC type. Whenever one of the three clones had only one berry, the genotype was regarded as U (uncertain) type. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,251,490,373]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bulked segregant analysis sequencing (BSA-Seq). PI 225689 was crossed with RH to produce the $\\mathrm{F_1}$ individuals that exhibited a 1:1 segregation ratio of SC to SI types. Four DNA pools were prepared using the female parent (PI 225689), the male parent (RH), 40 self-incompatible $\\mathrm{F_1}$ individuals, and 40 self-compatible $\\mathrm{F_1}$ plants. The sequencing of four libraries was performed using NovaSeq 6000 platform (Anoroad Gene Technology, Beijing, China). Raw reads were supplied by Anoroad, and clean reads were obtained by quality evolution. Then, the filtered short reads were aligned against the potato reference DM genome (V4.03), the variant calling of SNPs, and small Indels were excavated by Platypus (V0.7.4) software. The heterozygous and inconsistent SNPs, and small indels between the two $\\mathrm{F_1}$ pools were selected for calculating the $\\Delta$ (SNP-index) values. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,390,490,533]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fine mapping of Sli. To fine map the Sli locus, recombinants for the Indel marker M-1 and M-2 were screened using 238 plants of $\\mathrm{F_1}$ population (created by a cross between PI 225689 and RH). Considering the SC/SI type of the recombinants of $\\mathrm{F_1}$ plants, the Sli locus was further mapped to the interval between F1-4 and F3-4 with a physical interval of $941\\mathrm{Kb}$ . Genotyping of $1800\\mathrm{F}_2$ progenies from 23 selfed $\\mathrm{F_1}$ plants revealed an extreme segregation distortion (no a/a haplotype). Thus, 6624 $\\mathrm{F}_2$ individuals from 131 selfed $\\mathrm{F_1}$ plants were screened for the recombinants, and the Sli locus was mapped to the interval between C7-1 and D5-2 with a physical interval of $64.61\\mathrm{kb}$ . The genomic DNA fragments of the interval in RH and PI 225689 were sequenced and aligned. The polymorphic markers were developed based on the re-sequencing data of RH and PI 225689 according to the method described by Zhang et al.[28]. The markers and primers used in this analysis are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,549,490,671]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gene transformation of S15-65. For functional identification of the Sli gene, DNA fragments containing the native promoter and genomic sequence of Sli were amplified from RH, and then inserted into BamH I and Hind III sites of the binary vector pCAMBIA1301. This construct was transformed into the Agrobacterium tumefaciens strain GV3101. The S15-65, a diploid self-incompatible line from S. tuberosum group Phureja, was kindly provided by CIP and used in the Agrobacterium-mediated transformation of potato internodes as previously described[8]. The ploidy of transgenic lines was analyzed by a flow cytometry assay, and the expression level of Sli in the diploid transgenic lines was verified by qRT-PCR. SC/ SI phenotypes of the diploid transgenic lines were recorded. The primers used in this analysis are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,687,487,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aniline blue fluorochrome staining of pollen tubes. Five pistils were collected $72\\mathrm{h}$ post pollination and immediately treated with 3:1 $95\\%$ ethanol:glacial acetic acid. After rinsing twice with double-distilled water, the pistils were incubated in $0.005\\mathrm{mg / mL}$ aniline blue fluorochrome in $0.1\\mathrm{M}$ $\\mathrm{K}_2\\mathrm{HPO}_4$ buffer for $24\\mathrm{h}$ . The colored pistil was placed on a glass slide and viewed under a fluorescence microscope. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,772,490,872]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Quantitative RT-PCR analysis. Total RNA was isolated using a RNAprep Pure plant Kit (Tiangen) according to the manufacturer's protocols. First-strand cDNA was synthesized from $1\\mu \\mathrm{g}$ total RNA using the PrimeScript $1^{\\mathrm{st}}$ strand cDNA Synthesis Kit (Takara). PCRs were performed using SYBR Premix (Takara) on a 7500 Fast Real-Time PCR system (Applied Biosystems) according to the manufacturer's instructions. Three independent biological experiments were performed in all cases. StEF1- $\\alpha$ was used as an internal control gene for normalization. The relative gene expression was calculated using $2^{-\\Delta \\Delta \\mathrm{Ct}}$ . The primers used in this analysis are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,888,490,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In situ hybridization. The 256-bp Sli-specific probe was amplified and labeled using the DIG RNA Labeling Kit according to the manufacturer's recommendation (SP6/T7, Roche). Pretreatment of tissue sections, hybridization, and immunological detection were performed in accordance with the previously described methods<sup>33</sup>. The primer pairs used are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,62,926,195]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Phylogenetic analysis of Sli. The protein sequence of Sli was queried against Phytozome v13 (https://phytozome next.jgi.doe.gov/) to retrieve its orthologs or homologs from other dicot and monocot species. Protein sequences showing a similarity of $40\\%$ or above and evaluet lower than 1e-10 blastp to the query sequence were retrieved and multiple aligned using Mafft (https://mafft.cbrc.jp/alignment/software/). Only the two most similar sequences were retained in each species. For SLFs, the F-box protein located within the S-locus region of RH was considered as the potential SLF (http://solanaceae.plantbiology.msu.edu/ rh_potato_download.shtml). A maximum likelihood (ML) phylogenetic tree was constructed using the ML based on the Poisson correction model. The bootstrap consensus tree inferred from 1000 replicates was taken to represent the evolutionary history of Sli. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,208,927,286]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Identification of S-RNases from diploid lines. Specific primers were designed according to the de novo assembly of RNA-sequencing data from the mature styles of the 125 diploid lines using the method described by Ye et al. The cDNA sample prepared from the styles of each diploid line was used to clone the pistil-specific S-RNase. The positive PCR products were then sequenced and considered as the multiple allelic variants of S-RNases. The primers used in this analysis are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,299,927,464]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Yeast two-hybrid assay. The codon region of each S-RNase (S1-S14) except for its signal peptide was cloned into the pGADT7 vector (AD-S-RNase). The C-terminal region harboring the PP2 domain (84 to 266 amino acid), and full length of Sli, in addition to the C-terminal region harboring the F-box protein interaction domain (114 to 393 amino acid) of the negative control gene (RHC01H2G1617) were constructed into the pGBKT7 vector [BD-PP2, BD-Sli, and BD-StSLF(t)]. Each type of AD-S-RNase was co-transformed with BD-PP2, BD-Sli, or BD-StSLF(t), respectively, into the Y2H Gold Yeast Strain according to the manufacturer's instruction (Clontech). The yeast cell harboring pGADT7-T and pGBKT7-53 was used as a positive control, and the cell harboring pGADT7-T and pGBKT7-Lam was used as a negative control. The plate was then incubated for 4 days at $30^{\\circ}\\mathrm{C}$ , and the yeast was grown on the synthetically defined medium (SD/-Trp/-Leu/-His/-Ade) as recorded. The experiments were repeated, independently, at least three times with similar results. The primers used in this analysis are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,476,927,673]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Luciferase complementation assay in N. benthamiana leaves. The C-terminal region harboring the PP2 domain (85 to 266 amino acid) of Sli was cloned into pCAMBIA1301-cLUC (cLUC-PP2). The codon region of each S-RNase (S1-S14) except for its signal peptide was cloned into pCAMBIA1301-nLUC (nLUC-S-RNase). Each construct was next transformed into Agrobacterium tumefaciens strain GV3101. Each strain was grown at $28^{\\circ}\\mathrm{C}$ in LB media with kanamycin $(50\\mathrm{mg / L})$ and rifampicillin $(50\\mathrm{mg / L})$ to an $\\mathrm{OD}_{600}$ of 0.8. Cells were then harvested by centrifugation at $3000\\times \\mathrm{g}$ for $5\\mathrm{min}$ and resuspended in $500\\mathrm{mM}$ MES buffer containing $1\\mathrm{M}$ $\\mathrm{MgCl}_2$ and $100\\mathrm{mM}$ acetosyringone (Sigma), to a final $\\mathrm{OD}_{600}$ of 0.6. For co-infiltration, equal volumes of the strain harboring cLUC-PP2 and the strain harboring nLUC-S-RNase were mixed and infiltrated into fully expanded leaves of 4-week-old tobacco using a needleless syringe. After the infiltration, plants were grown under dark for $8\\mathrm{h}$ and then grown under $16\\mathrm{h}$ light/8 h dark for $48\\mathrm{h}$ . Then the substrate D-luciferin (Sigma) was sprayed onto the infiltrated tobacco leaf. After $5\\mathrm{min}$ of incubation in dark, a chemiluminescence signal was observed and captured using NightSHADE LB 985 (Berthold, Germany). The experiments were repeated, independently, at least three times with similar results. The primers used in this analysis are listed in Supplementary Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,687,927,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,726,621,739]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,739,927,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The BSA-Seq data (SRR14637423 and SRR14637422) has been deposited in NCBI under project number PRJNA732509. All other data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,800,813,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 8 January 2021; Accepted: 8 June 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,814,687,827]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published online: 06 July 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,870,586,882]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,883,917,939]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. 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Shimizu, K. K. & Tsuchimatsu, T. Evolution of selfing: recurrent patterns in molecular adaptation. Annu. Rev. Ecol. Evol. Syst. 46, 593-622 (2015). \",\"32. Jacobs, J. M. E. et al. A genetic map of potato (Solanum tuberosum) integrating molecular markers, including transposons, and classical markers. Theor. Appl. Genet. 91, 289-300 (1995). \",\"33. Ma, L. et al. ABNORMAL VASCULAR BUNDLES regulates cell proliferation and procambium cell establishment during aerial organ development in rice. New Phytol. 213, 275-286 (2017). \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[505,171,643,184]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,184,927,297]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We thank Prof. K. Hosaka (Obihiro University of Agriculture and Veterinary Medicine), Prof. Jianjian Qi (Inner Mongolia University), Prof. Xueyong Yang (Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences), and Prof. Guangtao Zhu (Yunnan Normal University) for experimental and bioinformatics support. This work was supported by the National Natural Science Foundation of China (32002032 and 31972433), Yunnan Science Fund (202005AE160015 and 2019FJ004 to Y.S.), Shenzhen Science and Technology Program (KQTD2016113010482651 to S.H.), and special funds for Science Technology Innovation and Industrial Development of Shenzhen Dapeng New District (RC201901-05 to S.H.). This work was also supported by Yunnan Provincial and Shenzhen Municipal Governments. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,310,653,323]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author contributions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,324,927,392]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Y.S., S.H., L.M., C.L., and C.Z. conceived and organized the research. Q.L., D.T., and Y.J. performed the bioinformatics analyses. B.Z., F.T., F.L., and H.Y. carried out the phenotyping assay. B.Z., F.T., F.L., M.G., and J.Z. performed the cloning and functional analysis of Sli. C.Z. and D.G. tested the efficiency of Sli in SI-breaking. C.Z., B.Z., F.T., X.L., and F.L. identified the alleles of S-RNases from diploid potatoes. Y.S., L.M., and S.H. wrote the manuscript. L.W. and H.G. revised the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,407,648,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Competing interests ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,420,719,432]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare no competing interests. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,446,665,457]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Additional information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,460,900,483]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-24266-7. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,493,915,503]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Correspondence and requests for materials should be addressed to C.L., S.H. or Y.S. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,512,927,546]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Peer review information Nature Communications thanks Roger Chetelat, David Douches, and the other, anonymous reviewer(s) for their contribution to the peer review of this work. Peer review reports are available. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,558,919,570]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reprints and permission information is available at http://www.nature.com/reprints ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,581,927,604]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,629,579,648]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0299/462abcbf8d9e422e8561b19a34e8f0bdf4c9592f5a64974155b9c24a988d399c.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[583,630,927,652]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,653,927,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,774,616,786]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© The Author(s) 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,17,166,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[477,23,927,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[70,957,78,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[176,957,831,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[68,161,161,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[806,159,828,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0134/c6cf4b6a3880d9ed1a2c8a4ac45790012ce86b1443b0b348f109c9c8989bd1c9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[831,162,922,173]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,189,349,203]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[391,187,443,202]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,212,927,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A nonS-locus F-box gene breaks self-incompatibility in diploid potatoes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,290,927,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ling Ma $^{1,7}$ , Chunzhi Zhang $^{2,7}$ , Bo Zhang $^{1,7}$ , Fei Tang $^{1}$ , Futing Li $^{1}$ , Qinggang Liao $^{2}$ , Die Tang $^{2}$ , Zhen Peng $^{3}$ , Yuxin Jia $^{2}$ , Meng Gao $^{1}$ , Han Guo $^{4}$ , Jinzhe Zhang $^{5}$ , Xuming Luo $^{2}$ , Huiqin Yang $^{1}$ , Dongli Gao $^{1}$ , William J. Lucas $^{2,6}$ , Canhui Li $^{1\\\\boxtimes}$ , Sanwen Huang $^{2\\\\boxtimes}$ & Yi Shang $^{1\\\\boxtimes}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,401,690,612]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Potato is the third most important staple food crop. To address challenges associated with global food security, a hybrid potato breeding system, aimed at converting potato from a tuber-propagated tetraploid crop into a seed-propagated diploid crop through crossing inbred lines, is under development. However, given that most diploid potatoes are self-incompatible, this represents a major obstacle which needs to be addressed in order to develop inbred lines. Here, we report on a self-compatible diploid potato, RH89-039-16 (RH), which can efficiently induce a mating transition from self-incompatibility to self-compatibility, when crossed to self-incompatible lines. We identify the S-locusinhibitor (Sli) gene in RH, capable of interacting with multiple allelic variants of the pistil-specific S-ribonucleases (S-RNases). Further, Sli gene functions like a general S-RNase inhibitor, to impart SC to RH and other self-incompatible potatoes. Discovery of Sli now offers a path forward for the diploid hybrid breeding program. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[53,21,539,94]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"nature COMMUNICATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,841,929,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"<sup>1</sup>Key Laboratory for Potato Biology of Yunnan Province, The CAAS-YNNU-YINMORE Joint Academy of Potato Science, Yunnan Normal University, Kunming, China. <sup>2</sup>Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. <sup>3</sup>College of Plant Science and Technology, Beijing University of Agriculture, Beijing, China. <sup>4</sup>Department of Economic Plants and Biotechnology, Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. <sup>5</sup>Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of Ministry of Agriculture, Sino-Dutch Joint Lab of Horticultural Genomics, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China. <sup>6</sup>Department of Plant Biology, College of Biological Sciences, University of California, Davis, CA, USA. <sup>7</sup>These authors contributed equally: Ling Ma, Chunzhi Zhang, Bo Zhang. <sup>8</sup>email: ch2010201@163.com; huangsanwen@caas.cn; shangyi@ynnu.edu.cn \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[68,957,724,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[917,957,927,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[67,61,490,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Potato is consumed as a staple food by approximately 1.3 billion people<sup>1</sup>. Currently, most potato cultivars are tetraploids, carrying four copies of chromosome sets, thereby complicating breeding efforts to introduce new traits. This constitutes a major challenge in terms of expanding potato's contribution to feeding the fast-growing global population, especially under the threat of climate change<sup>2</sup>. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,154,490,329]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A potential pathway to circumvent this impediment of potato breeding is the development of a hybrid potato breeding system $^{3,4}$ , which would convert potato into a diploid seed crop by crossing elite inbred lines. In diploid potato, beneficial alleles can be efficiently introgressed into these inbred lines, thereby shortening the breeding period $^{3,5}$ . Moreover, the hybrid offspring, propagated via true seeds rather than tubers, would facilitate both botanical seed storage and delivery, along with eliminating the risks presently associated with tuber-borne pathogens $^{6}$ . However, given that a majority of diploid potatoes are self-incompatible, this obligate outcrossing mating system poses a major obstacle (another big hurdle is inbreeding depression, including poor vigor and low fertility in potato) to develop diploid inbred lines $^{7-10}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,329,489,583]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Solanaceae, the self-incompatibility (SI) system is gametophytic and controlled by a single polymorphic locus, called S-locus $^{11}$ . This locus encodes two types of determinants: female/pistil S-determinant (a cytotoxic S-ribonuclease, S-RNase) $^{12}$ and male/pollen S-determinant (a set of pollen-specific S-locus F-box proteins, SLFs) $^{13}$ . The S-RNase inhibits the growth of self-pollen tubes by either degrading ribosomal RNA (rRNA) $^{14}$ or disrupting the dynamic equilibrium of the cytoskeleton $^{15}$ . Based on the collaborative non-self recognition system, the S-RNase could be polyubiquitinated and degraded by the interactions with the collective action of 16-20 nonself SLFs that induce compatibility $^{16,17}$ . Otherwise, the S-RNase would not be degraded, as it is not recognized by the self SLFs $^{18}$ . Thus, loss-of-function mutations of S-RNase $^{8,9}$ , and degradation of this protein by the introduction of nonself SLFs $^{19}$ , have been reported to confer self-compatibility (SC) in Solanaceae. However, as genetically modified crops are still widely prohibited and even the acceptance of genome-edited crop is under debate, alternative strategies for addressing SI in the development of diploid inbred lines are preferred. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,584,490,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Previous studies have shown that a dominant locus, S-locus inhibitor (Sli), from a wild diploid potato species, Solanum chacoense Bitt., is responsible for breaking down the stylar incompatible response[7,20-22]. Although Eggers et al. reported the identification of Sli from the wild species in the Solanaceae International Online Meeting[23], the molecular mechanism of Sli was not described. Furthermore, this wild accession produces long stolons and high levels of toxic steroidal glycoalkaloids in tubers[8,24,25], which also limits its breeding potential. Alternatively, RH89-039-16 (RH), a long-day adaptive line derived from S. tuberosum group Tuberosum, is another self-compatible diploid potato that produces tubers[26,27]. Clot et al. has shown that RH also harbors the Sli SC haplotype at the distal end of chromosome $12^{22}$ . However, the molecular basis underlying the SI to SC transition in RH remains unknown, and it is unknown whether RH can transmit heritable SC to self-incompatible diploid potatoes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,797,490,879]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this study, we identify a non-S-locus $F$ -box (NSF) gene in RH. This gene is identical to the Sli gene, and capable of interacting with multiple allelic variants of S-RNases, functioning like a general S-locus inhibitor to introduce SC to both RH and other self-incompatible lines. The discovery of Sli offers a new and effective path for the hybrid diploid potato breeding program. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,902,124,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,916,490,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SC gene colocalizes with a segregation distortion region. As shown in Fig. 1a, self-pollinated RH plants produced fruits, and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,61,927,287]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"their pollen tubes penetrated the style and reached the ovary. To explore the genetic basis underlying the SC phenotype of RH, $\\\\mathrm{F_1}$ hybrids (PI $225689\\\\times \\\\mathrm{RH}$ ) from RH crossed with PI 225689, a self-incompatible diploid line (a/a) from S. tuberosum group Phureja, were evaluated for self-compatibility (Fig. 1a and Supplementary Fig. 1a). Genetic analysis of $\\\\mathrm{F_1}$ progeny established a $\\\\sim 1:1$ segregation ratio of SC to SI (131 self-compatible plants versus 107 self-incompatible plants; $\\\\chi^2 = 2.42 < \\\\chi^{2}_{0.05} = 3.84$ ), indicating that SC in RH is caused by a single dominant heterozygous gene (A/a) or gametophytic factor. Next, 40 self-compatible and 40 self-incompatible $\\\\mathrm{F_1}$ individuals were carefully selected for a bulked segregant analysis (BSA), which exhibited a peak associated with SC/SI located at the end of chromosome 12 (58~61 Mb, Fig. 1b). InDel markers were then developed, and a total of 238 self-compatible and self-incompatible $\\\\mathrm{F_1}$ individuals were used to pinpoint the location of the candidate to an interval between the marker M-1 and M-2 (2.24 Mb, Fig. 1c). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,289,927,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accurate evaluation of self-compatible/incompatible individuals from mapping populations is essential for the fine mapping of the SC gene. Unfortunately, this phenotyping process is labor-intensive and time-consuming, which may explain why the most established SC gene Sli has not been cloned since it was first reported in $1998^{20,21}$ . Interestingly, we observed an extreme segregation distortion (SD), in that only homozygous haplotype A/A or heterozygote A/a, but no homozygous haplotype a/a, was identified in the $\\\\mathrm{F}_2$ progeny from crossing PI 225689 and RH (A/A:A/a = 3030:2954 ≈ 1:1, $\\\\chi^2 = 0.97 < \\\\chi_{0.05}^2 = 3.84$ ). Furthermore, the same SD region was also observed in the $\\\\mathrm{S}_1$ population of $\\\\mathrm{RH}^{27,28}$ . Based on these observations, we hypothesized that selfing of heterozygote self-compatible plants (A/a) would result in SD of the progeny, and the absence of homozygous haplotype a/a in the offspring is linked either to lethal genes or to failed double fertilization resulting from the gametophytic SI in potato. Since RH may harbor SLFs that recognize the S-RNase harbored by PI 225689, individuals carrying the homozygous haplotype a/a were detected in the $\\\\mathrm{F}_1$ population (PI $225689 \\\\times \\\\mathrm{RH}$ ). This result suggests that the SD in the $\\\\mathrm{F}_2$ population and the $\\\\mathrm{S}_1$ population of RH are caused by the gametophytic SI. Thus, only the pollen harboring the SC gene could penetrate the self-style and fulfil the fertilization to produce progeny, and all the $\\\\mathrm{F}_2$ progeny would carry the SC gene and exhibit self-compatible phenotype (Fig. 1d). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,649,927,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SC in RH is controlled by a non-S-locus $F$ -box gene. The discovery of the SD in the $\\\\mathrm{F}_2$ population greatly accelerated the mapping of the SC gene in RH, by removing the laborious phenotyping requirement. In total, $6624\\\\mathrm{F}_2$ individuals produced from the 131 selfed $\\\\mathrm{F}_1$ plants were used to narrow down the SC gene to a $64.61\\\\mathrm{kb}$ interval (Fig. 1c). There were five annotated genes in this region (Fig. 1c), and two of them were expressed in pollen (Supplementary Fig. 1b). Interestingly, sequence variations including a $536\\\\mathrm{bp}$ insertion at $100\\\\mathrm{bp}$ upstream of the start codon of PGSC0003DMG400016861, encoding an $F$ -box gene, were observed between RH and PI 225689 (Fig. 1e). In addition, quantitative real-time RT-PCR (qRT-PCR) revealed that this gene was highly expressed in RH pollen, but not in the pollen of PI 225689 (Fig. 1f). Based on these findings, PGSC0003DMG400016861 was considered to be the target gene and was named, hereafter, non-S-locus $F$ -box (NSF) gene. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,863,927,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To confirm the in vivo role of $NSF$ , a 3839 bp DNA sequence, including a 2,100 bp promoter region (Fig. 1g), was cloned from RH and transformed into a self-incompatible diploid potato clone from S. phureja S15-65. A population of 3750 explants was screened, from which 26 transgenic positive lines were selected for further study. Flow cytometry assays revealed that only two of the 26 lines \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[477,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n 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The bar is $1\\\\\\\\mathrm{cm}$ on the four left images and $500\\\\\\\\mu \\\\\\\\mathrm{m}$ on the six right images. The arrested pollen tube is identified with the red arrow. The experiments were repeated five times with similar results. b BSA-Seq analysis of the $\\\\\\\\mathsf{F}_1$ hybrid population (PI $225689\\\\\\\\times \\\\\\\\mathsf{RH}$ ). The SNP index $(\\\\\\\\Delta)$ of SC and SI pools, prepared from the $\\\\\\\\mathsf{F}_1$ progeny, as mapped along the RH genome. The red arrow indicates a peak above the threshold value. c Fine mapping of NSF using $238~\\\\\\\\mathsf{F}_1$ and $6,624~\\\\\\\\mathsf{F}_2$ individuals. The number in the bracket indicates the number of recombinants with the same genotype. The NSF location is indicated in red. d The pollen elongation cease model is proposed to explain the distorted segregation of the $\\\\\\\\mathsf{F}_2$ population. Pollen with 'a' genotype is short of SC gene. Cease of pollen tube elongation resulted in unsuccessful fertilization. Thus, the individuals with 'aa' genotype (indicated in pale grey) cannot be identified in the $\\\\\\\\mathsf{F}_2$ population. e Allelic variation of the candidate gene, PGSC0003DMG400016861, between RH (SC) and PI 225689 (SI). The major difference between the two alleles was a 536 bp deletion within the promoter region of the candidate gene. f Expression level of the candidate gene, in the pollen of RH and PI 225689, normalized against an endogenous reference gene ( $StEF1-\\\\\\\\alpha$ , elongation factor $1\\\\\\\\alpha$ ). Data are presented as means $\\\\\\\\pm$ s.d. ( $n = 3$ biological replicates). g Phenotype transition, from SI to SC, after transformation of the candidate gene into a self-incompatible line S15-65. Plants transformed with an empty vector served as a negative control. Note the presence of fruit in L1 and L2 and absence in the vector control. L1/2, two NSF transgenic lines. The bar is $1\\\\\\\\mathrm{cm}$ . h Expression level of the candidate gene in the pollen of negative control and two transgenic lines, normalized against $StEF1-\\\\\\\\alpha$ . Data are presented as means $\\\\\\\\pm$ s.d. ( $n = 3$ biological replicates). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0629/14f89e2659cf652ab8663445e74b2eab2cdd24f00c7edabcc4ef55080e6bb7f9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[67,843,490,938]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"were diploid plants; the others were tetraploid (Supplementary Fig. 2). Consistent with our hypothesis, a phenotype change from SI to SC (Fig. 1g), and high NSF expression in pollen was observed in these two transgenic lines (Fig. 1h). In contrast, the SI phenotype of the plant transformed with an empty vector was not changed (Fig. 1g), suggesting that high expression of NSF in the pollen tissue is required to render SC to RH. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,843,929,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NSF/Sli is efficient in rendering SC to self-incompatible diploid potatoes. The most established method of conferring SC is with the dominant Sli gene $^{22}$ , identified in chc 525-3, a self-compatible clone of the self-incompatible species S. chacoense $^{20}$ . As the Sli gene was also mapped at the distal end of chromosome 12 in S. chacoense $^{21,22}$ , NSF in RH could be identical to the Sli gene in S. chacoense. This possibility was tested by analyzing the collinear \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,519,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[830,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n 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null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[547,333,700,407]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2 Characteristics of NSF/Sli in rendering SC to self-incompatible diploid potatoes. a Collinearity analysis of the distal ends of chromosome 12 between RH and M6. Orthologous relations between the different syntenic loci are depicted by gray. The NSF gene is identified with the red arrow. b The number of self-compatible diploid potatoes induced by NSF/Sli. Six groups (S. stenotomum, S. gonocalyx, S. tuberosom, S. phureja, S. ajanhui, and S. curtilobum) and two subgroups (tuberosum and andigena) are indicated with different colors. The number represents the accessions that transfer from SI to SC after crossing with RH or E172. c Expression patterns of Sli in different developmental stages of RH flowers. Development of the RH flower was divided into five stages, including four developing stages according to bud size (status of each stage was shown as illustration) and one mature stage. Expression level was normalized to the expression in stage 1. StEF1- $\\\\\\\\alpha$ was set as an endogenous reference gene. Data are presented as means $\\\\\\\\pm$ s.d. $(n = 3$ biological replicates). d In situ mRNA hybridization of Sli in the stage 4 flower bud and mature stamen. d1 and d4, the stage 4 flower bud (d1) and mature pollen (d4) used in the in situ hybridization assay. d2 and d5, the transverse sections of the stage 4 flower bud (d2) and mature stamen (d5). Bar $200\\\\\\\\mu m$ Magnification of the red square in d2 and d5 are presented in d3 and d6, respectively (bar is $20~{\\\\\\\\mu\\\\\\\\mathrm{m}}$ ). The experiments were repeated three times with similar results. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0342/f01d08ccf36eec42d7fcd3a330b4b3d093bf4276bdea674dd43da4827d41fd23.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[704,259,719,267]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"d3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[704,268,801,332]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[704,333,719,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"d6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[704,343,801,407]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,579,490,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"region at the distal end of chromosome 12 between RH and M6, a self-compatible inbred clone created by seven generations of self-pollination of S. chacoense $^{24,25}$ . A total of 12 collinear genes, including $NSF/Sli$ , and a $120\\\\mathrm{kb}$ synteny region were identified (Fig. 2a). We further amplified the collinear region, including the 2100 bp promoter and the 1810 bp gene coding sequence, where $NSF/Sli$ is located in $\\\\mathrm{E}172^{29}$ (a self-compatible $\\\\mathrm{F}_1$ individual generated by crossing a self-incompatible diploid line E and chc 525-3). The promoter sequences in E172 and M6 are identical to that of RH, but there are five DNA base differences within the $NSF/Sli$ coding region, resulting in two amino acid changes (C214R and Q249R) in M6 (Supplementary Fig. 3). Based on this result, we speculated that $NSF$ is the $Sli$ gene and confers the SC in M6 and E172. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,765,490,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To test whether the Sli gene is an efficient pollen SI-breaker, RH and E172 were used as the Sli gene donor to pollinate 125 self-incompatible diploid lines that belong to six groups (50 S. stenotomum, 37 S. goniocalyx, 25 S. phureja11 S. tuberosom, 1 S. ajanhuiiri, and 1 S. curtilobum lines, Fig. 2b and Supplementary Table 1). After pollination, $110\\\\mathrm{F}_1$ populations of the 125 crossings exhibited SC, including 43 S. stenotomum, 34 S. goniocalyx, 20 S. phureja, 11 S. tuberosum (7 tuberosum and 4 andigena), 1 S. ajanhuiiri, and 1 S. curtilobum lines (Fig. 2b, Supplementary Table 1). The remaining 15 diploid lines failed to cross with RH or E172 because of different flowering times when compared to that of RH or E172, resulting in unsuccessful pollination. In conclusion, the Sli gene in RH \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,579,927,608]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"can serve as an efficient SI-breaker to produce self-compatible diploid potatoes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,622,927,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sli is capable of interacting with a diverse set of S-RNases. Since Sli is specifically expressed in floral organs, and its transcript gradually increases with the development of pollen, reaching its maximum expression in the mature pollens' wall (Fig. 2c, d), Sli may play an essential role in mediating the interactions between pollen and stigma, and function like SLFs to interact with and detoxify the S-RNases during pollen tube elongation, to confer SC to self-incompatible lines. To test this hypothesis, firstly, 14 full-length variants of S-RNases (StS-RNase1-14), sharing an amino acid identity ranging from $39.62\\\\%$ to $87.38\\\\%$ , were cloned from diploid potatoes using the method described in Ye et al. (Supplementary Table 2). The phylogenetic analysis determined that StS-RNase1-14 and 35 potato S-RNase alleles obtained from Genebank belong to the class III type RNase (Fig. 3a and Supplementary Table 3). Thus, StS-RNase1-14 were considered as the potential female S-determinants, and used in the following assays. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,837,927,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The motifs located downstream of the F-box domain can confer substrate specificity for ubiquitination $^{30}$ . Phylogenetic analysis of Sli revealed a Phloem Protein 2 (PP2) domain with $\\\\sim 160$ amino acid residues at its C-terminus (Supplementary Fig. 4). Thus, the C-terminus containing the PP2 domain or the full length of Sli was used in yeast two-hybrid (Y2H) assay to assess the interactions between Sli and the S-RNase variants. As revealed by Y2H, the C-terminal region of Sli interacted with the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[477,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,957,80,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[176,957,831,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[90,61,910,502]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0554/f2d2838e42a556f60730b267d6dd48d8511f549e3e95318b576c1427258ccd8c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,525,838,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3 Wide interactions between Sli and 14 types of potential StS-RNases. a A phylogenetic tree analysis of the potatoes S-RNases. StS-RNase1-14 are 14 types of S-RNases reported in this study (indicated in red), while the other 35 S-RNases were obtained from GenBank. b Yeast two-hybrid (Y2H) analysis of the interactions between 14 potential S-RNases and the PP2 domain of Sli (BD-PP2). The conserved domains of Sli are indicated by rectangles. The interactions between potential S-RNases and the full length of Sli are shown in Supplementary Fig. 6. The F-box protein interaction domain of a SLF gene (RHC01H2G1617) was used as a negative control [BD-StSLF(t)]. WLHA, synthetic dropout media lacking tryptophan, leucine, histidine, and adenine. BD binding domain, AD activation domain. c The firefly luciferase (LUC) complementation imaging assays of the interactions between the S-RNases and the PP2 domain of Sli. LUC signal was captured in the leaf area co-expressing the PP2 domain of Sli and each of the S-RNases (indicated in red), except for S3, S9, S10, and S13. Sn denote each type of the StS-RNase1-14, nLUC the N terminal of LUC protein, cLUC the C terminal of LUC protein. The experiments were repeated three times with similar results. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0680/c450ff3a7f65c151ec4e751812c893fe624a52ea24b29d1ba279313fe5faaef9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[67,850,492,947]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"majority of the StS-RNases, with the exception of StS-RNase3, 9, 10, and 13 (Fig. 3b), while full-length Sli failed to interact with StS-RNase3, 9, 11, 13, and 14 (Supplementary Fig. 5). The in vivo interactions between Sli and the StS-RNase1-14 were further tested using a firefly luciferase (LUC) complementation assay. Here, a fluorescent signal was detected in tobacco leaves coexpressing the N-terminal half of Luc (nLUC) plus the PP2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,850,929,947]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"domain of Sli fusion protein, together with the C-terminal half of Luc (cLUC) plus each of the StS-RNase1, 2, 4-8, 11, 12, and 14 fusion protein (Fig. 3c). In contrast, the C-terminal region of a male SLF gene, RHC01H2G1617, selected from the 32 pollen-specific $F$ -box genes in chromosome 1 (Supplementary Fig. 6), could only interact with StS-RNase9 (Fig. 3b). This is consistent with the collaborative nonself-recognition model that one SLF \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,23,519,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[830,17,927,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,957,724,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[915,957,927,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[67,61,490,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"generally interacts with limited types of nonself S-RNases, and thus plants need to carry multiple types of SLFs in one S-haplotype to ensure the detoxification of nonself S-RNases, as well as out-crossing in Solanaceae $^{16}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,141,147,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,154,492,439]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The extensive interactions between various StS-RNases and Sli provide insight into the molecular basis of the phenotype transition from SI to SC in diploid potatoes. Support for such a model is presented by the facts that both Sli and SLFs belong to the F-box family of proteins, and that the collaborative nonself recognition model is conserved in Solanaceae[1]. It is very interesting to note that, in RH and M6, the SC arose from the evolution of a non-S-locus F box protein, not the novel SLFs as suggested in the two-step model[1],[3]. Since Sli interacts not only with the self S-RNase in RH, but also with multiple types of the S-RNases to promote out-crossing with other diploids, the appearance of Sli may represent an efficient route to introduce a fixed SC phenotype to S-RNase-based self-incompatible plants (Fig. 4). It is also interesting to note that all the three self-compatible lines (RH, M6, and E172) harbor a 536 bp insertion at the promoter of Sli (Fig. 1e, f). Although several SNP mutations were also identified within this region in self-compatible and self-incompatible lines, the 536 bp fragment is most likely to be involved in activating the expression of Sli in the pollen of self-compatible lines. Testing of this hypothesis would provide insights into the regulatory mechanism, as well as the evolutionary trajectory of the Sli gene. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,61,927,260]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although the Sli gene has been widely used in conferring SC, the fact that Sli cannot interact with all types of S-RNases indicates that the Sli gene cannot be used to confer SC to all the self-incompatible lines. On the other hand, loss-of-function mutations of the S-RNase have been shown to produce a stable SC phenotype in S. pennellii, S. habrochaites, and S. arcanum[18]. These non-GMO inactivating mutations thus provide another efficient method to break the SI of diploids. In our breeding program, we observed a semi-self-compatible diploid, PG6359, due to the low expression of $\\\\mathrm{S}_{\\\\mathrm{s}11}$ -RNase in this line[28]. Since Sli is located on Ch12 and S-RNase is on Ch01, usage of SC genes from different sources in breeding can effectively avoid the genetic bottlenecks caused by the deleterious mutations linked to these loci, considering that S-RNase is near the centromere while Sli is near the telomere. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,260,927,329]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In summary, the identification of RH as an efficient SC inducer, the general S-locus inhibitor Sli, as well as the markers associated with the SC/SI phenotype would pave the way for developing the inbred lines and accelerate the hybrid diploid potato breeding. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,347,571,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,359,927,438]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Plant materials. The self-compatible material chc525-3 (Solanum chacoense Bitt.) was kindly provided by Prof. K. Hosaka (Obihiro University of Agriculture and Veterinary Medicine) and we selected E172 from a vigorous self-compatible clone in the selfed progeny of chc525-3 to cross with $\\\\mathrm{E}^{32}$ . The RH was kindly provided by the Department of Plant Breeding at Wageningen University. The 115 self-incompatible lines and S15-65 were kindly provided by the International Potato Center (CIP). The self-compatible line M6 was kindly provided by the U. S. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,461,808,856]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4 A model depicting the evolution of Sli in diploid potatoes. In Solanaceae, a two-step model was proposed to explain the evolution of new SLFs to confer SC to self-incompatible plants, by first interacting with the self S-RNase. Then, the reverse from SC to SI is induced by the loss of ability for these new SLFs to interact with the self S-RNase. The appearance of Sli at the non-S-locus region represents a new strategy, in addition to the loss-of-function (LOF) mutations of S-RNases, to confer SC to self-incompatible lines. The S-haplotypes in RH are StS-RNases2 and 3. Negative regulations of the multiple StS-RNases by the nonself SLFs or Sli are indicated by the barred lines, which constitute the molecular basis to impart SC to RH and other self-incompatible potatoes. SI self-incompatibility, SC self-compatibility, S1-S14 14 types of S-RNases identified from self-incompatible diploid potatoes, Ch chromosome. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0741/1792ae6d99d1dacffc516cdf27dca72ab066fd58a101a27e43aebbd44dd1d248.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[70,17,166,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[477,23,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[70,957,80,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[176,957,831,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[67,62,490,118]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Department of Agriculture (USDA). All of the diploid lines were grown normally in a controlled glasshouse with a $16\\\\mathrm{h}$ photoperiod and $25^{\\\\circ}\\\\mathrm{C}$ day/18°C night temperatures. Self-incompatible PI 225689 was crossed with RH to produce the self-compatible $\\\\mathbf{F}_1$ individuals that were later selfed to obtain the $6624~\\\\mathrm{F}_2$ population for the map-based cloning of Sli. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,135,490,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SC/SI phenotyping. Mature pollen of the $\\\\mathrm{F_1}$ hybrids from RH crossed with PI 225689 (PI $225689\\\\times \\\\mathrm{RH}$ ) or RH/E172 crossed with the 125 self-incompatible lines was freshly collected and used to pollinate stigmas of the same plant at the blooming stage. Three clones were used to test the SC/SI phenotype for each genotype. This pollination process was repeated at least 30 times for each clone. If all the three clones failed to set berries, this genotype was termed as SI type, while if all the three clones had more than two berries, they were regarded as SC type. Whenever one of the three clones had only one berry, the genotype was regarded as U (uncertain) type. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,251,490,373]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bulked segregant analysis sequencing (BSA-Seq). PI 225689 was crossed with RH to produce the $\\\\mathrm{F_1}$ individuals that exhibited a 1:1 segregation ratio of SC to SI types. Four DNA pools were prepared using the female parent (PI 225689), the male parent (RH), 40 self-incompatible $\\\\mathrm{F_1}$ individuals, and 40 self-compatible $\\\\mathrm{F_1}$ plants. The sequencing of four libraries was performed using NovaSeq 6000 platform (Anoroad Gene Technology, Beijing, China). Raw reads were supplied by Anoroad, and clean reads were obtained by quality evolution. Then, the filtered short reads were aligned against the potato reference DM genome (V4.03), the variant calling of SNPs, and small Indels were excavated by Platypus (V0.7.4) software. The heterozygous and inconsistent SNPs, and small indels between the two $\\\\mathrm{F_1}$ pools were selected for calculating the $\\\\Delta$ (SNP-index) values. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,390,490,533]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fine mapping of Sli. To fine map the Sli locus, recombinants for the Indel marker M-1 and M-2 were screened using 238 plants of $\\\\mathrm{F_1}$ population (created by a cross between PI 225689 and RH). Considering the SC/SI type of the recombinants of $\\\\mathrm{F_1}$ plants, the Sli locus was further mapped to the interval between F1-4 and F3-4 with a physical interval of $941\\\\mathrm{Kb}$ . Genotyping of $1800\\\\mathrm{F}_2$ progenies from 23 selfed $\\\\mathrm{F_1}$ plants revealed an extreme segregation distortion (no a/a haplotype). Thus, 6624 $\\\\mathrm{F}_2$ individuals from 131 selfed $\\\\mathrm{F_1}$ plants were screened for the recombinants, and the Sli locus was mapped to the interval between C7-1 and D5-2 with a physical interval of $64.61\\\\mathrm{kb}$ . The genomic DNA fragments of the interval in RH and PI 225689 were sequenced and aligned. The polymorphic markers were developed based on the re-sequencing data of RH and PI 225689 according to the method described by Zhang et al.[28]. The markers and primers used in this analysis are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,549,490,671]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gene transformation of S15-65. For functional identification of the Sli gene, DNA fragments containing the native promoter and genomic sequence of Sli were amplified from RH, and then inserted into BamH I and Hind III sites of the binary vector pCAMBIA1301. This construct was transformed into the Agrobacterium tumefaciens strain GV3101. The S15-65, a diploid self-incompatible line from S. tuberosum group Phureja, was kindly provided by CIP and used in the Agrobacterium-mediated transformation of potato internodes as previously described[8]. The ploidy of transgenic lines was analyzed by a flow cytometry assay, and the expression level of Sli in the diploid transgenic lines was verified by qRT-PCR. SC/ SI phenotypes of the diploid transgenic lines were recorded. The primers used in this analysis are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,687,487,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aniline blue fluorochrome staining of pollen tubes. Five pistils were collected $72\\\\mathrm{h}$ post pollination and immediately treated with 3:1 $95\\\\%$ ethanol:glacial acetic acid. After rinsing twice with double-distilled water, the pistils were incubated in $0.005\\\\mathrm{mg / mL}$ aniline blue fluorochrome in $0.1\\\\mathrm{M}$ $\\\\mathrm{K}_2\\\\mathrm{HPO}_4$ buffer for $24\\\\mathrm{h}$ . The colored pistil was placed on a glass slide and viewed under a fluorescence microscope. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,772,490,872]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Quantitative RT-PCR analysis. Total RNA was isolated using a RNAprep Pure plant Kit (Tiangen) according to the manufacturer's protocols. First-strand cDNA was synthesized from $1\\\\mu \\\\mathrm{g}$ total RNA using the PrimeScript $1^{\\\\mathrm{st}}$ strand cDNA Synthesis Kit (Takara). PCRs were performed using SYBR Premix (Takara) on a 7500 Fast Real-Time PCR system (Applied Biosystems) according to the manufacturer's instructions. Three independent biological experiments were performed in all cases. StEF1- $\\\\alpha$ was used as an internal control gene for normalization. The relative gene expression was calculated using $2^{-\\\\Delta \\\\Delta \\\\mathrm{Ct}}$ . The primers used in this analysis are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,888,490,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In situ hybridization. The 256-bp Sli-specific probe was amplified and labeled using the DIG RNA Labeling Kit according to the manufacturer's recommendation (SP6/T7, Roche). Pretreatment of tissue sections, hybridization, and immunological detection were performed in accordance with the previously described methods<sup>33</sup>. The primer pairs used are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,62,926,195]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Phylogenetic analysis of Sli. The protein sequence of Sli was queried against Phytozome v13 (https://phytozome next.jgi.doe.gov/) to retrieve its orthologs or homologs from other dicot and monocot species. Protein sequences showing a similarity of $40\\\\%$ or above and evaluet lower than 1e-10 blastp to the query sequence were retrieved and multiple aligned using Mafft (https://mafft.cbrc.jp/alignment/software/). Only the two most similar sequences were retained in each species. For SLFs, the F-box protein located within the S-locus region of RH was considered as the potential SLF (http://solanaceae.plantbiology.msu.edu/ rh_potato_download.shtml). A maximum likelihood (ML) phylogenetic tree was constructed using the ML based on the Poisson correction model. The bootstrap consensus tree inferred from 1000 replicates was taken to represent the evolutionary history of Sli. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,208,927,286]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Identification of S-RNases from diploid lines. Specific primers were designed according to the de novo assembly of RNA-sequencing data from the mature styles of the 125 diploid lines using the method described by Ye et al. The cDNA sample prepared from the styles of each diploid line was used to clone the pistil-specific S-RNase. The positive PCR products were then sequenced and considered as the multiple allelic variants of S-RNases. The primers used in this analysis are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,299,927,464]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Yeast two-hybrid assay. The codon region of each S-RNase (S1-S14) except for its signal peptide was cloned into the pGADT7 vector (AD-S-RNase). The C-terminal region harboring the PP2 domain (84 to 266 amino acid), and full length of Sli, in addition to the C-terminal region harboring the F-box protein interaction domain (114 to 393 amino acid) of the negative control gene (RHC01H2G1617) were constructed into the pGBKT7 vector [BD-PP2, BD-Sli, and BD-StSLF(t)]. Each type of AD-S-RNase was co-transformed with BD-PP2, BD-Sli, or BD-StSLF(t), respectively, into the Y2H Gold Yeast Strain according to the manufacturer's instruction (Clontech). The yeast cell harboring pGADT7-T and pGBKT7-53 was used as a positive control, and the cell harboring pGADT7-T and pGBKT7-Lam was used as a negative control. The plate was then incubated for 4 days at $30^{\\\\circ}\\\\mathrm{C}$ , and the yeast was grown on the synthetically defined medium (SD/-Trp/-Leu/-His/-Ade) as recorded. The experiments were repeated, independently, at least three times with similar results. The primers used in this analysis are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,476,927,673]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Luciferase complementation assay in N. benthamiana leaves. The C-terminal region harboring the PP2 domain (85 to 266 amino acid) of Sli was cloned into pCAMBIA1301-cLUC (cLUC-PP2). The codon region of each S-RNase (S1-S14) except for its signal peptide was cloned into pCAMBIA1301-nLUC (nLUC-S-RNase). Each construct was next transformed into Agrobacterium tumefaciens strain GV3101. Each strain was grown at $28^{\\\\circ}\\\\mathrm{C}$ in LB media with kanamycin $(50\\\\mathrm{mg / L})$ and rifampicillin $(50\\\\mathrm{mg / L})$ to an $\\\\mathrm{OD}_{600}$ of 0.8. Cells were then harvested by centrifugation at $3000\\\\times \\\\mathrm{g}$ for $5\\\\mathrm{min}$ and resuspended in $500\\\\mathrm{mM}$ MES buffer containing $1\\\\mathrm{M}$ $\\\\mathrm{MgCl}_2$ and $100\\\\mathrm{mM}$ acetosyringone (Sigma), to a final $\\\\mathrm{OD}_{600}$ of 0.6. For co-infiltration, equal volumes of the strain harboring cLUC-PP2 and the strain harboring nLUC-S-RNase were mixed and infiltrated into fully expanded leaves of 4-week-old tobacco using a needleless syringe. After the infiltration, plants were grown under dark for $8\\\\mathrm{h}$ and then grown under $16\\\\mathrm{h}$ light/8 h dark for $48\\\\mathrm{h}$ . Then the substrate D-luciferin (Sigma) was sprayed onto the infiltrated tobacco leaf. After $5\\\\mathrm{min}$ of incubation in dark, a chemiluminescence signal was observed and captured using NightSHADE LB 985 (Berthold, Germany). The experiments were repeated, independently, at least three times with similar results. The primers used in this analysis are listed in Supplementary Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,687,927,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,726,621,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,739,927,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The BSA-Seq data (SRR14637423 and SRR14637422) has been deposited in NCBI under project number PRJNA732509. All other data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,800,813,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 8 January 2021; Accepted: 8 June 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,814,687,827]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published online: 06 July 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,870,586,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,883,917,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Devaux, A. et al. in The Potato Crop (eds Campos, H. & Ortiz, O.) 3-35 (Springer International Publishing, 2020). \\\",\\\"2. Stokstad, E. The new potato. Science 363, 574-577 (2019). \\\",\\\"3. Lindhout, P. et al. Towards $\\\\\\\\mathrm{F_1}$ hybrid seed potato breeding. Potato Res. 54, 301-312 (2011). \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[68,23,519,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24266-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[828,17,927,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,957,724,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NATURE COMMUNICATIONS | (2021)12:4142 | https://doi.org/10.1038/s41467-021-24266-7 | www.nature.com/naturecommunications \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[915,957,927,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[68,62,490,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"4. 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Kubo, K. et al. Collaborative non-self recognition system in S-RNase-based self-incompatibility. Science 330, 796-799 (2010). \\\",\\\"17. Williams, J. S., Der, J. P., dePamphilis, C. W. & Kao, T. Transcriptome analysis reveals the same 17 S-Locus F-box genes in two haplotypes of the self-incompatibility locus of Petunia inflata. Plant Cell 26, 2873-2888 (2014). \\\",\\\"18. Kubo, K. et al. Gene duplication and genetic exchange drive the evolution of S-RNase-based self-incompatibility in Petunia. Nat. Plants 1 (2015). \\\",\\\"19. McClure, B., Cruz-García, F. & Romero, C. Compatibility and incompatibility in S-RNase-based systems. Ann. Bot. 108, 647-658 (2011). \\\",\\\"20. Hosaka, K. & Hanneman, R. E. Jr Genetics of self-compatibility in a self-incompatible wild diploid potato species Solanum chacoense. 1. Detection of an S locus inhibitor (Sli) gene. *Euphytica* 99, 191-197 (1998). \\\",\\\"21. Hosaka, K. & Hanneman, R. E. Jr Genetics of self-compatibility in a self-incompatible wild diploid potato species Solanum chacoense. 2. Localization of an S locus inhibitor (Sli) gene on the potato genome using DNA markers. *Euphytica* 103, 265-271 (1998). \\\",\\\"22. Clot, C. R. et al. The origin and widespread occurrence of Sli-based self-compatibility in potato. Theor. Appl. Genet. 133, 2713-2728 (2020). \\\",\\\"23. Eggers, E. J. et al. in Abstract Book of SOL International Online Meeting 127 (Wageningen University & Research, 2020). \\\",\\\"24. Jansky, S. H., Chung, Y. S. & Kittipadukal, P. M6: A diploid potato inbred line for use in breeding and genetics research. J. Plant Regist. 8, 195-199 (2014). \\\",\\\"25. Leisner, C. P. et al. Genome sequence of M6, a diploid inbred clone of the high-glycoalkaloid-producing tuber-bearing potato species Solanum chacoense, reveals residual heterozygosity. Plant J. 94, 562-570 (2018). \\\",\\\"26. Peterson, B. A. et al. Self-fertility in a cultivated diploid potato population examined with the infinium 8303 potato single-nucleotide polymorphism array. Plant Genome 9, 1-13 (2016). \\\",\\\"27. Zhou, Q. et al. Haplotype-resolved genome analyses of a heterozygous diploid potato. Nat. Genet. 52, 1018-1023 (2020). \\\",\\\"28. Zhang, C. et al. The genetic basis of inbreeding depression in potato. Nat. Genet. 51, 374-378 (2019). \\\",\\\"29. Peng, Z. et al. Inheritance of steroidal glycoalkaloids in potato tuber flesh. J. Integr. Agric. 18, 2255-2263 (2019). \\\",\\\"30. Nguyen, K. M. & Busino, L. in Cullin-Ring Ligases and Protein Neddylation. (eds Sun, Y., Wei, W. & Jin, J.) Vol. 1217, p.111-122 (Springer, 2020). \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[505,63,927,153]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"31. Shimizu, K. K. & Tsuchimatsu, T. Evolution of selfing: recurrent patterns in molecular adaptation. Annu. Rev. Ecol. Evol. Syst. 46, 593-622 (2015). \\\",\\\"32. Jacobs, J. M. E. et al. A genetic map of potato (Solanum tuberosum) integrating molecular markers, including transposons, and classical markers. Theor. Appl. Genet. 91, 289-300 (1995). \\\",\\\"33. Ma, L. et al. ABNORMAL VASCULAR BUNDLES regulates cell proliferation and procambium cell establishment during aerial organ development in rice. New Phytol. 213, 275-286 (2017). \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[505,171,643,184]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,184,927,297]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We thank Prof. K. Hosaka (Obihiro University of Agriculture and Veterinary Medicine), Prof. Jianjian Qi (Inner Mongolia University), Prof. Xueyong Yang (Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences), and Prof. Guangtao Zhu (Yunnan Normal University) for experimental and bioinformatics support. This work was supported by the National Natural Science Foundation of China (32002032 and 31972433), Yunnan Science Fund (202005AE160015 and 2019FJ004 to Y.S.), Shenzhen Science and Technology Program (KQTD2016113010482651 to S.H.), and special funds for Science Technology Innovation and Industrial Development of Shenzhen Dapeng New District (RC201901-05 to S.H.). This work was also supported by Yunnan Provincial and Shenzhen Municipal Governments. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,310,653,323]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author contributions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,324,927,392]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Y.S., S.H., L.M., C.L., and C.Z. conceived and organized the research. Q.L., D.T., and Y.J. performed the bioinformatics analyses. B.Z., F.T., F.L., and H.Y. carried out the phenotyping assay. B.Z., F.T., F.L., M.G., and J.Z. performed the cloning and functional analysis of Sli. C.Z. and D.G. tested the efficiency of Sli in SI-breaking. C.Z., B.Z., F.T., X.L., and F.L. identified the alleles of S-RNases from diploid potatoes. Y.S., L.M., and S.H. wrote the manuscript. L.W. and H.G. revised the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,407,648,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Competing interests \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,420,719,432]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare no competing interests. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,446,665,457]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Additional information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,460,900,483]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-24266-7. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,493,915,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Correspondence and requests for materials should be addressed to C.L., S.H. or Y.S. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,512,927,546]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Peer review information Nature Communications thanks Roger Chetelat, David Douches, and the other, anonymous reviewer(s) for their contribution to the peer review of this work. Peer review reports are available. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,558,919,570]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reprints and permission information is available at http://www.nature.com/reprints \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,581,927,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,629,579,648]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0299/462abcbf8d9e422e8561b19a34e8f0bdf4c9592f5a64974155b9c24a988d399c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[583,630,927,652]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,653,927,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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N6 6. C. 5-16. doi: 10.17076/geo1887 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,648,769,676]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"N. A. Bozhko. GEODYNAMIC EVOLUTION OF THE EASTERN PART OF THE BALTIC SHIELD AGAINST THE BACKGROUND OF SUPERCONTINENTAL CYCLICITY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[95,686,791,701]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lomonosov Moscow State University, Faculty of Geology (1 Leninskiye Gory, 119991 Moscow, Russia) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,709,709,800]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An analysis of the geodynamics of the eastern part of the Baltic shield in the last 3 billion years of its history, set against the background of supercontinental cyclicity, showed the territory was fully involved in two supercontinental cycles associated with the development of the Kenorland and Columbia supercontinents. During the rest of the cycles, the territory was part of larger continental fragments and was not directly involved in the creation and disintegration of supercontinents, experiencing an intraplate regime under the impact of mantle plume tectonics. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,809,707,836]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: Supercontinent; supercontinental cycle; intraplate regime; magmatism; rifting; mantle plume ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,845,709,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For citation: Bozhko N. A. 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CpaBHNTJIbHbI aHaJIIN3 NOKa3bIBaET, UTo B pRae HeoApXeNCKNX KpaTOHOB O6hApYxNBAOTcR dpBHeuIe NaIEO-Me3OapxeckKne cerMentbI (npOTokpatoHbI), OkpyXeHHbIe HeoApXeNCKMn O6pa3OBaHHaMn, KOtOpbIE MOyT paccMaTPNBATCBsKa K«raPa\" KOHCOLndaun, fpaarmEtbl 6OJIee 6OUnPHOB BaANbApbl, TaKne kak 6LOKn ToKBe B KpaTOHe 3Im6a6Be, AHTOn B KpaTOHe CLeB n DpyrVe. B 3Tom IIaane INHTpec PpeDCTABJAE T BodIo3epckn 6LOK B ITOBOCTOHOJ qACTn KapelbCKoro KpaTOHa [JIo6aUxUyeHKO n dp., 1989 n dp.]. OH BblJeTcR kAc OblaCTb Pa3BHTnJaDpeBHeuIX Ha BaANTNCKOM uITe IIOPOd, PpeDCTABJIeHHbIX O6pa3OBaHHaMn TOHaINT-TpOHDbEMNT-rgaHODInOpTobOoi (TTF) accouinaun C Bo3pactom 6OJIee 3,O mlpI let, IN IO CBOemy TEKTOHueCKOMy CTpoEHIO B 3TOM OTHOWeHN CNODeH C DpyrIMN IpOTOKpatoHAMN, yIOMyHyTBIMN BVIIe. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,84,899,169]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PacnaBaaJbapbIOTMeueH B reoJorueckOJIeTOnNCi BaxHbIM CO6blm - 3aJIOKeHnEM Ipa3BHTnEM IO3dHeApXeNCKoR THepeauN 3eJeHOKaMeHHbIX NORCOB, 3BOJIIOUra KOTOpBX npINBeJaK Co3DaHNI MHOToUcJIeHHbIX rpaHNT-3eJeHOKaMeHHbIX OBJaCTeI (Γ30) - apXeNCKx KpaTOHOB. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,169,900,369]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Для Формировая Фундамента Карьского Кратона И спользуется Akкpeцнонho-Kоли-Зонная Гешиhamческа модь писоеденны Молобх Террейнов К древим Континецталь ядра Зеленокамених посов [Кожевников, 2000].В олочne ot Вodлозерско 6лoka -ядра мозорхейский консолдациochoьная чась Сеньталов Карели образовалась руtem akреси -последовatelбогоПрочileенners Серни Роздемрхейckeхх OCTpoВьх дуг с boctOKа на заад. Akреси Террейнов Okonto 2,83-2,75 млрд лет сmedиль сь колизи-й, korда必将 сфорmirobа на COврemeннаястуктура Карельского кратона. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,369,900,469]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ΦορΜιρΟΒαΗΝ ΚόβκΚΟΓΟ κραΤΟΗ [Μιτρο-φαΝΟ, 2009] B COCTΑBE MγρΜαнςΚΟ ΣΙΟΚΑ, 3εληδινικασμανηνηθο πογα Μολμούερο-Bοροῦνι Μ ΚόβκΚΟ-HɒρβεχκΚΟΓΟ ΣΩΜΕΗ 3ανερψινιούς ἀνυδεχεν 2,74 Μπρι.Д. Μεινικυρυετχαν ἡνεριδενημει Μ ΙΝτρύγεινηθου Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει $\\text{卡}$ Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,469,900,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ha ochobahn no6o6eHn daHHbIX [PaHHn... 2005; Cna6yHOB n np.. 2006; Cna6yHOB, 2008, 2019 n np. ] moxno npednoJoxntb cJeDyoUyIO reOdnhamNueckyUo moelb. K py6exy OKoIoo 2,75 mnpd letc fOpMnPOBaIncB DBA cTa6NJbHbIX 6loka KOHTINHeTaNBJHOKopbl - KoJIckn u KapeIbCKn, KOtOpBie 6bln pa3deJeHbI BeLOmOPCKIM OKeaHnueckn BaccseHOM. HauHna npimepHo c 2,72 mnpd let eT 3ta cnCTema BVCTynla B KOJIIN3IOHNHYO CTADIO PA3BNTN, KOtOpAa MapKnpyETc npoABLeHnMI NOKPBOHOn TEKTOHKN, BlicOKo6apuueckoro MetamOpΦn3Ma, rpaHnTO- o6pa3OBaHneM u B pe3yIbTaTe - o6pa3OBaHneM BeLOmOPCKORo KOLIN3IOHNHO TPOCA. KoJIIN3N4 KapeJIbCKORo I KOJIbCKo-MypMaHcCKORo 6LoKOB (cynepTepeRnHO) DaTnpuyETc npENoDM 2,71-2,68 mnpd let [Cna6yHOB, 2019]. B cTpykTYPHom OTHOWeHn OHa BbIPA3INAcB B CO3DaHn apxeckoro KapelbCKoro - BeLOmOPcKO-KolbcCKORo NaIeOKOTInHeTaNBJHOrO cerMeNTa. B nOJIb3Y TaKOH TPAKTOBKn IVCTOPIN PA3BVNTN BoLomOPCKORo PONCA MOXET CBNDeTEbCTBOBaTb IN pNcTyCTBnE 3DeCB apxecknx EKnOrITOB [BOIoNueBn I np.. 2004], KOtOpBie, PO-BvIDNMOMy, OTPaxaIOT cy6dyKUnIO u 3akpyITne OKeaHnueckoro baccSeHa, 3a KOtOpBIM NocleIOBaJa KOJIIN3N, O6pa3OBAHne BeLOmOPcKOrO IOraCa n CO3dAnHe eDInHO R KOHTINHeTaNBJHOrO o6pa3OBaHn, BOweJlWho B COCTAB CyNEpKOHTINHeTaN KeHOpNeHd. B erO foOpMnPOBaHn, TAKIM Obpa3OM, BblJeIANTOTCE BCE ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[695,914,702,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[99,923,576,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"TpydBi Kapelbckoro HaynHoro zentpa Pocsncko akaaemn hayk. 2024. N6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[95,85,489,125]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"fa3bCynepeKoHTnHeHtAJIbHOrO cUKNla: cyuecTBOBaHne DpeBHeRo CynepeKoHTnHeHtA,ero pacnaad nC6opka HOBOrO. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,127,489,269]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepkoHTHHeT KeHOpJIeHd (~2720- 2570 mJH JET) n CU (~2720-2320 mJH JET). IooDHeapXeIckn CypeKoHTHHeT C Bo3paCTOM OKOLO 2,7 Mnpd JET 6bIIN BbIeJIeN IOd Ha3BaHNc Em PaHRe 0 [XaHn, BoXko, 1988]. X. BInlbamc c CoABTopaMn B 1991 r. [Williams et al., 1991] IpeIIOxII IN TepMnH «KeHOpJIeHd» dIy HeoApXeIckOrO CypeKoHTHHeTa, KOToPbI NbIHe IuPOKO IcNoJIb3YeTcB R eOJIoRnueCKO IInTePaType [HaNP., Jy6HnHa, Cla6yHOB, 2011]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,270,489,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CTpykTypa BOCTOHNo YaCTn BaJItnCKOrO uNTaB COCTabe cynepeKoHTInHeNTa KeHOpIeHd anAIO-rnHa CTpykType KpatoHa KaIaxApn B IOxHoN AΦpKe, COCToJUero n3 KpatoHOB KaanBaalb N3IM6a6Be, pa3JeHnBix rpaHyNJTOBbIM NOrCOM JImnOIO, nJN CeBepo-KtAnCKoro KpatoHa cDBym8 6IokAMn, pa3JeHnBIMn TpaHcSeBepOKiTaNCKM NOrCOM. 3TO BpeMg OTMeueHO npoRBJHeHNEM BHYTpNIHTHOrO MarmAtn3Ma n TEKToHKn. B npedeJax KapelbckO npOBnCmN BblJeHbI 6a3nt-YJbTpa6a3NTOBbie KOMPLeKCb i INTEpBaJa2,74-2,60 mIN JET B BVide MHORofoa3hBix CaHyKtONIOB, KOMATNUTOB, 6a3aJIbTOB, a TaKKe INHTpy3n I daek 6a3NTOB [ApectoBa n dp., 2019]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,469,489,611]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PacnaKehOpJHeHaNIO6pa3OBAHne MoIobIbIX OKeaHOB OXBaTnIN B OCHOBHOM TeppntOpnnCOBpeMeHHbIX IOXHoN ABCTpAlIn, ANTpAKTnDbI, INdIn, CeBepHoro KnTaI. Ix 3akpytne npuBeNoK npoRbJIeHNIO KOJIIn3N i oporeHn i φOpMnpoBaHnIO cynePKoHTnHEHTa JTylnra [Boxxko, 2009]. B KpaToHax 3TxN KOHTnEHTOB OTMeuaOTc npoCeCbIMarMaTHn3Ma, DeΦopMaun N MeTamOpΦn3Ma B nHTepBaIe 2,56-2,42 MlpJ neT [Barley et al., 2005]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,612,489,839]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B Ebp3nn TeKToHnueckne npocecbb BpeMe- Hn paCnada n φOpMnPoBaHnna HOBO rCynePkoHTnHeTa npoBJIaNcB npenMyIeCTBeHNO B BVnde BHyTpInIINThbIX TeKTOHO-TepMaJIbHbIX CObItn. 3TO OTHocNTcra N K TeppntOpnn BaJtniCKOrO IuTta, rDe OTmeyaeTcR OTCyTCTBVe KOp0o6pa3yIOuX npoCeCCOB, CnHXPOHHbIX O3HaueHHbIM BblSe, n IpOReBLeHne PIIOMOBbIX TeKToHnKn N MaGMaTI3Ma. 3ToN 3Noxe NO BpeMeHN 3deCb B 3NaHTeJIbHO CTeNEHn COOTBeTCTByET CymNCKO-CapNOJnnckn 3tan pa3BnTna (2,55-2,30 Mnpd JeT), npoxoDbHn BO BHyTpInIINTHOio6ctaHOBKe. INHpU3NBhI MaMAtn3M CymNCKO-capNOJnnCKORO 3tana HocNT TnInuHbI KpaToHbI XapaKTep n yHnKaJIeH Obpa3OBAHnem paCCIoEHHbIX Ylb-TPamaΦHT-MaΦNTOBbIX PnyTOHOB. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,839,489,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Базntы палонореторозбкого отana (2,45-2,41 млрд лeТ)В Kapelьсков повици рпсдставны КрупнblIMп раслоЕнblIM ИНтузямN:Буразковский,ИнтузямОlaангсков Гупbl, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,84,900,198]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KOMaTnITamn BeTpEHO rO NOrCa, a TaKxe CymuCKIMN 6a3aJIbTaMn n DaIkAmn BO BCex DOMEHAX npOBuHcUIN [ApecToBa n dp., 2019]. BHeDpeHne 3Tnx MaRMaTnTOB pOnCXoDnIO B BVNe IPOrCOB, pInypOceHHbIX K pNΦTAM CeBepo-BOCTOCHOrnpocTnpaHn: KEmi-KoJlncMa (ФинlaHДЯ) - KInBaKka - KyHdo3epo (C Kapelna) n BypaKOBcKO-MohAcTbIpckOMy (IOB Kapelna). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,198,900,269]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Даики баиюв с Ворстом OKОLO 2,5-2,4 млрд яет установны в Кolyбко-Mурmaнский и Kapelьков повинцях [Стоно на，在..，2019], cootbetctbya по Врemeи дectpyk-ции сунерковшеньта. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,270,900,526]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marmatn3M 3TOrO BpeMeHx XopoIoo pa3BNT B npedeJax BeIOMOpCKoI NOraCBA BVnDE 60JIbIoTO OuIcna CpeDnIX MEnKnx TeI 6a3NtOB, YNbTPa-6a3NtOB, Ra6bPO-aHOPTo3NtOB (Dpy3NtOB) IN B MeHbWei CTeNEHIN - DNOpNTOB, rpaHOINOpNTOB IN rpaHNTOB, KOTOpBle CEkyT MetAMOpΦn3OBAHNBie IN DeΦOpMnIPOBaHHbIe NopoDbI 6eIOMOpCKoR KOIMJIeKCA IN C KOTOpBIMN CBzAHO IpOraBJIeHne BbICOKOTemPepHORo MetAMOpΦn3Ma CeIeZKO RzIKLa B INTEpBaIe 2,40-2,43 MlpI Let, PPOXODINBWeR O B aHOPOREHbIX yCIOBnX. B IPOOaX 6eIOMOpCKoI 3KIOrHTOBOI IPOBInCuN BaIITNckoro 5UIta UCTaHOBJeHO IPORABHeNe IaIeONPoTePO3OiCKoR BBICOKOTemPepHOro TpaHUYIITOBOro MetAMOpΦn3Ma C Bo3pactOM $\\sim 2,45$ MlpI JeT [DokyknHa n dp., 2019], KOTpbI B OTJIuHne OT BbICOKO6apUneCKoR yKa3bIBaET Ha BHyTpNIIThBI xapaKTep IpoCecca. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,526,899,555]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepKoHTnHeHrTyrIa ( $\\sim 2320 - 2170m$ nH IeT) u Cl (~2320-1800 mH neT). ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,555,900,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B cπnscke «O6üeπpHnIaTbIX» cynepeKoHTnHeHToB 3a KeHOpJIeHdOM cIeDyET KoIyM6nJ. Ondako paHee [BoXko, 2009] aBTOp BbIeJIIN MEXdy HmN B pa3pa6OtaHHoN IM cynepeKoHTnHeHTaJIbHOI ZIKJIInuHOCtN cynepeKoHTnHeHT ATyIINR (~2320 mIn IeT) Ha oCHOBaHn aHaJIIN3a TEKToHnuecknx Co6bITn, npOn3OWeIuNX nOcIe pacnaJa HeoapxeiCKOrO cynepeKoHTnHeHTa KeHOpJIeHd. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,682,900,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3noxa cyuaceTBoBAHnCynepKOHTHeTApTyI npi6IIN3nteJIbHO COOTBeTCTByET NODpa3deIeHNIO TyIIN (2,3-2,1 MlpJLeT) MeCTHO shKaJIbl. Emy COOTBeTCTBOBAJO CynepeNlOMOBoe CObITNE OKOLO 2,25 MnpJLeT, COnpOBXdABWeecnI3IINHEm TpaNNOB, OFOpMNPOBaHmE DaIKOBbIX KOMPJIeKCoB IN pNΦTOBbIX CnCTem [Cadman et al., 1993]. B 3TO BPEM TePPINTOpN KaJIbckoro KpatoHa PpeDCTaBnla Co60N eNkOHTnHEtAlhN MeJKNOBOnHb I baccEn, B npedeJax KOtOPOr HakaJIINBaJIncs TepRIneHbIe OcaKn I npONcXoJIo NpeNoDnueCKOE n3JIINHne TpaNNOBx Ba3aJIbTOB. TpeUHHbIe n3JIINHn Jab B rTuJIinCKoe BPEM OXBaTIIN ORPOMHyIO TePPINTOpN IO npedeJax BaIANTCKOrO zNTa I o6pa3OBAJI N o6wnipHoe ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[282,904,329,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[331,923,900,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[95,84,490,340]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JabOBoe pIaTo. O6pa3OBAHne cyNepKoHTnHeHa n IocJeUoUee TeKToHnueCKoe 3aTnUbe npBBeJI N K IOTepe apXeIckOro MeTaHa, OJeDeHEnmM n KncLOpODHomy CoCTaBy aTMocΦepb. B INHTepBaJIe 2,40-2,22 Mnpd JeT kpaTohBi CbIoNpHop, Kapelbckn i KaIaxapn IcNbItaJIu Tpr IocJeDoBaTeJIbHbIX OJeDeHEnH.N. K3TOMy BpeMeHN OTHOCTCra NaKoPJIeHne IpOTOIIaTΦOpMeHNbIX YexLoB B VInde 3NIkoHTnHeHTaJIbHbIX OTIOKeHn rpynnbl PpeTopnra (2350-2050 mIn JTe) cyNeprpynnbl TpaNCBaAaj, rpynnPiRnuBriR $(>2,15$ mnpd JTe) n YnbAnDa $(>2,16$ mnpd JTe) AΦpiKn; rpynn Typn KpnK (2,4-2,2 Mnpd JTe) n BnNy (2,2 Mnpd JTe) BO BnaDInHe XaMEpcn ABCTpaJIi; rpynnbl TypoN (2,4-2,2 Mnpd JTe) n Iporo BnaDIn H o3. BepxHee CeBepHoJ AmePkn; rpynnbl IapacnKa6a cyNeprpynnbl MnHac Bpa3nJIi; YdoKaHcKO sePin AnDaHcKOrO uNTa. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,340,489,596]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B BOCTOUHOJ qACTn BaIINCKO rHrTa nO BpeMeHN m COOTBeTCTBYOT oBa3OBAHnR JTyJIa (2,3-2,1 mnpd let) [PaHHn...., 2005]. PaneonpoTePO3OoCKne JTyJIuCKNe ByIKAHnueCKne npOdbI BO3pactOM 2,22-2,06 mnpd let wnpOKo pacnpocCTpaHENb I npdeJax Bcero FehNockaHnHaNBCKORO uHTa n Hau6OJe e NOIHO npEcdTaBnHeh bHa TepnTOPn KapeHn. TpeunHHbIe N3JIyHnRAJB B A TyLIINCKOE BPEM OXBAtNIr ORPOMHyIO TEPnTOPIO n O6pa3OBAJIn O6wnpHoe JaBOBoe pIato. Po reOIOnueckm I reoxIMnueckm xaPakTEpNCtKam A TyJIuCKNe ByIKAHNTbI COIOCTaBIMbl C fAHEpO3OuCKMn KOHTINHETAJIbHBIMn PIIaTO6a3aJIbTAMN. K 3TOMy BpeMeHN OTHCINTcraTahOBLeHne daIKOBbIX KOMnLEKCOB FInHLnHdINC Bo3pactOM 2200 mH let, npOdoJIxKeHne φOpMnroBaHnR pNfTOReHHoN cTpykTypb PeYeHraImaHdpa-Bap3yra (2,3-1,97 mnpd let). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,597,490,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BЛIOДИKOBи (2,1-1,92 Mnpd JIeT) O6CTaHOBka 6OuINHOI nIaTΦOpMbI n3MeHЯETcI. PacnpoCtpaHHeHne MaMAtN3Ma xapaKTepn3yETcR OTeJIINBOI pInypOueHHoCTbIO K 30HaAM rIy6INHHbIX pa3lOMOB,aOCO6EHHOCTn IPOdyKTOB MaMAtN3Ma yKa3bIBaIOT Ha BHyTpNIKOHTnHEtAJIbHbI pNΦTOReHHbI pEXIM 3TOr OpeNoDA.IpeXoD K IIOДИKOBII OTMeUH IOYBEHNEM INHTEHCNBHO TNIKpNTOBORO ByLkAH3Ma B OHexCKO CTpyK-Type,CINHXPOHHO C TaKOBbIM B PeueHrCKO CTpyKType KoIbCKOIO NOJyocTPOBA, YTO paCCMaTPIBaIOCb kak npn3NaKpackpbITnA OKeaHa. IocBOeMy COJepXaHnIO 3TO BpeM CoOTBETCTByET φa3e DeCTpyKcN CypePkoHTnHEtAJIbHOrO cIKNla. PioCTpaHCTBeHHO C6JInxKeHHbIE ByLkAHbI CEHTpaJIbHO TnPa, O6pa3yIOUne JInHeHbIE 3OHbI, MeJIKOBoHbI XapaKTEp 6accEHNOB ocAdKOHaKoJIeHnI rEOxIMmYeCKNe OC6eHHoCTn PnoDyKTOB MaMAtn3Ma yKa3bIBaIOT Ha BHyTpNIKOHTnHEtAJIbHbI pNΦTOReHHbI pEXIM 3TOr OpeNoDa. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,84,900,198]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Людниковский Вторгеля на Терптуни Ож-сков вадины заBEREPПLOСь BCПLEСКOM сунCAPСКОТО 6a3NT-ГИЕРБa3NTOBOТОВО BУЛКАНПЛУTOHIN3Ma,образовам MOUнье TOЛДи ЛаBOВых NOTOKOB, ПОКРОВИ NG cyБУЛКАнчecкnxTeJ OT ПИКРNT-бa3aJIbTOBOТОGO Do Плагноба3aJIbTOBOТОВО COCTaOBИ NOДавИВИМ TEPПгEHNOE OcaДКОнakОПлелпe. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,198,900,239]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ha JIOJIKOBNICKOe BpEma npNXODITcBaxHeiue co6bIte B perHOhe -packpbITne CBeKO-ΦEHNCKOTO (JIOJIKOBNICKOTO) OkeAna. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,241,900,298]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PacnaicynepkoHTnHeTaYtynHaBaTnCKOMuTeOTpaxeH BpackpyTINJaPnAnDcKO-KoIbckoroN CBeKoΦeHHCKOrO OkeaHOB [PaHn..,2005] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,298,900,397]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Оьразоваиме океанческого бarrassейна на мостесяшто Лалладско-Kольско Коллinasонного oporena начiningается окуо 2.0 Ga c packolinaдрев breeй контенталовй сормповая OTHCINTEЛьно Heширокого окена Красоморского Тига, о чем CBидenteльстbyOT палеогmar-hintные и n3OTOnHь die dahlbie [Daly et al., 2006]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,397,900,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ΦOpMnPOBaHnIO CBeKofoHHcKOrO aKKpeuONHO OPOReHa TAKKe IpreDiueCTBOBaIoo 6bpa3OBaHne OKeaHa B nepNoD 2,0-1,95 MnpD let, O yemCBnDETeJIbCTBvOt OFnoJNTbI MyC Bo3pactOM 1,97 MnpD let. IVx CyueCTBOBaHne yka3bIbaET Ha TO, YTO dInTeJIbHbI 3TaN rIo6aJIbHO pNΦTOREHe3a npIBeHn Ha py6eke 1,97-1,96 Mnpd let KpackpbITnIO LIOIDKOuNCKoro OKeaHa. NocJeero paACKpbITnI prIMbIkaIOUaK KpaIO KapelbCKORO KpatoHa (CabO-JaIOXckAa 3OHa) B KaJIeBnCKOE Bpemr (1,920-1,800 mln let) TeppntOpriapeWla B TEKTOHnueckn PexmPiaccNBHO OKpanHbI NΦOpMnPOBaHn PHTMNHybIX Typ6dNTHBIX OCAdKB C yuaCTnEM PrINBHOcmO IInpOKJaCTIKN I3 pa3MbIAIOUXcJIIOIDKOuNCKNX Obpa3OBaHn. ΘtOMy BpeMeHN BO BHYtpNKoHTInHeHTaJIbHbIX CTpykTypax COOTBETCTByIOT IpoRbIeHnMOUHO RBCMa CneuΦnueCKoro PIKKPITOBORO BYlKaHn3Ma I OboPA3OBaHn DaIKOBbIX POEB. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,669,900,754]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ΦopMnpoBaHne BaIITnCKOrO uNTa kaK φpaRMeHTa cynePKoHTnHeHTa KoIyMbIn npOnCxOdiNo, TaKIM O6pa3OM, B DBe CtaDN N C o6pa3OBaHNEM LaJIaHnDCKO-KoJIbCKOrO KOJIIN3IOHNOrO IN CBekOΦeHHCKOrO aKKpeCIOHOrO oporeHOB [BaIarAhnckn n dp., 2016]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,754,900,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JaplaHdCKo-Kolbckn oporeH YBJIeTcA cTpyKtpyoB VTOPO rOpraKa nO OTHoUeHIO K apxeuCKo-npOtePozOuCKOMy JaplaHdCKo-BeLomopcKOMy rpaHunIto-rHeiCobOMy nOaCy [BoXko n dp., 2021]. Oh npedctabJeT co6oT NIIuHbIKoJIIN3NoHHbI NOc DInBepReHTHOrO pOKpoBHOrO cTPOeHn. 3BOJIouzna IOnca 3aBepShnIacb cy6dykuzne, cOpboXdaBWeiesc o6pa3OBaHnem 3KLOrHToB [UkyNaHa n dp., 2015] n KoJIin3neKolbckoro n Kapelbcko-BeLomopcKoro ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[685,914,700,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[97,923,576,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[95,84,490,383]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"элархeіckx KONTINHENTaJIbHbIX 6LOKOB B KOH- ce paHHeRo npOTepO3oR, B INTepBaIe 1,93- 1,9 mnpД lat [Daly et al., 2006] c nikom 1,90- 1,91 mnpД lat [Balagansky et al., 2014],чTo npInBeJIO KΦOPMnPOBaHnIO COBpeMeHHoN CTpyk- Tpybl DOKeM6pniCKx O6pa3OBAHn PernoHa. 3TN C6bITnA COpBOXdALINcB rpaHyIITOBbIM MeTaMOpΦn3MOM NΦOPMnPOBaHnEM 3OH PnaCTUeCKOrO CDBuROBOrO TeueHnra Cy6UnpoTHoro n CeBepo-3aNaADHO npocTupAnHry. KolnizOnHbIe BbICOKo6apUneCKne rpaHyIITbI LanJaHdCKo-KolBnCkoR rpaHyIITOBrO NOraCa 6bln cΦopMnPOBaHbI B INTepBaIe 1900-1910 Mln Iet npi T 850 $^\\circ \\mathrm{C}$ nP 11-12 Kbap [Balagansky et al., 2014]. B CBOIO OuepeB, naJeONpOTepO3oNckne KoIJIIN3NoHNbIe C6bITnA LlanHaNDcKO-KolbCKoro OporeHa npoRbUIncB B BeJOMOpCKOM NoaCe B BVide TEKTOHO-TepMaJIbHOn Nepepa6tKn erO npoPd, BKJIIOuaOSeH HANOKeHHbIe DeΦOpMaun, MaFMaTIa3M, MetAMOpΦn3M, n3OTOnHoe OMOJIoXeHne NpOoi. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,383,489,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OДнOBрЕмнС OКОнчаниМ KОЛизИВ ЛапладсК-КOLьСКOM oporeHe Ha ITO-3aПанбов Okраинe KapelbckOrO kpaToHa NaayincB rIaBHbIe CBekoФeHHCKne aKKpeUHOHbIe CObItnB B VIne PruJleHEnHЯ OCTpoBOyXhIx TeppeHOB K KpaIO KapelbckOrO kpaToHa. 3TOT npOceC 3aKoHUnCЯ CBekoФeHHCKon oporeHnei 1,83-1,80 MlpД.Iet TOMy Hazd [PaHHN...，2005]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,498,489,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ha CBeKoΦeHHCKOM 3TaNe DeΦOpMauŋ TeppntopnBaItnckoro ⅢnTa nOdBeprIacb nHTeHcBHBIM CKJaUaTO-pa3pbIBHbIM DeΦOpMaunm. IpoBJIeHnA DeΦOpMaun B cHTpAlbHoJ caCTn BaItnckoro ⅢnTa, BBI3BaBwIX 3NaHTeJbHyIO nepeCTpOky CΦOpMnPOBaHHbIX CTpyKTyp (B TOM qncLe OHeXCKoB BpaDInh), n OnpdeJIinx xaPakTep pncyHka INx COBpeMeHHoJ TEKToHueCKoC TpyKTypbl. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,625,490,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Перноу заBERшЕня COJIЛИЗNOHHbIX ПОUCEC-COB в ЛапалдсКО-KOLьСКOM opOREн e началу akKpeционьix поцeccoBв CBekофEHнckOM NO-Яce OTBeueaet ФормЮВанne Крунов МагmaTN-чecкой повинци (KMП) в педахox KolьсКOrO n KapeьсКOrO 6LOKOB BOCToHOn ΦeHHOCKaHN Ha урове 1980 mInI leT, пeДCTaBLeHNoH KOMПLEKcamn TOLENTOBbix 6a3albTOB, pIKpNTOB, dINΦфepenuzipOBaHHbIX ra6bpo-aHOpTO3NT-CNEHHTOBbIX INHTpy3N, UIeIOUhBX INHTpy3N i KM-6berlntOB [CamcoHOB u np., 2019]. ПрогВлени TaKOrO MaCSTa6HOrO BHYTPnPllTHOrO MaMaTIN3Ma BO φpaRMeHTe KOHTINHeTAlbHOK Okpbl, OKpyxeHHom oporeHnueCKMn NOrCAMn, Tpe6yET CamOCToTeJbHOrO paccMOtpeHnry. Bo3MOxHo, OHO Bbl3BaHO DeiCTBnEM HeIy6OKnx MaHTnHBix PIIHOMOB, BO3NHkaIoZHX BO BpEMy cy6dYkCmN Prn DBVIXeHIM NITOCΦepHOrO cI36a BdoJIb rpaHnCbI HNXHNe I BepXHeMaHTnI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,84,900,226]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IocJIpepackpbITnBcEkoΦeHHCKOTo（JIouNKOBnCKOTo）OkeaHa B KaJIeBniCKoe BpeM TeppnTOpn，PpIMbIkaUo7aK KpaIO KapeJIbCKOTo KpaTOHa，IpeuJaB pexmPiaccNBHOkpanHbI NΦOpMnPOBaHnTOIuPI pNTMnHybIX TpybNDHTbIX OcaKDob C yAcTHeN PfuBHOcmO NipOKJlactKN Ipa3MbIBaIOUxXcra IIOuKOBNIckx O6pa3OBAHn.B CeBepo-BOCTOCHNo ChtN BaJItnCKOTo UHTa CBekOΦeHHCKn 3tan XapaKTepn3OBaJIcR npTOReHHbIM TEKTOHueCKM peXmOM. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,226,900,325]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3aBepWeHne yKa3aHHbIX BblIe n CnHxPOHbIX C HIMN OPOReHn Ha BCex MaTePnKax CnaJIo pa3pO3HeHHbIe φpaRMeHTbI KOHTnHeHTaJIbHOJ KOpbI B INTepBaJIe 2,1-1,8 MlpJ,JeT B cypeKoHTnHErT KoJyM6n. KaBnuIM, B npOceCe erO CO3dAnHn Ipo8BnIncB BCE φa3bI cypeKoHTnHEtTaJIbHOrO cUkJa. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,326,900,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepkoHTnHENT Kojum6n（\\~1920- 1770 mIh Iet) n CU ( $\\sim 1920 - 1520$ mIh Iet). CynepkoHTnHENT KOHca paHHeO npotepo3oA NOI h3BaHnEM PAnRey 1 6bl BbIeJeH [XaHn, BoXko, 1988] Ha OCHOB reoxpOHOnIOuYeCKnx I reJIoRrHuCKx DaHHbIX TOBOBpeMeHN. CyueCTBOBaHne cynepkoHTnHEnTA, COzDaHnHO B nepNoD 2,0- 1,8 Mnpd Iet, PpeIPOlaIaONcB pIOM NCCJIeIOBaTeJe. PoJxepc n CaHToW B 2002 r. HauBaHn eTOT cynepkoHTnHENT «Kojum6n» IO HauMeHOBAHNI O peKn KoJUM6n Ha 3anaDe CeBepHO AmePKn. Ero cyuEeCTBOBaHne OTmueHo pacnpocTpaHEHem PeTOJIOUReCKN IDeHTNUHbIX IOHOBO3PacTHbIX IopoD Ha paCSTOAHNE TbICrK M Upe3 rpaHnCbI HbIe CyuSeCTByIOUx KOHTnHEtOB. Ha BCEx KpaTOHAX OTmueHo paCnpocTpaHEHne IpoToTlAtΦOpMeHHbIX YexIOB, KOTOpBIE C yrIOBbIM HeCOrIaChEM NepeKpbIbAIOT pa3HOBO3pactHBie IODCTINLAIOUe NOMJIeKCSBI B YCSIOBIAHX HOBOrO cynepkoHTnHEnTa KoJUM6n: PopaMa (1,95- 1,88 mIrpd Iet), Atabacka (1,76 mIpd Iet), YMKOHDo 1,9-1,5 mIpd Iet) n dpyrIe. B aTo BpeMHa BaTnckom ZIte HakapLIbAOTc OTLOXeHnBeCNsra (1,8-1,7 mIpd Iet) [PaHnn ... , 2005]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,669,900,768]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepeKoHTnHeTaNbHaJeNoXKaIyMbHmOtMeueHa BHeDpeHnEM aHOporeHHbIX INHTpy3n I KOMaRMaTHuHbIX KNCJIbIX Cy6aepaIbHbIX ByIkaHITOB: IopOnIta CeIbepn (1,85 Mnpd JeT), KoIap (1,9Mlpd JeT), ByUBeIbDCKOrO KOMPLekCa (2,09-1,92 Mnpd JeT), paIakBn Ha6eppy (1,76 Mnpd JeT), ByIkaHITOB YaTuMa (1,85 Mnpd JeT) n dp. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,769,900,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IocJIe 3aBepSeHnI FOpmroBaHnJIIOJIOKOBnCKnx I, BO3MOxHO, YaCTN KaJIeBnCKnxO6pa3OBaHn TeppntOpnOHeXcko BpAnHbI PpeTppeJa CTpykTyHy OpeCToyKu N DeΦOpMaun, PPOBLeHne KOtOpbIX ONpeDeJIIo TpaHCrpeCCNBbI XapaKTeP 3aJIerAHN BblEJexaux ToJIu Bencn (1800-1650 MIn JET), KOTOpbIe C yIIOBbIM HeCOrJIacmE NepeKePbIBaIOT pa3HOBO3pactHbI PoIDCTNIaIOUne KOMNJIeKCbl. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[297,914,317,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[329,923,900,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,340,489,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ΦpaarmentaŋKoJyM6n cOpPobQxdaIacb 60lee 3HaunTeJIbHbIM dpo6leHneM IOXHOI POlycφepbl. B npedeJax BoCTOCHoI ToHDbAHbI (INHdN, AHTAPKTua, ABCTpAln) BO3NHK pRd MKNPOKOHTInHeTOb, B TO BpeM kAc JIabPa3N, NOBnDMOMy, npedCTaBnla c6oB o6OC6JeHHbIK ORepeHTbI 6Lok, OKaIMLeHHbI OKeaHAM, B paiohe TpeHBnIbCKo IpoBnHcN KAnAdbl, ITO3anaCUSA n Ppi6aNTnK. 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B IO3 qactn BaIITNCKORO UNTa OHa BbIpaKeHa IocLeDObATbHOCTBIO KopoObo3ayUoixxCobtBu INHTepBaIe 1,7-1,55 mInIeT (rotckar oporeHna)，BKNUOauX akKepeuio OCTPOBbIX dYr Ha φOHe o6paUeHHoN K 3anaNy cy6dyKuNN [Mansfeld，Andersen，1999；Connelly，2001]. 3Ta n cInxpoHNbIe oporeHn B dpuynx qactrx CBeta npuBeI N O6beDuHEnIO NOUTN BCEX KOHTINHEtALbHbxΦparMeHTOB HOBBI CypeKOHTHENT FOITN K py6exy OkIo 1500 mIn IeT.","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,840,489,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B BOCTOHON Yactn BaJItnIckoro UHTa, HAXOINBWEROsC B COCTabe KOHTInHeNTaJIbHOrO 0paRMeHTa, OHI He HAJIN IprAMORO OTPaxeHnra, 3deCb npoIOJXKALc BHYTpNIPTNbI peKIM. 3Ta 3noxa ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,84,900,226]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PnmuMeaTeIbHa IInpOKm npOReJIeHem anOpoReHHOro MaMAtu3Ma B INTepBaJe 1,4-1,5 MnpJLeT B vIe Cy6a3paIbHbIX ByIkaHHTOB, aHOPTo3NtOB, rpaHNTOB-panakINB. PAnHeme3OpPoTePO30ckne MaMAtuYeCKne NopObl SiWpOK paCpOcTpaHeHb B CeBepHom n BoCTOCHOM PpiJaDoXbe.3Decb OHI ppeCTaBHeBIOtOKamn CaImncknxΦeppo6a3aIbTOB, ra6bpOMOnHOITOBbIMn BaIaAMCKm mAmTcINHcaapCKm CnJIaMn, INTpy3neXOnyHbAapa n daIKaMn dByx reHepaun. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,226,900,440]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepkoHTnENT TOTn (1520-1370 MInH let) n Cz (1520-1120 mIn let) 6bln BblJeIeH [BoXko, 2009], kak yka3bBaIOcB, B pe3yJIbTaTe aHaJIIN3a KOJIIN3IOHHbIX CO6bITn, ppeIeCTByIOuXx 3OTMy py6Exy, B packpbIBWnxCЯocIe paTnaja KOnm6n OkeAHnuecknX 6accEHNax; 3NaHInTeJbHoe IN x HcIIO 6blIO COspEDOTOyeHO B IOXHOI POlycfepe 3emn: BoCTOHyON ABCTpaIIIM, ANTapKtnde, INIOCTaHe, AΦpNke, IOXHOI AmePKe, a TAKKe CkaHdINHabN IN CBeBO-BOCTOHyON LaBPeHTn. COBpeMeHHbIe DaHHbIe NODTBepXJaOT npaBOMOuHOCtB BblJeIeHnry CynepKOHTnHErTA. TaK, I. PecoHc c CoABTOpAMn [Pesonen et al., 2012] PpeDCTaBnI NaJEOMaRHTHyO peKOHCTpyKUIO cypeKoHTnHEnTa Ha yPoBHe 1,53 MIpI neT. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,440,900,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BpemcuyeeCTBOBAHnme3OpnoTePO3Ocko- ro cyneKoHTInHeTaTToNtOBeuaet B OCHOBHom paHHemy pIeEO OTeueCTBeHHoJ uXapaKTePn3yeTc npoe6laaHnEM IOndHrTu. IpopoTnlat- fOpMeHHbIe Yexbl TOTn IMeIN OprAnuehHOe pacnpoctpaHene. B EbpazmOn HpeDctabLeHb KAp6oHaTHO-TePPnREHHbIM ONlROMNKTOBBIM TOJIaAMn, ReHeTNUeCKn TeCHO CBraHHbIM C KOpAMn BBIETpNBAHn IΦOpMnPoBaBUsMNCS B PLOCKNX N3OJInpoBAHbIX BpaDNHax, NaIOxKeHHbIX Ha DpeBHe o6pa3OBaHn. BoJee 3NaUHTbeHoe OCAdKOHaKOpJIeHne IMeNo MeCTo B 3TO BpemB INHdoCTaHe, ABCTpaNN, IOxHoN AmePike. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,625,900,839]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PacnapI Gotnno Otpa3nIcB V opMnpOBaHn naccNBHOOKpaHbHa NaCEBPO-BOCTOKe BaNTKn, BNOCLJeCTBN BOJIeueHHoB TImaHCKn OPOReHe3, INCBra3aHHoC HeN pAJeOpNFTOBOO CNCTEmbl BeNoRo Mopr Okolo 1,2 MlpJ LeT Ha3ad. 3Ta CnCTema o6pa3OBAHa y3KIMn LInHehBMn IpOrnBaMn, BNaINHAMn CeBPO-3aNaADHO npocTnpaHnB DpEBHem rpaHHTORHeNCOBOM KpncTaNJIuYeCKOM FyHdAmHeTe, KOTOpBle 3aONJHnLNCb TeppnReHNbIMN OTLOXeHnMn, Typ6UHTAMn CpeDHeRo n BepxHero pNphiE. OHexCKo-KaHdaJaakssKn paJIeOpNF CBOm CeBPO-3aPaAdHbIM KOHcOM pacKaIbIbAet BOCToHyU qactb BaJItnckoro UNTa, a BapenHeBOMOPckn (Me3eHckn) o6paMlAreT noCleDnH CceBepa N CeBPO-BOCTOKa. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,840,900,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KoHBePReHTHa Za3a ZnKla CbI3Ha co c6OpKo cynepeKoHTInHeTa PoDInH. B erO φopMnpoBaHnn npHHMaJn yactne oporeHmB nHTepBaJIe MeJdy 1300 n 900 mJn Jet [Li et al., 2008]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[685,914,702,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[97,923,576,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[95,84,487,182]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"K HIM OTHOCITcA φa3a CBeKOHOBEXCKO oporeHn Ha ITO-3aIaIe BaIITNCKOTo Ⅲnta B INTePbale 1,14-0,96 Mnpd JeT [Bogdanova et al., 2008]. Co c6opkO PoDInHn (1285-1120 mNHeT) COBnadaet BHepeHne KIM6epJIITOB n JaAMnpoNTOB KyXMO-JeHTnpa-KocTOMyKwa KapeHn (1230 mHN JeT) [BoXko, PpycaKoba, 2014]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,184,489,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepeKoHTnHeT POnHHa (1120-970 MJIH let) n CU (1120 - 650 mJH let). B 6OJIbIuHCTBe peKoHCTpykUni PoOnHHn 3aJaIHaY qAcTb IITa NOMEuaeTcB COBMecTHo C JaIbPeHTnei, IpeHlaIaNHe i Ama3OHNe [Buchan et al., 2001]. B BoCTOuHOJ qAChn BaJItnckOTo IITa, He 3aTPOHyTOOporeHnueCKIMn pIOuceCCAMn, IMeIo MeCTO pa3BVtNe pNΦTOReHe3a i nnIOMOBOrO MaMAtn3Ma. BdIb naCCNBHOJ OKpaINbI pNOJXaIOT pa3BvBaTbcR pNΦTOBbIe 3ObI bEJOMOPCKo pNΦTOBOc CNTEmbl. B HeONpOTepo3OE (No3dHem pNphiee) pNΦTOBbIe BPaIaNbI pNaEOpNΦTOBOJ CNTEmbl BeJoro MOpR npOdoJIkaII yrgy6JIbTbcR. B HIX OTKlAdlbVAlNCb TepRnREHhIe OTLOXeHInB ePxHero pNphiEr Ha py6Exe pNphiEr n BEHdaB OHexcko-KaHdALakssckOM pNaEOpNΦTe npoRbINcByUkAn3M ToJeTOBoC cepIN. No3dHepNΦeCKn MMnyIbC paCTraXeHn rTMaHcKo OkpaINbI BaJItnKc CB83aH c paCpAodm PoOnHHn i paKpbITnEM pNaeooKeaHa Jnetyc [BaanyEB, 2013]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,469,489,568]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Haayano KOHBePHTHO CTaDN paccMaTPnBaEMOTo cKla OTMeUeHO KOHTNHeTaalbHbIMN KOJIIN3IaM.NIabHeJlne H3 HIX npoCxOaINB IOXHom POJyAupn, YTO npuBEno K o6pa3OBaHIO MeRakOHNTHeTa ToHDbAna. IOp-BuDmOMy, BaLTNa 6bla OTHOCHTeBHO MOHOLTHbIM PrpnoIDHrTbIM φpaRMentom nocle paCnada PoDInHN. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,568,489,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3TOMy BpeMeHn COOTBETCTBYIOT KIM6epJIHTbI (759-756 MInJ IeT) nOJa KyycMo, paCNoLoXeHNHO BBOCTOuHOn ΦHHaHdNn 6JIn3 rpaHnUcbl C PocCnei [Boxxo, IpypcaKoBa, 2014]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,625,489,681]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bpe3yIbTaTe cJnHnEeBpa3nCKnx OCKoKOB PoDInm MExdy C60oN iC HOBoo6pa3ObaHHOI ToHDbHoI Obpa3OBAJcra CynepkOHtHeHT PaHHOTnI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,682,489,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepkoHTnHeT PaHOTn（\\~650-570MJIH JeT) n C4 (~650-320 mH JeT). HeonpoTePO3OyCKn CynepkoHTnHEt, O cyuceCTBOBaHN KOToPOro npednoJagAI MHOrue NCCJeIOBATEJI, 6bl BbIeJIEN B 1995 r. C. PayaIIOM. PaHOTn paCNoJARacb ceNkOM B IOxHOM pOnyUapNI, 7TO o6ycNoBnIO aTmIoJorNIO aTOTO Ha3BaHnA («PaH» - BCE n «HOTnyc» - IOXhbl). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,796,489,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CuyieCTBOBAHIO PaHHOTIN COOTBECTBYeT IIO-6aJIbHOe pa3BNTne OJeDeHEnB INHTepBaJe 750-580 MInIeT. B npedeJax paHHeOKeM6pnIcknx PnlatΦOpM JaBpa3NCKOTO pJa 3aBepShNI pa3BNTne DpeBHNe KOHTINHETAJIbHbIe pNΦTOBblc CnCTeMbI (aBJIaKOReHbI), cΦOpMnPOBAHHbIe B I03dHem pNΦee B CB3N C packpbItnEM PAJIeOOKeAHOB. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,84,897,283]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Kak yka3bIbAIOCBbIe, BpempaCnada PAnHOTnn npINHMaETcHa yPOBHe OKOJ0 570 MmH JeT. PaCnad ee npINBeN K O6OC6JIeHNIO ToHDbA- HbI, KOtOpaR B paHHem PAnEo3OE COxpaHraJa CBOIO UeJIbHOCTb N CTa6NJbHOCTb, TOrJa KaK B IpeJeLaX JaBpa3NN ShIo AKTNBHOE OKeaHOOBpa3OBaHne (OKeaHbI JaNETyc, PAnEOa3NaTcKn, IpOTOTetnc). HOOO6pa3OBaHHbIe OKeaHbI 3aMKHyIncB OCHOB-HOM B pe3yIbTaTe KaJIeDOHCKNX I repUHNCHX oporeHn. Ha CeBepo-BOcTOke BOCTOCHNo-EBpo-NeiCKORO KpatoHa, NO-BNIMOMy, Ipon3OWeJ nepeXoJ naccuBHOJ OKpaHbI B aKTNBHyIO N φOpMnPobAHne KaJOMcko-TImaHCKOTO oporeHa B INHTepBaIe OKOJ0 600-550 MmH JeT [PnykOB, 2008]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,283,897,695]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Kpy6exy 320 MInIeT KOJIIN3nHOBOO6pa-3OBaHHoJIaBpa3nn IToHDbAhnI npNBela K Bo3HNKHOBeHnIO PaHren. BocTochna Jactb BaItnCKORO UHTa He 6blJa 3aTPOHyTA oporeHneckmnpocecam. 3TO Bpem OTBeyaet npoRbLeHIO B ee PpeJeax PanaEO3OcKo TKeTOHO-MaMaTNUeCKo AKTNIBN3aU, KOTOPa BbPa3nIacB NIOHATn, pIoTOReHe3e n PIIOMOBm PLaTΦOpMeHHOM MaMaTn3Me. PAnHePaeO3Ockne INTPy3nn UTeLOOHbIX rpaHnTOB OTMeueHbHa KoJIbCKOM POlyocTPOBE (xpe6et KeIbbl). B cpeHem n PO3dHem PanaEO3OE o6pa3OBaJInCb XbHnHckn IIOBO3epckn INTPy3uHBhie USeIOChbE MaccNBbl B ceHTpaJIbHOJuaCTn POlyocTPOBa. O6a MaccBaB OCHOBHOM BBypaXeHbI HeΦeJIINHOBBIMn CneHNTAM. B cpeHem-NO3dHem DeBOHE npON3oUla peReHepaunr 3aIOXeHHbIX B pNFee pNTOBbIX 3OH n pa3BHTne BHYTpNIITHOr MOarMaTHMa. B IOROBOCTOCHN IORpe6EHNOJ qACTn PanaeOpNTOBoCNCTEmbl BeIoro Mopr (3ImHe6epExhbl paioh) n Ha eE NOJHTbIX 6Lokax FyHdAmehTa φOpMnyTOCTa N3BecThbIe IOnr KIM6ePINTOBbIX n 6a3aJIbTOBbIX Tpy6OK C CONYTCBYIOUMm m DaIKamn USeIOHOrcoctaba.C6OpKe PAnReN (485-320 MInIeT) n BPemeHn COOTBeTCTByET BHeIpeHne Tpy6Kn ΓpNb a B ApxaHreJIbCKo IPOBnUcn (372 MInIeT JeT) n KIM6ePINTOB TepCKoro Bepera KOLbCKORO POlyocTPOBa (375-372 MInIeT) [Apzamucuev and., 2001; BoXko, IpycaKaBa, 2014]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,697,897,809]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CynepkoHTHeT PaHRe (320-170 MJIH LeT) n CU (320-? mJH LeT). OOpMnroBaHne PaHRe npOn3OuIIO 320 mJH LeT ha3aD B cpeI HEM Kap6OHe B pe3yIbTaTe o6beIeHNHeN KpyN HbIX PAnEOMaTePnKOB TOndBaHbI N JaBpa3nn. OkOHcATEJBHa Jx e C6OpKa I KjYbMInaUsn CInTHOCTn CypeKoHTHeNTa 3aBepuINlacb Ha rpaHnCe BepxHero n CpeIeHero TpNaCa (230 mJH LeT). 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,369,211,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3aKJIoueHne ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[95,397,487,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"TeKToHnuecka 3BOJIOUng BOCTOuHOu qactu BaIITnCKORO uNTa B NOCJIeHNHe 3 Mnpd JET OTpaxKaET NOCJIeDOBaTEJIbHOCTb CyNepKOHTINHEHTaJIbHbIX UIKJIOB B ee NCTOpNI. 3Ta TeppntOpNJNCblTAla IINb DBA NOLbIX CyNepKOHTINHEHTaJIbHbIX UIKJa C PPOABJIeHNEM BCEx eRo a3. 3Tu NcIKJIbl CBZ3aHbI C φOpMnPoBAHnEM CyNepKOHTINHETOB KeHOpJIeHnI KOnym6nI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,511,487,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PaccMaTpNaBaemar TeppntOpnB I dpynx cynepeKoHTnHeHTaJIbHbIX zIKJiaX BXOJILA B COCTaB KpyNbIX KOHTnHeHTaJIbHbIX $\\phi$ paMentOB, HeNoCpeIcTeBHeHO He 3aTpOHyTbIX paCnaOM i C6opKOc CyepKoHTnHeHTOB, pa3BnBaIacb BO BHyTpNIHTHom pexIme, nCtIbTBaR TEKTOHO-TePMaJIb-HyIO aKTNbU3aCuIO NOB Bo3JeICTBnEM TEKTOHKn MaHTnHBix PIIOMOB. 3TN npOceCCb BblpaKaIINCb B npOraBLeHnx BHyTpPiNTHO rMaMaTH3Ma, BblcOKOTempePaTyPhoro MetamOpfN3Ma, KOHTnHEHTaJIbHO pNToToreHe3a, deOpMaunx. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,669,487,809]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BmecTe C TEM OTMeueTcE ueI IIOXO n3- yUeHHbIK KOHTPOJIb pa3BVITnB BHyTpINlTHoH TEKTOHKn mMaftMaTH3Ma BOCTOCHN qACTn BaIaTNCKOTO uNTa 0a3aMn CynePKOHInHeHTaJIbHbIX UnkNoB. TaK, o6uemy pacnaNy c6OpKe cynePKOHInHETOB BCerMeHTax, HENOCpeDCTBeHHO He 3aTPOHYtBX 3TUMn PPOuceCCAMn, COOTBETCTByET YcIIeHne PpOBJIeHn BHyTpIKOHInHEHaJIbHO rPfTOReHe3a N CBraHHOrO C HIM MaFMaTH3Ma. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,811,487,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IHTEHCNBHOCTb IPOUeCCOB TEKTOHO-MaMmTu-yeCKoAKTINBn3aun OnpeJeJalacb TaKxe CTeneHbIO ydaJIeHHOCTn TeppntOpn OT pa3BnBaIoXxCr OPOReHOB COOTBeTCTByIOxN cIKJIOB. KpaEBbieCaCTn TeppntOpn Ha rpaHnCe C HmN BOBKeJaLncB pnoToREHe3. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,84,615,98]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Литуразуа ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,112,897,252]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ApecToBa H. A., YeKyaIaEB B. I., ErOpoba IO. C., KyUePoBcKn I. A. 3BOJIOUma COCTaba N uNCTOuHnKOBO OCHOBhIX yIbTpaOCHOBhIX npoD npn nepeXoJe OT HeoapxEr K napeOnpoTePO3oIO B KapelbCKoN pOBuHnCm, BaItnckn 1nt // 3TaIb foPmnpoBaHn N pa3BHTNA IpOTepO3oIKoN 3emHOk Kopbl: cTpaTnIpaFMy, MeTamOpFm3M, MaMaTHm3M, reOINHaMnKa: MaTepnaJIb VI Poccnicko KOHfepenHnN o npOBeMaMreOJorHn N reOINHaMnK DOKEm6pr (CaHKT-PeTebpyr, 22-24 OKTЯ6pr 2019 r). CPi6.: CBoe n3daTeJIbCTBO, 2019.C.23-25. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,252,897,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ap3amacueB A. A., Bea $\\Phi$ ., Tla3HeB B. H., Ap3amacueBa J. B., MoTepo I. KoJbcka YeNochay npOBnHcN B napeO30e: oUeHka COCTaBa NepBnuHbIX MaHTnHbX paCnJIaBOB u yCIOBm MarMORHePaCuN // Poccnckn KypHaI Hayk O 3emne. 2001. T. 3, N° 1. C. 1-35. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,330,897,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Banaarhckn B. B., Top6yHOB IV. A., Mydpyk C. B. PaineonpoTePO3OcKne IaJIaHndCKo-KoJIbckn n CBeKOfeHNckn oporeHbI (BaTNIckn Ⅲnt) // BeCTHnk KoJIbckOro HayHoro ueHTpa PAH. 1916. N° 3(26). C.5-11. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,394,897,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Banyeb A.C.KoHTInHeNTaIbHbI pNΦToreHe3 cBepeBa BocToUHO-EbponeNcKoI PnAΦOpMbIB HeORee: reIoIroI, NCTOpIpa3BUNIg, CpaBHTeJIbHbI aHaJIIN3: Dnc. ...DOKT. reOI.-MmH. Hayk.M., 2013. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,446,897,483]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Божко H. A. Супековинецьна сизлuchов востори Земли // Вectн. Мск. ун-та. Сер. 4. Геюгия. 2009. № 2. C. 13-27. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,484,897,522]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Божко H. A., Пусakова H. A. O nepcneKeTивх кореннoi щлмазоносости Kapelьского Кратона // Рдьи металы. 2014. № 4. C. 5-13. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,523,897,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Божко H. A., Прусakoba H. A., Гомцев K. B. Oсобенhoeст TeКToHnueckoro CTpoEня Лапандбко-БелOMOPCKO rpaHnyIto-rHeиCOBOro nOra ca И nepcneKeTINbbl erO KopeHNoI aIma30HOCHOCtN // OteuectBeHHaReTeJOrn. 2021. N° 6. C. 45-64. doi: 10.47765/0869-7175-2021-10031 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,599,897,650]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BOLODUHEB O. I., Cna6yHOB A. I., Bu6nKOBa E. B., KOHNIOB A. H., Ky3eHKO T. I. ApxeiCKne 3KnOHTbI BeJOMOPCKORo NOdBnXHoro NOraC (BaTNIckn Ⅲnt) // PeTpOJIorna. 2004. T. 12, N6 6. C. 609-631. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,650,897,802]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Дokуна К. A., KoHIOB A. H., BaH K. B., BaHOBa T. B., LeshykoB B. C., XybaHOB B. B., GolobahOBa T. N. Палоэпороетоиckm ГаунлтовьйmetamopФИЗМ CB03pactOM ~ 2.45 Мрд Лет В подахБеломорско ЭКLOГNTOBОng Робици ФенhhockанДинавСКОTO StTa, PocSry // Этны Формпоганьиnpa3ВИТЯnpOTeP03OYCKOЗ ЗEMHОКОБы: CTpaTURpaФИЯ, MetamOpФИЗМ, МaramTN3M, reODINAMKa: MaTeprnabl Vl PocCnIckO KoHфepENZN NO npO6JIeMaMReOJOrN IN reODINAMKIN DOKeM6Pry (CaHKT-ПeTpE6ypr, 22-24 OKTЯбР 2019 r). CП6.: CBoe n3daTeJIbCTBO, 2019.C.68-70. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,805,897,843]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KoXeBnKOB B.И. ApxeIckne 3eJIeHOKaMeHHbIe IOra Ca KapelbCKOrO KpaToHa kak aKKpeUHOHHbIe oporeHbl. ITePo3aBOIDcK: KapHL, PAH, 2000. 223 c. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,843,897,895]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JIo6aay-KyueyHko C. B., CepreeB C. A., JIeByeHKO B. M., OBuHHNkoBA F. B., KOToba J. H., KpbIIOB I. H., JKOBoBeBA C. 3. BoJIo3epckn rHeiCoBbI KOMPJIeKc paHero apxera n erO cTpkyTypHO ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[685,914,705,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[97,923,576,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[97,85,489,893]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"MeTaMOpΦHuecka ΘBOLIOUry // N3OTOnHa rTeoxpOHOJIoRnДOKeM6pry.J.:Hayka,1989.C.14-45. \",\"Лубнha H. B., Сларов A. И. Реконструкшия Нeoархейскою сунерковинента Кенил end no napeomamгншьим и геологиеским данhhim // Вecthnik Mockobскою уньерситета. Сер. 4. Галогия. 2011. № 4. C. 23-30. \",\"MntpofoHOB.П. PaHHeIOKEM6pniCKa rTeOINHAMnka, MaMaTu3m n MetaJILOReHnKa KoJIbCKoI npOBUHcun//BecTHNK MFTY.2009.T.12,N#4.C.567-570. \",\"ПeТРВСКИМ. H., ПeТРВСКАЛ. C., БaHOBa T. B. ；\\nЗВОЛЮЦЯ Магматизma B reOJIoRnueCKо NCTOPmN\\nMypMaHcKOrO HeoApXeIckOrO kpaToHa // Marmatn3M\\nи MeTamOpФизм В nCTopnN 3eMЛ: XI BcepocciNCKoe\\nпeТрографчecкое COBEUaHne: Te3ncbl DOKlaNoB.\\nT.2.Ekatepin6bypr,2010.C.130-131. \",\"IpykoB B. H. TeKToHnKa I reOuHaMnKa TmHaHnD // CtpyKTypHO-BeUeCTBHeHHbIe KOMPJIeKcbl I npo6JIeMbI rEoUHaMnKn DOKem6pRnaHepO30iCKnx oporeHOB: MaT-JbIMeXdYHap. Hayu. KOHΦ. (III tTeHnI naMaTn C. H. IBaHoBa). EkaTepeH6Bypr: IΓnI YpO PAH, 2008. C. 104-109. \",\"PanhnDIOKEm6pN BaNTuCKOrO uTAt / PoI peI.B.A. TJIe6oBnUcKOrO.CN6.:Hayka,2005.C.711. \",\"CamcoHOB A. B., CTeNaHOBA A. B., Ap3aMaCueB A. A., CaIbHnKOBa E. B., JApnoHOBa IO. O., JApnoHOB A. I., ErOpOBA C. B. KpyHna MarMaTneCKaJI npOBnUZnB BoCToUHOJ ΦeHHOCKaHdN: napareHeTneCKoe pa3-Hoo6pa3ne B rEoDInHaMnueCKOM eINHCTBe // 3TaIbI φOpMnPOBaHnI N pa3BNTN I pOteP03oNcKoI 3EmHOJ KOpbl: CTpaTnRpaΦn, MeTamOpΦn3M, MaRMAtn3M, rEoDInHaMnka: MaTePnAbl Vl PocsnckoK KOhΦepenuN IIO npObIeMaM rEoIognn I rEoDInHaMnKn DOKeM6pNIA (CaHKT-PeTepe6ypr, 22-24 OKT6pbra 2019r). Cπ6.: CBoe n3daTeJIbCTBO, 2019.C.198-200. \",\"Cna6yHOB A.И. Apxeckneи n paIeIpoTePO3oIckne oporeHb: cpaBnHTeJIbHb aHaJIu3 reOduHAMUeCKNX npoueeccOB npuix foOpMupOBaHm (Ha npImepe FoHooCKaHINHABCKOTO uNTa) // 3TaIbI foOpMupOBaHm npa3BtNIA npOTepO3oIKo ZemHOJ KOpbl: CtpaTIRpaΦn, MetamOpΦn3M, MaMaTHzM, reOduHAMuKa: MaTePnaJIbVI PocnckO KoHΦepeHcNIO npOboJEMam reOJorN INreOduHAMuK NdoKem6pr (CaHKr-TeTe6Bypr, 22-24 OKT86p8 2019 r.). CPi6.: CBoe n3daTeJIbCTBO, 2019.C.210-212. \",\"Cna6yHOB A. H. TeoIognI r TeoIINHAMnka apxeiCKnx IOaBnKbIX IORcOB (Ha npImepe BEnOMOpCKoI npO-BHHuNΦeHHOCKaHdINHABCKOrO uNTa). PeTpO3aBOJcK: Kapen. Hayu. cHTp PAH, 2008. 294 c. \",\"Cna6yHOB A.И.,Ioba-ЖучЕнкO C.Б.,Bn6nKoBa E.B.,BaIarAHcKn B.B.,CopboHeH-BapД П.,BoIooNueB O.II,IIuNaHcKn A.A.CBeTOB C.A.,YeKyJaeb B.II.,ApectOba H.A.CTeNaHOB B.C.Apxei BaIantnCKoro Ⅲnta:reoiJorN, reoxpoHOJIOrN, reoiHaMnueckne o6ctahOBkn // TeOTeKToHnka.2006.N6C.1-29. \",\"CTeNaHOBA A. B., CamcoHOB A. B., CaJIbHnKOBa E. B., Ap3aMaCseB A. A., ErOpBa C. B., BeCeIobCKn P. B., NapHOBa IO. O., EpoΦeeBa K. Γ., CtaΦeeBa M. B. PaIeONpOtePozOienCKne MaΦuYeCKne DaIkn KapelbCKoN n Kolbcko-MypMaHcCKo N pOBoHNzM ΦEHNOckAhandHbAChKO r OHTa: reOxPOHOJOrN, KoppeLZuN, TEKToHnueCKne CLeIcTBn // 3TaIbI φOpMnPOBaHnY n \"]","page_idx":"9","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[507,85,897,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"pa3BnTna npoTePo3oNcKo 3eMHoN KOpb: cTpaTnrgpA. \\nfno, Metamopn3M, MaMaTHn3M, rOOnHaMnka: Ma- \\nTepnaJIb VI PocCNIcko KOHpeHcUNI IO npo6JIeMaM \\nrEoJIoRnN n rOOnHaMnKn DOKeM6pN (CaHKT-NeTpE \\n6ypr, 22-24 OKT86Pra 2019 r). CPi6.: CBoe n3daTeJIbCTBO, 2019.C.221-222. \",\"XaH B. E., BoKko H. A. NCTOpUeCKa rEOTeKToHnKa. JOKem6pni. M.: HeJa, 1988. 381 c. \",\"LlykHa E. B., AraueB A. M., TolOBnH H. H., IoxnJeHko H. П. 3KBnurpaHnyIrpHbIe 3KJIoIrntbI n3 KIM6epJIInTOB0I Tpy6Kn IIM. B. Frp6a: CBnIeTeJIbCTBa naJIeONpOteP03oNcKo cy6dyKznn Ha TeppnTOpnApXaHReIbckO aIma3OHocHoi npOBnCUn // DOKnaDbI Akademn Hayk. 2015. T. 462. C. 208-212. doi: 10.7868/S0869565215140248 \",\"Balagansky V. V., Gorbunov L. A., Mudruk S. V. Paleoproterozoic Lapland-Kola collisional orogen, Northen Fennoscandian. Baltic shield // Precambrian high-grade mobile belts: Extended abstracts. Петрозаюск: KapHLP RAH, 2014. C. 7-10. \",\"Barley M. E., Bekker A., Krapez B. Late Archean to Early Paleoproterozoic global tectonics, environmental change and the rise of atmospheric oxygen // Earth Planet. Sci. Lett. 2005. Vol. 238. P. 156-171. doi: 10.1016/j.epsl.2005.06.062 \",\"Bogdanova S. V., Bingen B., Gorbatschev R., Kheraskova T. N., Kozlov V. I., Puchkov V. N., Volozh Yu. A. The East European Craton (Baltica) before and during the assembly of Rodinia // Precambr. Res. 2008. Vol. 160(1). P. 23-45. doi: 10.1016/j.precamres.2007.04.024 \",\"Buchan K. L., Ernst R. E., Hamilton M. A., Mertanen S., Pesonen L., Elming S.-Å. Rodinia the evidence from integrated palaeomagnetism and U-Pb geochronology// Precambr. Res. 2001. Vol. 110, no. 1-4. P. 99-631. doi: 10.1016/S0301-9268(01)00178-4 \",\"Cadman A. C., Heaman L., Tarney J., Wardle R., Krogh T. E. U-Pb geochronology and geochemical variation within two Proterozoic mafic dyke swarms, Labrador // Can. J. Earth Sci. 1993. Vol. 30(7). P. 1490-1504. doi: 10.1139/e93-128 \",\"Connelly J. N. Accretionary growth of the Sveconorwegian province of the Baltic shield between 1,7-1,5 Ga and links to intracontinental magmatism // GSA Annual Meeting, November 5-8, 2001 Sess. 11: Proterozoic tectonic evolution of the Grenville Orogen in Eastern North America I. 2001. Pap. 11. \",\"Daly J. S., Balagansky V. V., Timmerman M. J., Whitehouse V. J. The Lapland-Cola orogen: Paleoproterozoic collision and accretion of the northern Fennoscandian lithosphere // European Lithosphere Dynamics. Geological Society, London memoirs. 2006. Vol. 32. P. 579-598. doi: 10.1144/GSL.MEM.2006.032.01.35 \",\"Li Z. X., Bogdanova S. V., Collins A. S., Davidson A., De Waele B., Ernst R. E., Fitzsimons I. C. W., Fuck R. A., Gladkochub D. P., Jacobs J., Karlstrom K. E., Lu S., Natapov L. M., Pease V., Pisarevsky S. A., Thrane K., Vernikovsky V. Assembly, configuration, and break-up history of Rodinia: A synthesis // Precambr. Res. 2008. Vol. 160. P. 179-210. doi: 10.1016/j.precamres.2007.04.021 \",\"Mansfeld J., Andersen T. Formation of New Crust in Scandinavia Between 1,75 and 1,55 Ga as Evident from the Gothian Units of the stfold - Akershus Sector, \"]","page_idx":"9","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[282,903,329,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[329,923,900,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[97,84,489,200]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"SE Norway // J. Conf. Abstr. EUG 10. 1999. Vol. 4, no. 1. P. 137. \",\"Pesonen L. J., Mertanen S., Veikkolainen T. Paleomesoproterozoic supercontinents - A paleomagnetic view // Geophysics. 2012. Vol. 48, no. 1-2. P. 5-47. \",\"Williams H., Hoffman P. F., Lewry J. F., Monger J. W. H., Rivers T. Anatomy of North America: thematic portrayals of the continent//Tectonophysics. 1991. Vol. 187. P. 117-134. doi: 10.1016/0040-1951(91)90416-P \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[97,212,200,226]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[97,237,489,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Arestova N. A., Chekulaev V. P., Egorova Yu. S., Kucherovskii G. A. Evolution of the composition and sources of basic and ultrabasic rocks during the transition from the Neoarchean to the Paleoproterozoic in the Karelian province, Baltic Shield, Russia. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 23-25. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,416,489,494]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Arzamastsev A. A., Bea F., Glaznev V. N., Arzamastseva L. V., Montero P. The Kola Alkaline Province in the Paleozoic: an assessment of the composition of primary mantlemelts and magmogeneration conditions. Rossiiiskii zhurnal nauk o Zemle = Russian Journal of Earth Sciences. 2001;3(1):1-35. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,494,489,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Balagansky V. V., Gorbunov L. A., Mudruk S. V. Paleoproterozoic Lapland-Kola collisional orogen, Northen Fennoscandian. Baltic Shield. Precambrian high-grade mobile belts: Extended abstracts. Petrozavodsk: KarRC RAS; 2014. P. 7-10. 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Continental rifting of the north of the East European Platform in the Neogee: geology, history of development, comparative analysis: DSc (Dr. of Geol.-Miner.) thesis. Moscow; 2013. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,686,489,750]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Barley M. E., Bekker A., Krapez B. Late Archean to Early Paleoproterozoic global tectonics, environmental change and the rise of atmospheric oxygen. Earth Planet. Sci. Lett. 2005;238:156-171. doi: 10.1016/j.epsl.2005.06.062 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,751,489,814]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bogdanova S. V., Bingen B., Gorbatschev R., Kheraskova T. N., Kozlov V. I., Puchkov V. N., Volozh Yu. A. The East European Craton (Baltica) before and during the assembly of Rodinia. Precambrian Res. 2008;160(1): 23-45. doi: 10.1016/j.precamres.2007.04.024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,814,489,866]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bozhko N. A. Supercontinental cyclicity in the history of the Earth. Vestn. Mosk. un-ta. Ser. 4. Geologiya = Moscow University Bulletin. Series 4. Geology. 2009;4(2):13-27. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,866,489,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bozhko N. A., Prusakova N. A. On the prospects of the indigenous diamond content of the Karelian cra ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,84,895,109]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ton. Rudy i metally = Oresand Metals. 2014;4:5-13. (In Russ.) ","text_format":null,"text_level":null,"type":"ref_text"},{"bbox":"[507,110,895,186]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bozhko N. A., Prusakova N. A., Gromtsev K. V. Features of the tectonic structure of the Lapland-White Sea granulite-gneiss belt and prospects of its indigenous diamond content. Otechestvennaya geologiya = National Geology. 2021;6:45-64. (In Russ.). doi: 10.47765/0869-7175-2021-10031 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,186,895,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Buchan K. L., Ernst R. E., Hamilton M. A., Mertanen S., Pesonen L., Elming S.-A. Rodinia the evidence from integrated palaeomagnetism and U-Pb geochronology. Precambr. Res. 2001;110(1-4):99-631. doi: 10.1016/S0301-9268(01)00178-4 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,251,895,314]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cadman A. C., Heaman L., Tarney J., Wardle R., Krogh T. E. U-Pb geochronology and geochemical variation within two Proterozoic mafic dyke swarms, Labrador. Can. J. Earth Sci. 1993;30(7):1490-1504. doi: 10.1139/e93-128 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,315,895,391]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Connelly J. N. Accretionary growth of the Sveconorwegian province of the Baltic shield between 1,7-1,5 Ga and links to intracontinental magmatism. GSA Annual Meeting, November 5-8, 2001 Sess. 11: Proterozoic tectonic evolution of the Grenville Orogen in Eastern North America I. 2001. Pap. 11. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,391,895,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daly J. S., Balagansky V. V., Timmerman M. J., Whitehouse V. J. The Lapland-Cola orogen: Paleoproterozoic collision and accretion of the northen Fennoscandian lithosphere. European Lithosphere Dynamics. Geological Society, London memoirs. 2006;32:579-598. doi: 10.1144/GSL.MEM.2006.032.01.35 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,469,895,648]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dokukina K. A., Konilov A. N., Wang K. V., Bayanova T. B., Sheshukov V. S., Khubanov V. B., Golovanova T. I. Paleoproterozoic granulite metamorphism with an age of $\\sim 2.45$ billion years in rocks of the White Sea eclogite province of the Fennoscandian Shield, Russia. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 68-70. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,648,895,674]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Glebovitskii V. A. (ed.). Early Precambrian of the Baltic Shield. St. Petersburg: Nauka; 2005. P. 711. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,674,895,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Khain V. E., Bozhko N. A. Historical geotectonics. Precambrian. Moscow: Nedra; 1988. 381 p. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,700,895,738]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Kozhevnikov V. I. Archean greenstone belts of the Karelian craton as accretion orogenes. Petrozavodsk: KarRC RAS; 2000. 223 p. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,738,895,840]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li Z. X., Bogdanova S. V., Collins A. S., Davidson A., De Waele B., Ernst R. E., Fitzsimons I. C. W., Fuck R. A., Gladkochub D. P., Jacobs J., Karlstrom K. E., Lu S., Natapov L. M., Pease V., Pisarevsky S. A., Thrane K., Vernikovsky V. Assembly, configuration, and break-up history of Rodinia: A synthesis. Precambr. Res. 2008;160:179-210. doi: 10.1016/j.precamres.2007.04.021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,840,895,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lobach-Zhuchenko S. B., Sergeev S. A., Levchenkov G. M., Ovchinnikova G. V., Kotova L. N., Krylov I. N., Yakovleva S. Z. Vodlozersky gneiss complex of the Early Archean an dits structural and metamorphic evolution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[685,914,705,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[97,923,576,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[97,84,487,123]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Izotopnaya geokhronologiya dokembriya = Isotopic geochronology of the Precambrian. Leningrad: Nauka; 1989. P. 14-45. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,123,487,187]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lubnina N. V., Slabunov A. Reconstruction of the Neoarchean supercontinent Kenorland based on paleomagnetic and geological data. Vestnik Moskovskogo universiteta. Ser. 4. Geologiya = Moscow University Bulletin. Series 4. Geology. 2011;4(4):23-30. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,187,487,238]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Mansfeld J., Andersen T. Formation of New Crust in Scandinavia Between 1,75 and 1,55 Ga as Evident from the Gothic Units of the stfold - Akershus Sector, SE Norway. J. Conf. Abstr. EUG 10. 1999;4(1):137. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,238,487,290]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Mitrofanov F. P. Early Precambrian geodynamics, magmatism and metallogeny of the Kola province. Vestnik MGTU = Bulletin of the Moscow State Technical University. 2009;12(4):567-570. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,290,487,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pesonen L. J., Mertanen S., Veikkolainen T. Paleomesoproterozoic supercontinents - A paleomagnetic view. Geophysics. 2012;48(1-2):5-47. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,328,487,429]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Petrovsky M. N., Petrovskaya L. S., Bayanova T. B. Evolution of magmatism in the geological history of the Murmansk Neoarchean craton. Magmatizm i metamorfizm vistorii Zemli: XI Vserossiiskoe petrograficheskoe soveshchanie: Tezisy dokladov = Magmatism and metamorphism in the history of the Earth. Proceed. XI All-Russian petrographic meeting. Vol. 2. Ekaterinburg; 2010. P. 130-131. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,431,487,546]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Puchkov V. N. Tectonics and geodynamics of ti manides. Strukturo-veshchestvennye kompleksey i problemy geodinamiki dokembriya fanerozoiskikh orogenov: Mat-ly mezhdunar. nauch. konf. (III chteniya pamyati S. N. Ivanova) = Structural-material complexes and problems of geodynamics of the Precambrian Phanerozoic orogens. Proceed. Scientific conference (III Readings in memory of S. N. Ivanov). Ekaterinburg: IGiG UrO RAN; 2008. P. 104-109. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,547,487,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Samsonov A. V., Stepanova A. V., Arzamastsev A. A., Sal'nikova E. B., Larionova Yu. O., Larionov A. I., Egorova S. V. The large magmatic province of Eastern Fennoscandia: paragenetic diversity in geodynamic unity. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemmag geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 198-200. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,713,487,738]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Shchukina E. V., Agashev A. M., Pokhilenko N. P., Golovin N. N. Equipgranular eclogites from the V. Grib ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,84,895,135]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"kimberlite pipe: evidence for Paleoproterozoic subduction on the territory of the Arkhangelsk diamondiferous province. Doklady Earth Sciences. 2015;462(1):497-501. doi: 10.1134/S1028334X15050165 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,136,895,302]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Slabunov A. I. Archaean and Paleoproterozoic orogens: a comparative analysis of geodynamic processes during their formation (on the example of the Fennoscandian Shield). Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 210-212. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,302,895,353]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Slabunov A. I. Geology and geodynamics of Archean mobile belts (on the example of the White Sea province of the Fennoscandian Shield). Petrozavodsk: KarRC RAS; 2008. 294 p. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,353,895,442]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Slabunov A. I., Lobach-Zhuchenko S. B., Bibikova E. V., Balagansky V. V., Soryonen-Ward P., Volodichev O. I., Shchipansky A. A., Svetov S. A., Chekulaev V. P., Arestova N. A., Stepanov V. S. Archaean of the Baltic Shield: geology, geochronology, geodynamic conditions. Geotektonika = Geotectonics. 2006;6:1-29. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,442,895,635]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Stepanova A. V., Samsonov A. V., Sal'nikova E. B., Arzamastsev A. A., Egorova S. V., Veselovskii R. V., Larionova Yu. O., Erofeeva K. G., Stafeeva M. V. Paleoproterozoic mafic dykes of the Karelian and Kola-Murmansk provinces of the Fennoscandian Shield: geochronology, correlation, tectonic consequences. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 221-222. (In Russ.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,636,895,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Volodichev O. I., Slabunov A. I., Bibikova E. V., Konilov A. N., Kuzenko T. I. Archean eclogites of the White Sea Mobile Belt (Baltic Shield). Petrologiya = Petrology. 2004;12(6):609-631. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,687,895,738]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Williams H., Hoffman P. F., Lewry J. F., Monger J. W. H., Rivers T. Anatomy of North America: thematic portrayals of the continent. Tectonophysics. 1991; 187:117-134. doi: 10.1016/0040-1951(91)90416-P ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[152,760,838,786]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IocTynna B peJaKuio / received: 28.03.2024; npinra T K nybIkaun / accepted: 23.09.2024. ABTOp 3aBnT o6 OTCyTCTBn KOHfLkTa HHTepecoB / The author declares no conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,820,307,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CBEDEHNOOBATOPE: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[97,840,289,853]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Божко Нikuолай Аndрeeвч ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[97,856,465,877]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Д-р reOl.-MnH. HayK, npofoeccop KafoepbI DInHaMnueckoI reOJOrn ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[121,883,290,894]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"e-mail: bozhko@yandex.ru ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,820,643,833]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CONTRIBUTOR: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,840,616,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bozhko, Nikolai ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,855,710,866]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dr. Sci. (Geol.-Miner.), Professor ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[295,914,317,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[329,923,900,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[97,219,221,233]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ydk551.248.1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,247,828,307]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ГEOДИНAMNUECKAЯ эВOLЮЦЯ BOCTOчHOJ YACTNBAЛТиСКОТо LцNTAВ PAMKAX CYNEPKOHTINHEHTAJьHOTUNKЛINHOCTHI \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,321,233,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"H.A.Бохко \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,349,786,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MocKBcN rOcyIaPCTBeHHb yHbEpcNTeT mHeu M. B. JOMOHOCBa, FeONOrnueckn foKyJIbTeT (JeHHcKne ropbl, 1, MockBa, PocSna, 119991) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,423,710,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B pe3yIbTaTe npOBeHNO aHaJIa3a reOuHAMNK BOCToHOn qactn BaIITNCKORO ⅢNTa B NocJedHne 3 Mnpd JeT ee NCTOpn Ha oHe cyNEpKOHTInHeTAJIbHOU CKJIINHOCTH yCTaHOBJIeHO NOLHoe uACTne 3TOJ TepnTOPn B DByX CyNEpKOHTInHeTAJIbHbIX CUNKJax, CBa3aHHbIX c pa3BnTHeM cyNEpKOHTInHETOB KeHOpJIeHn I KONYM6n. B TeueHne OCTaJIbHbIX UKNIOB paCCMaTPBaEMar TepnTOPn HAXOINAcB B COCTabe 60Jee KpyNHbIX KOHTInHeTAJIbHbIX φpaMeHTOB, He yuaCTByr HEnOcpeDCTBeHNO B CO3JaHm n I paCNaDe cyNEpKOHTInHETOB, INCbIbIBaR BHYTpNIITHbI pEXIM IOB BLINHEm TEKTOHNK MaHTNIbIX PIIOMOB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,541,709,566]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KJIIOUeBbIe CNoBa: cynepeKOHTnHErT; cynepeKOHTnHErTaIbHbIy cIKJI; BHYTpNIINTHbIy peKIM; MaMAtu3M; pNΦToREHe3; MaHTnHbIy PJIOM \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,579,709,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Для ситураху Ситу Вангьдддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддддд徳сьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпcьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсьпсay CnKInuHocT// TpydBi Kapelbckoro Haynoro cHTpa PAH. 2024. N6 6. C. 5-16. doi: 10.17076/geo1887 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,648,769,676]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"N. A. Bozhko. GEODYNAMIC EVOLUTION OF THE EASTERN PART OF THE BALTIC SHIELD AGAINST THE BACKGROUND OF SUPERCONTINENTAL CYCLICITY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,686,791,701]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lomonosov Moscow State University, Faculty of Geology (1 Leninskiye Gory, 119991 Moscow, Russia) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,709,709,800]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An analysis of the geodynamics of the eastern part of the Baltic shield in the last 3 billion years of its history, set against the background of supercontinental cyclicity, showed the territory was fully involved in two supercontinental cycles associated with the development of the Kenorland and Columbia supercontinents. During the rest of the cycles, the territory was part of larger continental fragments and was not directly involved in the creation and disintegration of supercontinents, experiencing an intraplate regime under the impact of mantle plume tectonics. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,809,707,836]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: Supercontinent; supercontinental cycle; intraplate regime; magmatism; rifting; mantle plume \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,845,709,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For citation: Bozhko N. A. Geodynamic evolution of the Eastern part of the Baltic shield against the background of supercontinental cyclicity. Trudy Karel'skogo nauchnogotsentra RAN = Transactions of the Karelian Research Centre RAS. 2024. No. 6. P. 5-16. doi: 10.17076/geo1887 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,80,643,119]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TpydBi KapeJIbCKOrO HayHOrO ueHTpa PAH. 2024. N° 6. C. 5-16 Transactions of the Karelian Research Centre RAS. 2024. No. 6. P. 5-16 DOI: 10.17076/geo1887 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[512,125,709,153]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPINHNAJIbHbIE CTATbN Original articles \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[685,914,700,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[97,923,576,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. 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Pn3TOM NOI TepMNHom CynepKoHTInHeTaJIbHbINzIKL》(CU) IOHmaeTc RkyroBOPOT pOceccOBB LINTOCfpe, BNaJale PnpBODaIuxK O6beDInHeHIO BCExC CyUeCTBOBabUHX Ha 3EmLe pa3o6uEHbIX KOHTInHeTAJIbHbIX MACC B EdINhBI CypePKoHTInHeT, erO NocJeDuOSei φpaRMeHTaUNIpaCnady, a Ha 3aKJIuOHtJIbHoN CTaDN - K C6OpKe HOBOr CypePKoHTInHeTA. PocJeDoBaTEJIbHOCTb CLcoCTaBIAET cypePKoHTInHeTaJIbHyUZIKLIuHOCtB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,441,485,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B ctpykType IIO6oro CL npednoIaraeTc cyIeCTBOBaHne DByx CTaI,OTpaKaIOuXn DBa\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,85,897,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COCTOHNJIITOCΦeBi: C06CTBHeHNO CynePKoHTINHETAlbHOI (ODHH KOHTINHEHT - ODNH OKeaH) IN MEXCynepKoHTInHETAlbHOI (HeCKoJIbKO KOHTInHETOB IN HeCKoJIbKO OKeaHOB) [BOXko, 2009] (pnc.). KaxdAraN3 3tIX CTADNI COCTOnT N3 DByX $\\\\phi a3$ . B pamkax nepBoi CTADNI pa3JnUaOTcra $\\\\phi a3a$ arIOMepaucn, IIN cJnHnR (cJnPAnHn) KOHTInHETAlbHbIX $\\\\phi$ paarmeHToB HOBOOpa3OBaHHOM cynePKoHTInHETe n $\\\\phi a3a$ erO JeCTpyKuIN B BVnde npoRbIeHn KOHTInHeTAlbHoro pIoTOReHe3a, HameaIOx6byuipn pacnaD. NepBaar $\\\\phi a3a$ (Oparmentaun) BTOPO CTADNI CL, COOTBeCTByIOUaIpaCnpdy, XapaKTepn3yETc8 bICTpblm CNpeDINrGM B packpbIBuNXcRA OKeaHax, a BTOPAJ $\\\\phi a3a$ (KOHBepReHUn) - AKTNHBIMn PPOuceCCAMN cy6dyKUnn KOLIIu3N, PNBOJaUuMn K 3akpbI-TnM OKeaHOB, FOPMnPOBaHnM KOJIIN3IOHHbIX OPOREHOB IN C6OpKe HOBOrO CYnePKoHTInHeTa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,340,897,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B hactoiee Bpem OTCyTcByet o6eepnnaTaa OueHka dInTeIbHOCTn CU. B hauem aHaJIne3e IcnoJb3yeTc zKlnuHocTb c npOdoJIxntelbHOCTbIO CU B 400 mIn let (pnc.) [BoXko, 2009] c fazamn arIomepaun (90 mIn let), dcETpykun (60 mIn let), pfarmentaun (85 mIn let) n KOHBeprEun (165 mIn let). 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Pn NTOM BaxHO BbIaBNTB BlnHne CLn Ha XOD rOOnHAMnueCKNX N DpyrNX pOuceCCOB B KOHKpETHOM peNoHe Ha OCHOBE NMeIoUxxCra rEOJLOrO-TeOXPOHOJOrnueCKNX DaHHbx. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,169,489,440]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B 3TOM pIaHe TepnTOPn BaIITNCKOTo npRedCTabJIeTcR NOxODJaSeI dIy TaKOro aHaJIi-3a, yUHTbIBaI 60rAByI DOKEm6pNIckn MaTePnAJI, CoDEpXaUHNCsR B HeI, n To O6CToR TeJIbCTBO, UTO BCE cyupeKoHTnHEnTbI Ha 3eMJe, 3a NCKJIIOUChENm PAnHRe, CyUeCTBOBaII B DOKEm6pNI. BaIITNckn 5nt XapakTePn3yETcR dLIteJIbHbIM N3UeHNMe, BKIOUay paOtBt 3ApYbExHHbIX n OTeYeCTBeHHbIX KlaACCNOB ReOJOrn DOKEm6pNIa, aTAKKe BbldauOuIeCSc NocJeDyUOuNe I COBpeMeHNbIe NCCLeIDOBAHn. Ha OCHOBHn 3TIX BeCbMa MHOroUcJIeHNbIX pa6OT B BoCTOuHoi qAcTN BaIITNCKOTo 5NTa CCB HA IO3 B OCHOBHOM BbldJIaIOTcR YeTBIpe KpyHbIE TEkTOHnueCKne EdyHnCi: Kolbckn apXeIckn KpaToH, IaIpaHndcko-BeIoMOPCKn apXeIcko-PAleONpOTepo3Oiockn rpaHyJIInTO-rHeiCOBbI pOrc, Kapelbckn apXeIKckn KpaToH n CBekOfoHHckn paHHeNPOTepo3Oiockn oporeHnueCKn Ioc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,441,489,482]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Hnke paCCMOrpeHbIOOCo6eHHOcTNIeOINHaMnKu BOCTOuHOJuaTcBaIaTmckCkOrO uNTaBzNKJax pa3JIuHbIX CynePkoHTInHeHTOB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,483,489,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepkoHTHnENT Baan6apa (~3120- 2970 mIh let) n CU (~3120-2720 mIh let). Iod Takim Ha3BaHnem T. 3eepcom 6bl BbIeJen CynepkoHTHnENT, o6pa3OBaHHb B INTEpBAJIe 3,3-3,1 Mnpd let, o6beDInHbWm HbIHe pa3O6uHbIe KpaTObI NpIL6apa n KaanBaAJIb, npedCTabJIauOuIe dpeBHeuIe Me3OapxeckKne rpaHNT-3eJIeHOKaMeHHbIe oIbactn (r3O). PpeIIOlaRaEmbIe rpaHnUbI n 3TOrO cynepkoHTHnEHTa n Cl DaHbI corglaCHO bblweyka3AHNO cxeme uKNiHuOCTn. CpaBHNTJIbHbI aHaJIIN3 NOKa3bIBaET, UTo B pRae HeoApXeNCKNX KpaTOHOB O6hApYxNBAOTcR dpBHeuIe NaIEO-Me3OapxeckKne cerMentbI (npOTokpatoHbI), OkpyXeHHbIe HeoApXeNCKMn O6pa3OBaHHaMn, KOtOpbIE MOyT paccMaTPNBATCBsKa K«raPa\\\" KOHCOLndaun, fpaarmEtbl 6OJIee 6OUnPHOB BaANbApbl, TaKne kak 6LOKn ToKBe B KpaTOHe 3Im6a6Be, AHTOn B KpaTOHe CLeB n DpyrVe. B 3Tom IIaane INHTpec PpeDCTABJAE T BodIo3epckn 6LOK B ITOBOCTOHOJ qACTn KapelbCKoro KpaTOHa [JIo6aUxUyeHKO n dp., 1989 n dp.]. OH BblJeTcR kAc OblaCTb Pa3BHTnJaDpeBHeuIX Ha BaANTNCKOM uITe IIOPOd, PpeDCTABJIeHHbIX O6pa3OBaHHaMn TOHaINT-TpOHDbEMNT-rgaHODInOpTobOoi (TTF) accouinaun C Bo3pactom 6OJIee 3,O mlpI let, IN IO CBOemy TEKTOHueCKOMy CTpoEHIO B 3TOM OTHOWeHN CNODeH C DpyrIMN IpOTOKpatoHAMN, yIOMyHyTBIMN BVIIe. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,84,899,169]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PacnaBaaJbapbIOTMeueH B reoJorueckOJIeTOnNCi BaxHbIM CO6blm - 3aJIOKeHnEM Ipa3BHTnEM IO3dHeApXeNCKoR THepeauN 3eJeHOKaMeHHbIX NORCOB, 3BOJIIOUra KOTOpBX npINBeJaK Co3DaHNI MHOToUcJIeHHbIX rpaHNT-3eJeHOKaMeHHbIX OBJaCTeI (Γ30) - apXeNCKx KpaTOHOB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,169,900,369]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Для Формировая Фундамента Карьского Кратона И спользуется Akкpeцнонho-Kоли-Зонная Гешиhamческа модь писоеденны Молобх Террейнов К древим Континецталь ядра Зеленокамених посов [Кожевников, 2000].В олочne ot Вodлозерско 6лoka -ядра мозорхейский консолдациochoьная чась Сеньталов Карели образовалась руtem akреси -последовatelбогоПрочileенners Серни Роздемрхейckeхх OCTpoВьх дуг с boctOKа на заад. Akреси Террейнов Okonto 2,83-2,75 млрд лет сmedиль сь колизи-й, korда必将 сфорmirobа на COврemeннаястуктура Карельского кратона. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,369,900,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ΦορΜιρΟΒαΗΝ ΚόβκΚΟΓΟ κραΤΟΗ [Μιτρο-φαΝΟ, 2009] B COCTΑBE MγρΜαнςΚΟ ΣΙΟΚΑ, 3εληδινικασμανηνηθο πογα Μολμούερο-Bοροῦνι Μ ΚόβκΚΟ-HɒρβεχκΚΟΓΟ ΣΩΜΕΗ 3ανερψινιούς ἀνυδεχεν 2,74 Μπρι.Д. Μεινικυρυετχαν ἡνεριδενημει Μ ΙΝτρύγεινηθου Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει $\\\\text{卡}$ Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει Μαντρούμει \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,469,900,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ha ochobahn no6o6eHn daHHbIX [PaHHn... 2005; Cna6yHOB n np.. 2006; Cna6yHOB, 2008, 2019 n np. ] moxno npednoJoxntb cJeDyoUyIO reOdnhamNueckyUo moelb. K py6exy OKoIoo 2,75 mnpd letc fOpMnPOBaIncB DBA cTa6NJbHbIX 6loka KOHTINHeTaNBJHOKopbl - KoJIckn u KapeIbCKn, KOtOpBie 6bln pa3deJeHbI BeLOmOPCKIM OKeaHnueckn BaccseHOM. HauHna npimepHo c 2,72 mnpd let eT 3ta cnCTema BVCTynla B KOJIIN3IOHNHYO CTADIO PA3BNTN, KOtOpAa MapKnpyETc npoABLeHnMI NOKPBOHOn TEKTOHKN, BlicOKo6apuueckoro MetamOpΦn3Ma, rpaHnTO- o6pa3OBaHneM u B pe3yIbTaTe - o6pa3OBaHneM BeLOmOPCKORo KOLIN3IOHNHO TPOCA. KoJIIN3N4 KapeJIbCKORo I KOJIbCKo-MypMaHcCKORo 6LoKOB (cynepTepeRnHO) DaTnpuyETc npENoDM 2,71-2,68 mnpd let [Cna6yHOB, 2019]. B cTpykTYPHom OTHOWeHn OHa BbIPA3INAcB B CO3DaHn apxeckoro KapelbCKoro - BeLOmOPcKO-KolbcCKORo NaIeOKOTInHeTaNBJHOrO cerMeNTa. B nOJIb3Y TaKOH TPAKTOBKn IVCTOPIN PA3BVNTN BoLomOPCKORo PONCA MOXET CBNDeTEbCTBOBaTb IN pNcTyCTBnE 3DeCB apxecknx EKnOrITOB [BOIoNueBn I np.. 2004], KOtOpBie, PO-BvIDNMOMy, OTPaxaIOT cy6dyKUnIO u 3akpyITne OKeaHnueckoro baccSeHa, 3a KOtOpBIM NocleIOBaJa KOJIIN3N, O6pa3OBAHne BeLOmOPcKOrO IOraCa n CO3dAnHe eDInHO R KOHTINHeTaNBJHOrO o6pa3OBaHn, BOweJlWho B COCTAB CyNEpKOHTINHeTaN KeHOpNeHd. B erO foOpMnPOBaHn, TAKIM Obpa3OM, BblJeIANTOTCE BCE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[695,914,702,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[99,923,576,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TpydBi Kapelbckoro HaynHoro zentpa Pocsncko akaaemn hayk. 2024. N6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[95,85,489,125]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"fa3bCynepeKoHTnHeHtAJIbHOrO cUKNla: cyuecTBOBaHne DpeBHeRo CynepeKoHTnHeHtA,ero pacnaad nC6opka HOBOrO. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,127,489,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepkoHTHHeT KeHOpJIeHd (~2720- 2570 mJH JET) n CU (~2720-2320 mJH JET). IooDHeapXeIckn CypeKoHTHHeT C Bo3paCTOM OKOLO 2,7 Mnpd JET 6bIIN BbIeJIeN IOd Ha3BaHNc Em PaHRe 0 [XaHn, BoXko, 1988]. X. BInlbamc c CoABTopaMn B 1991 r. [Williams et al., 1991] IpeIIOxII IN TepMnH «KeHOpJIeHd» dIy HeoApXeIckOrO CypeKoHTHHeTa, KOToPbI NbIHe IuPOKO IcNoJIb3YeTcB R eOJIoRnueCKO IInTePaType [HaNP., Jy6HnHa, Cla6yHOB, 2011]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,270,489,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CTpykTypa BOCTOHNo YaCTn BaJItnCKOrO uNTaB COCTabe cynepeKoHTInHeNTa KeHOpIeHd anAIO-rnHa CTpykType KpatoHa KaIaxApn B IOxHoN AΦpKe, COCToJUero n3 KpatoHOB KaanBaalb N3IM6a6Be, pa3JeHnBix rpaHyNJTOBbIM NOrCOM JImnOIO, nJN CeBepo-KtAnCKoro KpatoHa cDBym8 6IokAMn, pa3JeHnBIMn TpaHcSeBepOKiTaNCKM NOrCOM. 3TO BpeMg OTMeueHO npoRBJHeHNEM BHYTpNIHTHOrO MarmAtn3Ma n TEKToHKn. B npedeJax KapelbckO npOBnCmN BblJeHbI 6a3nt-YJbTpa6a3NTOBbie KOMPLeKCb i INTEpBaJa2,74-2,60 mIN JET B BVide MHORofoa3hBix CaHyKtONIOB, KOMATNUTOB, 6a3aJIbTOB, a TaKKe INHTpy3n I daek 6a3NTOB [ApectoBa n dp., 2019]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,469,489,611]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PacnaKehOpJHeHaNIO6pa3OBAHne MoIobIbIX OKeaHOB OXBaTnIN B OCHOBHOM TeppntOpnnCOBpeMeHHbIX IOXHoN ABCTpAlIn, ANTpAKTnDbI, INdIn, CeBepHoro KnTaI. Ix 3akpytne npuBeNoK npoRbJIeHNIO KOJIIn3N i oporeHn i φOpMnpoBaHnIO cynePKoHTnHEHTa JTylnra [Boxxko, 2009]. B KpaToHax 3TxN KOHTnEHTOB OTMeuaOTc npoCeCbIMarMaTHn3Ma, DeΦopMaun N MeTamOpΦn3Ma B nHTepBaIe 2,56-2,42 MlpJ neT [Barley et al., 2005]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,612,489,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B Ebp3nn TeKToHnueckne npocecbb BpeMe- Hn paCnada n φOpMnPoBaHnna HOBO rCynePkoHTnHeTa npoBJIaNcB npenMyIeCTBeHNO B BVnde BHyTpInIINThbIX TeKTOHO-TepMaJIbHbIX CObItn. 3TO OTHocNTcra N K TeppntOpnn BaJtniCKOrO IuTta, rDe OTmeyaeTcR OTCyTCTBVe KOp0o6pa3yIOuX npoCeCCOB, CnHXPOHHbIX O3HaueHHbIM BblSe, n IpOReBLeHne PIIOMOBbIX TeKToHnKn N MaGMaTI3Ma. 3ToN 3Noxe NO BpeMeHN 3deCb B 3NaHTeJIbHO CTeNEHn COOTBeTCTByET CymNCKO-CapNOJnnckn 3tan pa3BnTna (2,55-2,30 Mnpd JeT), npoxoDbHn BO BHyTpInIINTHOio6ctaHOBKe. INHpU3NBhI MaMAtn3M CymNCKO-capNOJnnCKORO 3tana HocNT TnInuHbI KpaToHbI XapaKTep n yHnKaJIeH Obpa3OBAHnem paCCIoEHHbIX Ylb-TPamaΦHT-MaΦNTOBbIX PnyTOHOB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,839,489,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Базntы палонореторозбкого отana (2,45-2,41 млрд лeТ)В Kapelьсков повици рпсдставны КрупнblIMп раслоЕнblIM ИНтузямN:Буразковский,ИнтузямОlaангсков Гупbl, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,84,900,198]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KOMaTnITamn BeTpEHO rO NOrCa, a TaKxe CymuCKIMN 6a3aJIbTaMn n DaIkAmn BO BCex DOMEHAX npOBuHcUIN [ApecToBa n dp., 2019]. BHeDpeHne 3Tnx MaRMaTnTOB pOnCXoDnIO B BVNe IPOrCOB, pInypOceHHbIX K pNΦTAM CeBepo-BOCTOCHOrnpocTnpaHn: KEmi-KoJlncMa (ФинlaHДЯ) - KInBaKka - KyHdo3epo (C Kapelna) n BypaKOBcKO-MohAcTbIpckOMy (IOB Kapelna). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,198,900,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Даики баиюв с Ворстом OKОLO 2,5-2,4 млрд яет установны в Кolyбко-Mурmaнский и Kapelьков повинцях [Стоно на，在..，2019], cootbetctbya по Врemeи дectpyk-ции сунерковшеньта. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,270,900,526]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marmatn3M 3TOrO BpeMeHx XopoIoo pa3BNT B npedeJax BeIOMOpCKoI NOraCBA BVnDE 60JIbIoTO OuIcna CpeDnIX MEnKnx TeI 6a3NtOB, YNbTPa-6a3NtOB, Ra6bPO-aHOPTo3NtOB (Dpy3NtOB) IN B MeHbWei CTeNEHIN - DNOpNTOB, rpaHOINOpNTOB IN rpaHNTOB, KOTOpBle CEkyT MetAMOpΦn3OBAHNBie IN DeΦOpMnIPOBaHHbIe NopoDbI 6eIOMOpCKoR KOIMJIeKCA IN C KOTOpBIMN CBzAHO IpOraBJIeHne BbICOKOTemPepHORo MetAMOpΦn3Ma CeIeZKO RzIKLa B INTEpBaIe 2,40-2,43 MlpI Let, PPOXODINBWeR O B aHOPOREHbIX yCIOBnX. B IPOOaX 6eIOMOpCKoI 3KIOrHTOBOI IPOBInCuN BaIITNckoro 5UIta UCTaHOBJeHO IPORABHeNe IaIeONPoTePO3OiCKoR BBICOKOTemPepHOro TpaHUYIITOBOro MetAMOpΦn3Ma C Bo3pactOM $\\\\sim 2,45$ MlpI JeT [DokyknHa n dp., 2019], KOTpbI B OTJIuHne OT BbICOKO6apUneCKoR yKa3bIBaET Ha BHyTpNIIThBI xapaKTep IpoCecca. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,526,899,555]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepKoHTnHeHrTyrIa ( $\\\\sim 2320 - 2170m$ nH IeT) u Cl (~2320-1800 mH neT). \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,555,900,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B cπnscke «O6üeπpHnIaTbIX» cynepeKoHTnHeHToB 3a KeHOpJIeHdOM cIeDyET KoIyM6nJ. Ondako paHee [BoXko, 2009] aBTOp BbIeJIIN MEXdy HmN B pa3pa6OtaHHoN IM cynepeKoHTnHeHTaJIbHOI ZIKJIInuHOCtN cynepeKoHTnHeHT ATyIINR (~2320 mIn IeT) Ha oCHOBaHn aHaJIIN3a TEKToHnuecknx Co6bITn, npOn3OWeIuNX nOcIe pacnaJa HeoapxeiCKOrO cynepeKoHTnHeHTa KeHOpJIeHd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,682,900,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3noxa cyuaceTBoBAHnCynepKOHTHeTApTyI npi6IIN3nteJIbHO COOTBeTCTByET NODpa3deIeHNIO TyIIN (2,3-2,1 MlpJLeT) MeCTHO shKaJIbl. Emy COOTBeTCTBOBAJO CynepeNlOMOBoe CObITNE OKOLO 2,25 MnpJLeT, COnpOBXdABWeecnI3IINHEm TpaNNOB, OFOpMNPOBaHmE DaIKOBbIX KOMPJIeKCoB IN pNΦTOBbIX CnCTem [Cadman et al., 1993]. B 3TO BPEM TePPINTOpN KaJIbckoro KpatoHa PpeDCTaBnla Co60N eNkOHTnHEtAlhN MeJKNOBOnHb I baccEn, B npedeJax KOtOPOr HakaJIINBaJIncs TepRIneHbIe OcaKn I npONcXoJIo NpeNoDnueCKOE n3JIINHne TpaNNOBx Ba3aJIbTOB. TpeUHHbIe n3JIINHn Jab B rTuJIinCKoe BPEM OXBaTIIN ORPOMHyIO TePPINTOpN IO npedeJax BaIANTCKOrO zNTa I o6pa3OBAJI N o6wnipHoe \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[282,904,329,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[331,923,900,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[95,84,490,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JabOBoe pIaTo. O6pa3OBAHne cyNepKoHTnHeHa n IocJeUoUee TeKToHnueCKoe 3aTnUbe npBBeJI N K IOTepe apXeIckOro MeTaHa, OJeDeHEnmM n KncLOpODHomy CoCTaBy aTMocΦepb. B INHTepBaJIe 2,40-2,22 Mnpd JeT kpaTohBi CbIoNpHop, Kapelbckn i KaIaxapn IcNbItaJIu Tpr IocJeDoBaTeJIbHbIX OJeDeHEnH.N. K3TOMy BpeMeHN OTHOCTCra NaKoPJIeHne IpOTOIIaTΦOpMeHNbIX YexLoB B VInde 3NIkoHTnHeHTaJIbHbIX OTIOKeHn rpynnbl PpeTopnra (2350-2050 mIn JTe) cyNeprpynnbl TpaNCBaAaj, rpynnPiRnuBriR $(>2,15$ mnpd JTe) n YnbAnDa $(>2,16$ mnpd JTe) AΦpiKn; rpynn Typn KpnK (2,4-2,2 Mnpd JTe) n BnNy (2,2 Mnpd JTe) BO BnaDInHe XaMEpcn ABCTpaJIi; rpynnbl TypoN (2,4-2,2 Mnpd JTe) n Iporo BnaDIn H o3. BepxHee CeBepHoJ AmePkn; rpynnbl IapacnKa6a cyNeprpynnbl MnHac Bpa3nJIi; YdoKaHcKO sePin AnDaHcKOrO uNTa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,340,489,596]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B BOCTOUHOJ qACTn BaIINCKO rHrTa nO BpeMeHN m COOTBeTCTBYOT oBa3OBAHnR JTyJIa (2,3-2,1 mnpd let) [PaHHn...., 2005]. PaneonpoTePO3OoCKne JTyJIuCKNe ByIKAHnueCKne npOdbI BO3pactOM 2,22-2,06 mnpd let wnpOKo pacnpocCTpaHENb I npdeJax Bcero FehNockaHnHaNBCKORO uHTa n Hau6OJe e NOIHO npEcdTaBnHeh bHa TepnTOPn KapeHn. TpeunHHbIe N3JIyHnRAJB B A TyLIINCKOE BPEM OXBAtNIr ORPOMHyIO TEPnTOPIO n O6pa3OBAJIn O6wnpHoe JaBOBoe pIato. Po reOIOnueckm I reoxIMnueckm xaPakTEpNCtKam A TyJIuCKNe ByIKAHNTbI COIOCTaBIMbl C fAHEpO3OuCKMn KOHTINHETAJIbHBIMn PIIaTO6a3aJIbTAMN. K 3TOMy BpeMeHN OTHCINTcraTahOBLeHne daIKOBbIX KOMnLEKCOB FInHLnHdINC Bo3pactOM 2200 mH let, npOdoJIxKeHne φOpMnroBaHnR pNfTOReHHoN cTpykTypb PeYeHraImaHdpa-Bap3yra (2,3-1,97 mnpd let). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,597,490,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BЛIOДИKOBи (2,1-1,92 Mnpd JIeT) O6CTaHOBka 6OuINHOI nIaTΦOpMbI n3MeHЯETcI. PacnpoCtpaHHeHne MaMAtN3Ma xapaKTepn3yETcR OTeJIINBOI pInypOueHHoCTbIO K 30HaAM rIy6INHHbIX pa3lOMOB,aOCO6EHHOCTn IPOdyKTOB MaMAtN3Ma yKa3bIBaIOT Ha BHyTpNIKOHTnHEtAJIbHbI pNΦTOReHHbI pEXIM 3TOr OpeNoDA.IpeXoD K IIOДИKOBII OTMeUH IOYBEHNEM INHTEHCNBHO TNIKpNTOBORO ByLkAH3Ma B OHexCKO CTpyK-Type,CINHXPOHHO C TaKOBbIM B PeueHrCKO CTpyKType KoIbCKOIO NOJyocTPOBA, YTO paCCMaTPIBaIOCb kak npn3NaKpackpbITnA OKeaHa. IocBOeMy COJepXaHnIO 3TO BpeM CoOTBETCTByET φa3e DeCTpyKcN CypePkoHTnHEtAJIbHOrO cIKNla. PioCTpaHCTBeHHO C6JInxKeHHbIE ByLkAHbI CEHTpaJIbHO TnPa, O6pa3yIOUne JInHeHbIE 3OHbI, MeJIKOBoHbI XapaKTEp 6accEHNOB ocAdKOHaKoJIeHnI rEOxIMmYeCKNe OC6eHHoCTn PnoDyKTOB MaMAtn3Ma yKa3bIBaIOT Ha BHyTpNIKOHTnHEtAJIbHbI pNΦTOReHHbI pEXIM 3TOr OpeNoDa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,84,900,198]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Людниковский Вторгеля на Терптуни Ож-сков вадины заBEREPПLOСь BCПLEСКOM сунCAPСКОТО 6a3NT-ГИЕРБa3NTOBOТОВО BУЛКАНПЛУTOHIN3Ma,образовам MOUнье TOЛДи ЛаBOВых NOTOKOB, ПОКРОВИ NG cyБУЛКАнчecкnxTeJ OT ПИКРNT-бa3aJIbTOBOТОGO Do Плагноба3aJIbTOBOТОВО COCTaOBИ NOДавИВИМ TEPПгEHNOE OcaДКОнakОПлелпe. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,198,900,239]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ha JIOJIKOBNICKOe BpEma npNXODITcBaxHeiue co6bIte B perHOhe -packpbITne CBeKO-ΦEHNCKOTO (JIOJIKOBNICKOTO) OkeAna. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,241,900,298]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PacnaicynepkoHTnHeTaYtynHaBaTnCKOMuTeOTpaxeH BpackpyTINJaPnAnDcKO-KoIbckoroN CBeKoΦeHHCKOrO OkeaHOB [PaHn..,2005] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,298,900,397]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Оьразоваиме океанческого бarrassейна на мостесяшто Лалладско-Kольско Коллinasонного oporena начiningается окуо 2.0 Ga c packolinaдрев breeй контенталовй сормповая OTHCINTEЛьно Heширокого окена Красоморского Тига, о чем CBидenteльстbyOT палеогmar-hintные и n3OTOnHь die dahlbie [Daly et al., 2006]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,397,900,668]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ΦOpMnPOBaHnIO CBeKofoHHcKOrO aKKpeuONHO OPOReHa TAKKe IpreDiueCTBOBaIoo 6bpa3OBaHne OKeaHa B nepNoD 2,0-1,95 MnpD let, O yemCBnDETeJIbCTBvOt OFnoJNTbI MyC Bo3pactOM 1,97 MnpD let. IVx CyueCTBOBaHne yka3bIbaET Ha TO, YTO dInTeJIbHbI 3TaN rIo6aJIbHO pNΦTOREHe3a npIBeHn Ha py6eke 1,97-1,96 Mnpd let KpackpbITnIO LIOIDKOuNCKoro OKeaHa. NocJeero paACKpbITnI prIMbIkaIOUaK KpaIO KapelbCKORO KpatoHa (CabO-JaIOXckAa 3OHa) B KaJIeBnCKOE Bpemr (1,920-1,800 mln let) TeppntOpriapeWla B TEKTOHnueckn PexmPiaccNBHO OKpanHbI NΦOpMnPOBaHn PHTMNHybIX Typ6dNTHBIX OCAdKB C yuaCTnEM PrINBHOcmO IInpOKJaCTIKN I3 pa3MbIAIOUXcJIIOIDKOuNCKNX Obpa3OBaHn. ΘtOMy BpeMeHN BO BHYtpNKoHTInHeHTaJIbHbIX CTpykTypax COOTBETCTByIOT IpoRbIeHnMOUHO RBCMa CneuΦnueCKoro PIKKPITOBORO BYlKaHn3Ma I OboPA3OBaHn DaIKOBbIX POEB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,669,900,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ΦopMnpoBaHne BaIITnCKOrO uNTa kaK φpaRMeHTa cynePKoHTnHeHTa KoIyMbIn npOnCxOdiNo, TaKIM O6pa3OM, B DBe CtaDN N C o6pa3OBaHNEM LaJIaHnDCKO-KoJIbCKOrO KOJIIN3IOHNOrO IN CBekOΦeHHCKOrO aKKpeCIOHOrO oporeHOB [BaIarAhnckn n dp., 2016]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,754,900,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JaplaHdCKo-Kolbckn oporeH YBJIeTcA cTpyKtpyoB VTOPO rOpraKa nO OTHoUeHIO K apxeuCKo-npOtePozOuCKOMy JaplaHdCKo-BeLomopcKOMy rpaHunIto-rHeiCobOMy nOaCy [BoXko n dp., 2021]. Oh npedctabJeT co6oT NIIuHbIKoJIIN3NoHHbI NOc DInBepReHTHOrO pOKpoBHOrO cTPOeHn. 3BOJIouzna IOnca 3aBepShnIacb cy6dykuzne, cOpboXdaBWeiesc o6pa3OBaHnem 3KLOrHToB [UkyNaHa n dp., 2015] n KoJIin3neKolbckoro n Kapelbcko-BeLomopcKoro \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[685,914,700,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[97,923,576,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[95,84,490,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"элархeіckx KONTINHENTaJIbHbIX 6LOKOB B KOH- ce paHHeRo npOTepO3oR, B INTepBaIe 1,93- 1,9 mnpД lat [Daly et al., 2006] c nikom 1,90- 1,91 mnpД lat [Balagansky et al., 2014],чTo npInBeJIO KΦOPMnPOBaHnIO COBpeMeHHoN CTpyk- Tpybl DOKeM6pniCKx O6pa3OBAHn PernoHa. 3TN C6bITnA COpBOXdALINcB rpaHyIITOBbIM MeTaMOpΦn3MOM NΦOPMnPOBaHnEM 3OH PnaCTUeCKOrO CDBuROBOrO TeueHnra Cy6UnpoTHoro n CeBepo-3aNaADHO npocTupAnHry. KolnizOnHbIe BbICOKo6apUneCKne rpaHyIITbI LanJaHdCKo-KolBnCkoR rpaHyIITOBrO NOraCa 6bln cΦopMnPOBaHbI B INTepBaIe 1900-1910 Mln Iet npi T 850 $^\\\\circ \\\\mathrm{C}$ nP 11-12 Kbap [Balagansky et al., 2014]. B CBOIO OuepeB, naJeONpOTepO3oNckne KoIJIIN3NoHNbIe C6bITnA LlanHaNDcKO-KolbCKoro OporeHa npoRbUIncB B BeJOMOpCKOM NoaCe B BVide TEKTOHO-TepMaJIbHOn Nepepa6tKn erO npoPd, BKJIIOuaOSeH HANOKeHHbIe DeΦOpMaun, MaFMaTIa3M, MetAMOpΦn3M, n3OTOnHoe OMOJIoXeHne NpOoi. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,383,489,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OДнOBрЕмнС OКОнчаниМ KОЛизИВ ЛапладсК-КOLьСКOM oporeHe Ha ITO-3aПанбов Okраинe KapelbckOrO kpaToHa NaayincB rIaBHbIe CBekoФeHHCKne aKKpeUHOHbIe CObItnB B VIne PruJleHEnHЯ OCTpoBOyXhIx TeppeHOB K KpaIO KapelbckOrO kpaToHa. 3TOT npOceC 3aKoHUnCЯ CBekoФeHHCKon oporeHnei 1,83-1,80 MlpД.Iet TOMy Hazd [PaHHN...，2005]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,498,489,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ha CBeKoΦeHHCKOM 3TaNe DeΦOpMauŋ TeppntopnBaItnckoro ⅢnTa nOdBeprIacb nHTeHcBHBIM CKJaUaTO-pa3pbIBHbIM DeΦOpMaunm. IpoBJIeHnA DeΦOpMaun B cHTpAlbHoJ caCTn BaItnckoro ⅢnTa, BBI3BaBwIX 3NaHTeJbHyIO nepeCTpOky CΦOpMnPOBaHHbIX CTpyKTyp (B TOM qncLe OHeXCKoB BpaDInh), n OnpdeJIinx xaPakTep pncyHka INx COBpeMeHHoJ TEKToHueCKoC TpyKTypbl. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,625,490,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Перноу заBERшЕня COJIЛИЗNOHHbIX ПОUCEC-COB в ЛапалдсКО-KOLьСКOM opOREн e началу akKpeционьix поцeccoBв CBekофEHнckOM NO-Яce OTBeueaet ФормЮВанne Крунов МагmaTN-чecкой повинци (KMП) в педахox KolьсКOrO n KapeьсКOrO 6LOKOB BOCToHOn ΦeHHOCKaHN Ha урове 1980 mInI leT, пeДCTaBLeHNoH KOMПLEKcamn TOLENTOBbix 6a3albTOB, pIKpNTOB, dINΦфepenuzipOBaHHbIX ra6bpo-aHOpTO3NT-CNEHHTOBbIX INHTpy3N, UIeIOUhBX INHTpy3N i KM-6berlntOB [CamcoHOB u np., 2019]. ПрогВлени TaKOrO MaCSTa6HOrO BHYTPnPllTHOrO MaMaTIN3Ma BO φpaRMeHTe KOHTINHeTAlbHOK Okpbl, OKpyxeHHom oporeHnueCKMn NOrCAMn, Tpe6yET CamOCToTeJbHOrO paccMOtpeHnry. Bo3MOxHo, OHO Bbl3BaHO DeiCTBnEM HeIy6OKnx MaHTnHBix PIIHOMOB, BO3NHkaIoZHX BO BpEMy cy6dYkCmN Prn DBVIXeHIM NITOCΦepHOrO cI36a BdoJIb rpaHnCbI HNXHNe I BepXHeMaHTnI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,84,900,226]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IocJIpepackpbITnBcEkoΦeHHCKOTo（JIouNKOBnCKOTo）OkeaHa B KaJIeBniCKoe BpeM TeppnTOpn，PpIMbIkaUo7aK KpaIO KapeJIbCKOTo KpaTOHa，IpeuJaB pexmPiaccNBHOkpanHbI NΦOpMnPOBaHnTOIuPI pNTMnHybIX TpybNDHTbIX OcaKDob C yAcTHeN PfuBHOcmO NipOKJlactKN Ipa3MbIBaIOUxXcra IIOuKOBNIckx O6pa3OBAHn.B CeBepo-BOCTOCHNo ChtN BaJItnCKOTo UHTa CBekOΦeHHCKn 3tan XapaKTepn3OBaJIcR npTOReHHbIM TEKTOHueCKM peXmOM. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,226,900,325]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aBepWeHne yKa3aHHbIX BblIe n CnHxPOHbIX C HIMN OPOReHn Ha BCex MaTePnKax CnaJIo pa3pO3HeHHbIe φpaRMeHTbI KOHTnHeHTaJIbHOJ KOpbI B INTepBaJIe 2,1-1,8 MlpJ,JeT B cypeKoHTnHErT KoJyM6n. KaBnuIM, B npOceCe erO CO3dAnHn Ipo8BnIncB BCE φa3bI cypeKoHTnHEtTaJIbHOrO cUkJa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,326,900,668]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepkoHTnHENT Kojum6n（\\\\~1920- 1770 mIh Iet) n CU ( $\\\\sim 1920 - 1520$ mIh Iet). CynepkoHTnHENT KOHca paHHeO npotepo3oA NOI h3BaHnEM PAnRey 1 6bl BbIeJeH [XaHn, BoXko, 1988] Ha OCHOB reoxpOHOnIOuYeCKnx I reJIoRrHuCKx DaHHbIX TOBOBpeMeHN. CyueCTBOBaHne cynepkoHTnHEnTA, COzDaHnHO B nepNoD 2,0- 1,8 Mnpd Iet, PpeIPOlaIaONcB pIOM NCCJIeIOBaTeJe. PoJxepc n CaHToW B 2002 r. HauBaHn eTOT cynepkoHTnHENT «Kojum6n» IO HauMeHOBAHNI O peKn KoJUM6n Ha 3anaDe CeBepHO AmePKn. Ero cyuEeCTBOBaHne OTmueHo pacnpocTpaHEHem PeTOJIOUReCKN IDeHTNUHbIX IOHOBO3PacTHbIX IopoD Ha paCSTOAHNE TbICrK M Upe3 rpaHnCbI HbIe CyuSeCTByIOUx KOHTnHEtOB. Ha BCEx KpaTOHAX OTmueHo paCnpocTpaHEHne IpoToTlAtΦOpMeHHbIX YexIOB, KOTOpBIE C yrIOBbIM HeCOrIaChEM NepeKpbIbAIOT pa3HOBO3pactHBie IODCTINLAIOUe NOMJIeKCSBI B YCSIOBIAHX HOBOrO cynepkoHTnHEnTa KoJUM6n: PopaMa (1,95- 1,88 mIrpd Iet), Atabacka (1,76 mIpd Iet), YMKOHDo 1,9-1,5 mIpd Iet) n dpyrIe. B aTo BpeMHa BaTnckom ZIte HakapLIbAOTc OTLOXeHnBeCNsra (1,8-1,7 mIpd Iet) [PaHnn ... , 2005]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,669,900,768]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepeKoHTnHeTaNbHaJeNoXKaIyMbHmOtMeueHa BHeDpeHnEM aHOporeHHbIX INHTpy3n I KOMaRMaTHuHbIX KNCJIbIX Cy6aepaIbHbIX ByIkaHITOB: IopOnIta CeIbepn (1,85 Mnpd JeT), KoIap (1,9Mlpd JeT), ByUBeIbDCKOrO KOMPLekCa (2,09-1,92 Mnpd JeT), paIakBn Ha6eppy (1,76 Mnpd JeT), ByIkaHITOB YaTuMa (1,85 Mnpd JeT) n dp. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,769,900,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IocJIe 3aBepSeHnI FOpmroBaHnJIIOJIOKOBnCKnx I, BO3MOxHO, YaCTN KaJIeBnCKnxO6pa3OBaHn TeppntOpnOHeXcko BpAnHbI PpeTppeJa CTpykTyHy OpeCToyKu N DeΦOpMaun, PPOBLeHne KOtOpbIX ONpeDeJIIo TpaHCrpeCCNBbI XapaKTeP 3aJIerAHN BblEJexaux ToJIu Bencn (1800-1650 MIn JET), KOTOpbIe C yIIOBbIM HeCOrJIacmE NepeKePbIBaIOT pa3HOBO3pactHbI PoIDCTNIaIOUne KOMNJIeKCbl. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[297,914,317,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[329,923,900,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[95,84,490,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IocTBcEkoΦeHHcknM CObItnM B npedeJax Kapelbckoro KpaToHa OTBeuaet no BpemeHn φOpMnpOBaHne 3anaDHO-OHexckoro KOMJIeKca, npedCTaBJeHHoro JALOBbIMN IOTOKAMN (6a3aJIbTb KaJlaxTa) nPiactOBbIM nHTpy3NBOM ra6bpoJolepNTob (PonpyeNCKn Cnll), a TaKxe KIm6bpNTamN Kmo3epo. Bencnckoe cO6blTne Cnlllo06pa3OBaHnra C Bo3pactom 1770 mInIet B IOxHo-OHexcko MyIbe NocLeDobALIO NocLe HAKOpJIeHnB KONTHeNTaJIbHbIX CTa6NbHBix YCLOBnX OTLOKeHn CEpoUcbETHo TOnuIN PeTPO3aBOJcKO CBtBc MAlOMOuHbIMn JaBaAMN OCHOBHOrO COCTaBA u KOPaMn BBiBTpNBaHnB KpOBJIe IOTOKOB, a TaKxe KpaCHOBEThBX KBAPUNTO-NEChAHKOB WOKUHNCKO CBtBBeNCn, PNOrO 3aJIeRaIoUxxC yIbOBbIM HeCOrJaCnEM Ha DeΦopMnpOBaHHbIX NopOaX 6OJIee DpeBHX Ropn3OHTOB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,340,489,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ΦpaarmentaŋKoJyM6n cOpPobQxdaIacb 60lee 3HaunTeJIbHbIM dpo6leHneM IOXHOI POlycφepbl. B npedeJax BoCTOCHoI ToHDbAHbI (INHdN, AHTAPKTua, ABCTpAln) BO3NHK pRd MKNPOKOHTInHeTOb, B TO BpeM kAc JIabPa3N, NOBnDMOMy, npedCTaBnla c6oB o6OC6JeHHbIK ORepeHTbI 6Lok, OKaIMLeHHbI OKeaHAM, B paiohe TpeHBnIbCKo IpoBnHcN KAnAdbl, ITO3anaCUSA n Ppi6aNTnK. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,469,489,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PacnapKolym6n，coOTBETCTByUoI npi6I3ntelbHO nHTepBaIy 1770-1685 mIn IeT,OTMeueHIIpOKIM npoBJIeHNem aHOporeHNO MarMaTH3Ma Ha IIIOUaDN CynepeKOHTINHEtA pNTOReHe3OM Ha eO OKpaIHax. OH He npoRbINcB INpRAMOfOpme Ha TeppITOpuN BOCToHOn qactn BaIITNCKORO UNTa，KOTOPa IPOdoJXaNA pa3BvIBaTbcra BO BHyTPnIINTHOM pEXmE. IIO BpemeHn EMy OTBeuaet FOpMnPOBaHNe 3aNaIDHO-OHexCKoro KOMJIeKCa，npedCTaBNEHHOrO JaBOBbIMN NOTOkAMN (6a3aJIbTb KaJnxTa) u POppyeNckm CnJILOMRab6pOdoJIepTuOB (1770 mIn IeT). KOHBeprEHTHa φa3a DaHHoro CL npoRbJIeHa oporeHnueckMN CObItnMn B packpbIBxNXcI NOcIe paCnadaKolym6n OkeAHueckNx baccseHax，3NaHTeNbHOe YNCNo KOTopbIX 6blIO COspEDOTOueHO B IOXHOI NOUCfepe 3EmNI. B IO3 qactn BaIITNCKORO UNTa OHa BbIpaKeHa IocLeDObATbHOCTBIO KopoObo3ayUoixxCobtBu INHTepBaIe 1,7-1,55 mInIeT (rotckar oporeHna)，BKNUOauX akKepeuio OCTPOBbIX dYr Ha φOHe o6paUeHHoN K 3anaNy cy6dyKuNN [Mansfeld，Andersen，1999；Connelly，2001]. 3Ta n cInxpoHNbIe oporeHn B dpuynx qactrx CBeta npuBeI N O6beDuHEnIO NOUTN BCEX KOHTINHEtALbHbxΦparMeHTOB HOBBI CypeKOHTHENT FOITN K py6exy OkIo 1500 mIn IeT.\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,840,489,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B BOCTOHON Yactn BaJItnIckoro UHTa, HAXOINBWEROsC B COCTabe KOHTInHeNTaJIbHOrO 0paRMeHTa, OHI He HAJIN IprAMORO OTPaxeHnra, 3deCb npoIOJXKALc BHYTpNIPTNbI peKIM. 3Ta 3noxa \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,84,900,226]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PnmuMeaTeIbHa IInpOKm npOReJIeHem anOpoReHHOro MaMAtu3Ma B INTepBaJe 1,4-1,5 MnpJLeT B vIe Cy6a3paIbHbIX ByIkaHHTOB, aHOPTo3NtOB, rpaHNTOB-panakINB. PAnHeme3OpPoTePO30ckne MaMAtuYeCKne NopObl SiWpOK paCpOcTpaHeHb B CeBepHom n BoCTOCHOM PpiJaDoXbe.3Decb OHI ppeCTaBHeBIOtOKamn CaImncknxΦeppo6a3aIbTOB, ra6bpOMOnHOITOBbIMn BaIaAMCKm mAmTcINHcaapCKm CnJIaMn, INTpy3neXOnyHbAapa n daIKaMn dByx reHepaun. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,226,900,440]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepkoHTnENT TOTn (1520-1370 MInH let) n Cz (1520-1120 mIn let) 6bln BblJeIeH [BoXko, 2009], kak yka3bBaIOcB, B pe3yJIbTaTe aHaJIIN3a KOJIIN3IOHHbIX CO6bITn, ppeIeCTByIOuXx 3OTMy py6Exy, B packpbIBWnxCЯocIe paTnaja KOnm6n OkeAHnuecknX 6accEHNax; 3NaHInTeJbHoe IN x HcIIO 6blIO COspEDOTOyeHO B IOXHOI POlycfepe 3emn: BoCTOHyON ABCTpaIIIM, ANTapKtnde, INIOCTaHe, AΦpNke, IOXHOI AmePKe, a TAKKe CkaHdINHabN IN CBeBO-BOCTOHyON LaBPeHTn. COBpeMeHHbIe DaHHbIe NODTBepXJaOT npaBOMOuHOCtB BblJeIeHnry CynepKOHTnHErTA. TaK, I. PecoHc c CoABTOpAMn [Pesonen et al., 2012] PpeDCTaBnI NaJEOMaRHTHyO peKOHCTpyKUIO cypeKoHTnHEnTa Ha yPoBHe 1,53 MIpI neT. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,440,900,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BpemcuyeeCTBOBAHnme3OpnoTePO3Ocko- ro cyneKoHTInHeTaTToNtOBeuaet B OCHOBHom paHHemy pIeEO OTeueCTBeHHoJ uXapaKTePn3yeTc npoe6laaHnEM IOndHrTu. IpopoTnlat- fOpMeHHbIe Yexbl TOTn IMeIN OprAnuehHOe pacnpoctpaHene. B EbpazmOn HpeDctabLeHb KAp6oHaTHO-TePPnREHHbIM ONlROMNKTOBBIM TOJIaAMn, ReHeTNUeCKn TeCHO CBraHHbIM C KOpAMn BBIETpNBAHn IΦOpMnPoBaBUsMNCS B PLOCKNX N3OJInpoBAHbIX BpaDNHax, NaIOxKeHHbIX Ha DpeBHe o6pa3OBaHn. BoJee 3NaUHTbeHoe OCAdKOHaKOpJIeHne IMeNo MeCTo B 3TO BpemB INHdoCTaHe, ABCTpaNN, IOxHoN AmePike. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,625,900,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PacnapI Gotnno Otpa3nIcB V opMnpOBaHn naccNBHOOKpaHbHa NaCEBPO-BOCTOKe BaNTKn, BNOCLJeCTBN BOJIeueHHoB TImaHCKn OPOReHe3, INCBra3aHHoC HeN pAJeOpNFTOBOO CNCTEmbl BeNoRo Mopr Okolo 1,2 MlpJ LeT Ha3ad. 3Ta CnCTema o6pa3OBAHa y3KIMn LInHehBMn IpOrnBaMn, BNaINHAMn CeBPO-3aNaADHO npocTnpaHnB DpEBHem rpaHHTORHeNCOBOM KpncTaNJIuYeCKOM FyHdAmHeTe, KOTOpBle 3aONJHnLNCb TeppnReHNbIMN OTLOXeHnMn, Typ6UHTAMn CpeDHeRo n BepxHero pNphiE. OHexCKo-KaHdaJaakssKn paJIeOpNF CBOm CeBPO-3aPaAdHbIM KOHcOM pacKaIbIbAet BOCToHyU qactb BaJItnckoro UNTa, a BapenHeBOMOPckn (Me3eHckn) o6paMlAreT noCleDnH CceBepa N CeBPO-BOCTOKa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,840,900,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KoHBePReHTHa Za3a ZnKla CbI3Ha co c6OpKo cynepeKoHTInHeTa PoDInH. B erO φopMnpoBaHnn npHHMaJn yactne oporeHmB nHTepBaJIe MeJdy 1300 n 900 mJn Jet [Li et al., 2008]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[685,914,702,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[97,923,576,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[95,84,487,182]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"K HIM OTHOCITcA φa3a CBeKOHOBEXCKO oporeHn Ha ITO-3aIaIe BaIITNCKOTo Ⅲnta B INTePbale 1,14-0,96 Mnpd JeT [Bogdanova et al., 2008]. Co c6opkO PoDInHn (1285-1120 mNHeT) COBnadaet BHepeHne KIM6epJIITOB n JaAMnpoNTOB KyXMO-JeHTnpa-KocTOMyKwa KapeHn (1230 mHN JeT) [BoXko, PpycaKoba, 2014]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,184,489,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepeKoHTnHeT POnHHa (1120-970 MJIH let) n CU (1120 - 650 mJH let). B 6OJIbIuHCTBe peKoHCTpykUni PoOnHHn 3aJaIHaY qAcTb IITa NOMEuaeTcB COBMecTHo C JaIbPeHTnei, IpeHlaIaNHe i Ama3OHNe [Buchan et al., 2001]. B BoCTOuHOJ qAChn BaJItnckOTo IITa, He 3aTPOHyTOOporeHnueCKIMn pIOuceCCAMn, IMeIo MeCTO pa3BVtNe pNΦTOReHe3a i nnIOMOBOrO MaMAtn3Ma. BdIb naCCNBHOJ OKpaINbI pNOJXaIOT pa3BvBaTbcR pNΦTOBbIe 3ObI bEJOMOPCKo pNΦTOBOc CNTEmbl. B HeONpOTepo3OE (No3dHem pNphiee) pNΦTOBbIe BPaIaNbI pNaEOpNΦTOBOJ CNTEmbl BeJoro MOpR npOdoJIkaII yrgy6JIbTbcR. B HIX OTKlAdlbVAlNCb TepRnREHhIe OTLOXeHInB ePxHero pNphiEr Ha py6Exe pNphiEr n BEHdaB OHexcko-KaHdALakssckOM pNaEOpNΦTe npoRbINcByUkAn3M ToJeTOBoC cepIN. No3dHepNΦeCKn MMnyIbC paCTraXeHn rTMaHcKo OkpaINbI BaJItnKc CB83aH c paCpAodm PoOnHHn i paKpbITnEM pNaeooKeaHa Jnetyc [BaanyEB, 2013]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,469,489,568]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Haayano KOHBePHTHO CTaDN paccMaTPnBaEMOTo cKla OTMeUeHO KOHTNHeTaalbHbIMN KOJIIN3IaM.NIabHeJlne H3 HIX npoCxOaINB IOXHom POJyAupn, YTO npuBEno K o6pa3OBaHIO MeRakOHNTHeTa ToHDbAna. IOp-BuDmOMy, BaLTNa 6bla OTHOCHTeBHO MOHOLTHbIM PrpnoIDHrTbIM φpaRMentom nocle paCnada PoDInHN. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,568,489,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3TOMy BpeMeHn COOTBETCTBYIOT KIM6epJIHTbI (759-756 MInJ IeT) nOJa KyycMo, paCNoLoXeHNHO BBOCTOuHOn ΦHHaHdNn 6JIn3 rpaHnUcbl C PocCnei [Boxxo, IpypcaKoBa, 2014]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,625,489,681]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bpe3yIbTaTe cJnHnEeBpa3nCKnx OCKoKOB PoDInm MExdy C60oN iC HOBoo6pa3ObaHHOI ToHDbHoI Obpa3OBAJcra CynepkOHtHeHT PaHHOTnI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,682,489,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepkoHTnHeT PaHOTn（\\\\~650-570MJIH JeT) n C4 (~650-320 mH JeT). HeonpoTePO3OyCKn CynepkoHTnHEt, O cyuceCTBOBaHN KOToPOro npednoJagAI MHOrue NCCJeIOBATEJI, 6bl BbIeJIEN B 1995 r. C. PayaIIOM. PaHOTn paCNoJARacb ceNkOM B IOxHOM pOnyUapNI, 7TO o6ycNoBnIO aTmIoJorNIO aTOTO Ha3BaHnA («PaH» - BCE n «HOTnyc» - IOXhbl). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,796,489,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CuyieCTBOBAHIO PaHHOTIN COOTBECTBYeT IIO-6aJIbHOe pa3BNTne OJeDeHEnB INHTepBaJe 750-580 MInIeT. B npedeJax paHHeOKeM6pnIcknx PnlatΦOpM JaBpa3NCKOTO pJa 3aBepShNI pa3BNTne DpeBHNe KOHTINHETAJIbHbIe pNΦTOBblc CnCTeMbI (aBJIaKOReHbI), cΦOpMnPOBAHHbIe B I03dHem pNΦee B CB3N C packpbItnEM PAJIeOOKeAHOB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,84,897,283]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Kak yka3bIbAIOCBbIe, BpempaCnada PAnHOTnn npINHMaETcHa yPOBHe OKOJ0 570 MmH JeT. PaCnad ee npINBeN K O6OC6JIeHNIO ToHDbA- HbI, KOtOpaR B paHHem PAnEo3OE COxpaHraJa CBOIO UeJIbHOCTb N CTa6NJbHOCTb, TOrJa KaK B IpeJeLaX JaBpa3NN ShIo AKTNBHOE OKeaHOOBpa3OBaHne (OKeaHbI JaNETyc, PAnEOa3NaTcKn, IpOTOTetnc). HOOO6pa3OBaHHbIe OKeaHbI 3aMKHyIncB OCHOB-HOM B pe3yIbTaTe KaJIeDOHCKNX I repUHNCHX oporeHn. Ha CeBepo-BOcTOke BOCTOCHNo-EBpo-NeiCKORO KpatoHa, NO-BNIMOMy, Ipon3OWeJ nepeXoJ naccuBHOJ OKpaHbI B aKTNBHyIO N φOpMnPobAHne KaJOMcko-TImaHCKOTO oporeHa B INHTepBaIe OKOJ0 600-550 MmH JeT [PnykOB, 2008]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,283,897,695]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Kpy6exy 320 MInIeT KOJIIN3nHOBOO6pa-3OBaHHoJIaBpa3nn IToHDbAhnI npNBela K Bo3HNKHOBeHnIO PaHren. BocTochna Jactb BaItnCKORO UHTa He 6blJa 3aTPOHyTA oporeHneckmnpocecam. 3TO Bpem OTBeyaet npoRbLeHIO B ee PpeJeax PanaEO3OcKo TKeTOHO-MaMaTNUeCKo AKTNIBN3aU, KOTOPa BbPa3nIacB NIOHATn, pIoTOReHe3e n PIIOMOBm PLaTΦOpMeHHOM MaMaTn3Me. PAnHePaeO3Ockne INTPy3nn UTeLOOHbIX rpaHnTOB OTMeueHbHa KoJIbCKOM POlyocTPOBE (xpe6et KeIbbl). B cpeHem n PO3dHem PanaEO3OE o6pa3OBaJInCb XbHnHckn IIOBO3epckn INTPy3uHBhie USeIOChbE MaccNBbl B ceHTpaJIbHOJuaCTn POlyocTPOBa. O6a MaccBaB OCHOBHOM BBypaXeHbI HeΦeJIINHOBBIMn CneHNTAM. B cpeHem-NO3dHem DeBOHE npON3oUla peReHepaunr 3aIOXeHHbIX B pNFee pNTOBbIX 3OH n pa3BHTne BHYTpNIITHOr MOarMaTHMa. B IOROBOCTOCHN IORpe6EHNOJ qACTn PanaeOpNTOBoCNCTEmbl BeIoro Mopr (3ImHe6epExhbl paioh) n Ha eE NOJHTbIX 6Lokax FyHdAmehTa φOpMnyTOCTa N3BecThbIe IOnr KIM6ePINTOBbIX n 6a3aJIbTOBbIX Tpy6OK C CONYTCBYIOUMm m DaIKamn USeIOHOrcoctaba.C6OpKe PAnReN (485-320 MInIeT) n BPemeHn COOTBeTCTByET BHeIpeHne Tpy6Kn ΓpNb a B ApxaHreJIbCKo IPOBnUcn (372 MInIeT JeT) n KIM6ePINTOB TepCKoro Bepera KOLbCKORO POlyocTPOBa (375-372 MInIeT) [Apzamucuev and., 2001; BoXko, IpycaKaBa, 2014]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,697,897,809]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CynepkoHTHeT PaHRe (320-170 MJIH LeT) n CU (320-? mJH LeT). OOpMnroBaHne PaHRe npOn3OuIIO 320 mJH LeT ha3aD B cpeI HEM Kap6OHe B pe3yIbTaTe o6beIeHNHeN KpyN HbIX PAnEOMaTePnKOB TOndBaHbI N JaBpa3nn. OkOHcATEJBHa Jx e C6OpKa I KjYbMInaUsn CInTHOCTn CypeKoHTHeNTa 3aBepuINlacb Ha rpaHnCe BepxHero n CpeIeHero TpNaCa (230 mJH LeT). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,811,897,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Iocjedyuoune Me3o-KaHOn3Ockne co6bItnra, TaKne KaPacnpad PAnHReB reOpOnueCKoN uCTOpnn paccMaTpnaeMoTeppntOpnn, yXe He NaJIn 3NaHTeJIbHOr OTrpaXeHn. 3To BpeMx XapakTepn3yETcR DOCTaTOUHO CNOKOBHbIM pexNMOM 6e3 CyUeCTBeHHbIX npoABLeHn \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[297,915,317,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[329,923,900,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[95,85,487,182]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BHyTpNiJIHTHOI TEKTOHKn I MaMAtn3Ma. NIMNyIbCbl BbICOKOI TEKTOHnueCKoAKTNBHOCTNMeJIN MecTO B HeOReHe I NIIIOSeHe, BbIpaxJaCbB VePTNKaJIbHOM IepemeUeHn 6ILOKOB BIOJb HOBbIX N O6HOBJeHHbIX DpeBnIX pa3JlOMOB. B TeueHne BCero Me3030r Ha BaJItniCKOM UNTe rOcNoDCTBOBaJI N KOHTNIHENTaJIbHbIe YCLOBnIy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,185,487,283]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HeoreH-yeTBePtnuHa aKTINBn3aunr TeKToHNuecknx DvNKeHn Oo6eHNO CnIbHO npoRbIaCb Ha TeppiTOpnn BefomopBy, BbIpa3NBUncB OBpa3OBaHm CNCTembl pa3JOMOB CeBepo-3aPaNDHO pOCTnPAHn, npoBJIeHnEM BdoJIb HNX MHOroUcJIeHHbIX OuaROB 3eMJIETpCeHn, IN BvaCTHOCTn, BIOJIb KaHdJaakUCKOrO pNΦTa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,283,487,355]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CObpeMeHHbI (No3dHeKaHHO3Ockn) PAnH - 6oBa3OBaHne CObpeMeHHbIX TEKTOHueCKNX BpAin HBeIoro Mopra, HacJeDyIOUx npΦeNcKne pNΦTbl, CBa3bIbaETcRc paACKpbITnem CeBepoATnHTnueCKOrO n ApKTNUeCKOrO oKeaHOB [BaanyEB, 2013]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,369,211,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aKJIoueHne \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,397,487,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TeKToHnuecka 3BOJIOUng BOCTOuHOu qactu BaIITnCKORO uNTa B NOCJIeHNHe 3 Mnpd JET OTpaxKaET NOCJIeDOBaTEJIbHOCTb CyNepKOHTINHEHTaJIbHbIX UIKJIOB B ee NCTOpNI. 3Ta TeppntOpNJNCblTAla IINb DBA NOLbIX CyNepKOHTINHEHTaJIbHbIX UIKJa C PPOABJIeHNEM BCEx eRo a3. 3Tu NcIKJIbl CBZ3aHbI C φOpMnPoBAHnEM CyNepKOHTINHETOB KeHOpJIeHnI KOnym6nI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,511,487,668]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PaccMaTpNaBaemar TeppntOpnB I dpynx cynepeKoHTnHeHTaJIbHbIX zIKJiaX BXOJILA B COCTaB KpyNbIX KOHTnHeHTaJIbHbIX $\\\\phi$ paMentOB, HeNoCpeIcTeBHeHO He 3aTpOHyTbIX paCnaOM i C6opKOc CyepKoHTnHeHTOB, pa3BnBaIacb BO BHyTpNIHTHom pexIme, nCtIbTBaR TEKTOHO-TePMaJIb-HyIO aKTNbU3aCuIO NOB Bo3JeICTBnEM TEKTOHKn MaHTnHBix PIIOMOB. 3TN npOceCCb BblpaKaIINCb B npOraBLeHnx BHyTpPiNTHO rMaMaTH3Ma, BblcOKOTempePaTyPhoro MetamOpfN3Ma, KOHTnHEHTaJIbHO pNToToreHe3a, deOpMaunx. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,669,487,809]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BmecTe C TEM OTMeueTcE ueI IIOXO n3- yUeHHbIK KOHTPOJIb pa3BVITnB BHyTpINlTHoH TEKTOHKn mMaftMaTH3Ma BOCTOCHN qACTn BaIaTNCKOTO uNTa 0a3aMn CynePKOHInHeHTaJIbHbIX UnkNoB. TaK, o6uemy pacnaNy c6OpKe cynePKOHInHETOB BCerMeHTax, HENOCpeDCTBeHHO He 3aTPOHYtBX 3TUMn PPOuceCCAMn, COOTBETCTByET YcIIeHne PpOBJIeHn BHyTpIKOHInHEHaJIbHO rPfTOReHe3a N CBraHHOrO C HIM MaFMaTH3Ma. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,811,487,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IHTEHCNBHOCTb IPOUeCCOB TEKTOHO-MaMmTu-yeCKoAKTINBn3aun OnpeJeJalacb TaKxe CTeneHbIO ydaJIeHHOCTn TeppntOpn OT pa3BnBaIoXxCr OPOReHOB COOTBeTCTByIOxN cIKJIOB. KpaEBbieCaCTn TeppntOpn Ha rpaHnCe C HmN BOBKeJaLncB pnoToREHe3. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,84,615,98]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Литуразуа \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,112,897,252]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ApecToBa H. A., YeKyaIaEB B. I., ErOpoba IO. C., KyUePoBcKn I. A. 3BOJIOUma COCTaba N uNCTOuHnKOBO OCHOBhIX yIbTpaOCHOBhIX npoD npn nepeXoJe OT HeoapxEr K napeOnpoTePO3oIO B KapelbCKoN pOBuHnCm, BaItnckn 1nt // 3TaIb foPmnpoBaHn N pa3BHTNA IpOTepO3oIKoN 3emHOk Kopbl: cTpaTnIpaFMy, MeTamOpFm3M, MaMaTHm3M, reOINHaMnKa: MaTepnaJIb VI Poccnicko KOHfepenHnN o npOBeMaMreOJorHn N reOINHaMnK DOKEm6pr (CaHKT-PeTebpyr, 22-24 OKTЯ6pr 2019 r). CPi6.: CBoe n3daTeJIbCTBO, 2019.C.23-25. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,252,897,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ap3amacueB A. A., Bea $\\\\Phi$ ., Tla3HeB B. H., Ap3amacueBa J. B., MoTepo I. KoJbcka YeNochay npOBnHcN B napeO30e: oUeHka COCTaBa NepBnuHbIX MaHTnHbX paCnJIaBOB u yCIOBm MarMORHePaCuN // Poccnckn KypHaI Hayk O 3emne. 2001. T. 3, N° 1. C. 1-35. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,330,897,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Banaarhckn B. B., Top6yHOB IV. A., Mydpyk C. B. PaineonpoTePO3OcKne IaJIaHndCKo-KoJIbckn n CBeKOfeHNckn oporeHbI (BaTNIckn Ⅲnt) // BeCTHnk KoJIbckOro HayHoro ueHTpa PAH. 1916. N° 3(26). C.5-11. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,394,897,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Banyeb A.C.KoHTInHeNTaIbHbI pNΦToreHe3 cBepeBa BocToUHO-EbponeNcKoI PnAΦOpMbIB HeORee: reIoIroI, NCTOpIpa3BUNIg, CpaBHTeJIbHbI aHaJIIN3: Dnc. ...DOKT. reOI.-MmH. Hayk.M., 2013. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,446,897,483]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Божко H. A. Супековинецьна сизлuchов востори Земли // Вectн. Мск. ун-та. Сер. 4. Геюгия. 2009. № 2. C. 13-27. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,484,897,522]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Божко H. A., Пусakова H. A. O nepcneKeTивх кореннoi щлмазоносости Kapelьского Кратона // Рдьи металы. 2014. № 4. C. 5-13. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,523,897,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Божко H. A., Прусakoba H. A., Гомцев K. B. Oсобенhoeст TeКToHnueckoro CTpoEня Лапандбко-БелOMOPCKO rpaHnyIto-rHeиCOBOro nOra ca И nepcneKeTINbbl erO KopeHNoI aIma30HOCHOCtN // OteuectBeHHaReTeJOrn. 2021. N° 6. C. 45-64. doi: 10.47765/0869-7175-2021-10031 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,599,897,650]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BOLODUHEB O. I., Cna6yHOB A. I., Bu6nKOBa E. B., KOHNIOB A. H., Ky3eHKO T. I. ApxeiCKne 3KnOHTbI BeJOMOPCKORo NOdBnXHoro NOraC (BaTNIckn Ⅲnt) // PeTpOJIorna. 2004. T. 12, N6 6. C. 609-631. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,650,897,802]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Дokуна К. A., KoHIOB A. H., BaH K. B., BaHOBa T. B., LeshykoB B. C., XybaHOB B. B., GolobahOBa T. N. Палоэпороетоиckm ГаунлтовьйmetamopФИЗМ CB03pactOM ~ 2.45 Мрд Лет В подахБеломорско ЭКLOГNTOBОng Робици ФенhhockанДинавСКОTO StTa, PocSry // Этны Формпоганьиnpa3ВИТЯnpOTeP03OYCKOЗ ЗEMHОКОБы: CTpaTURpaФИЯ, MetamOpФИЗМ, МaramTN3M, reODINAMKa: MaTeprnabl Vl PocCnIckO KoHфepENZN NO npO6JIeMaMReOJOrN IN reODINAMKIN DOKeM6Pry (CaHKT-ПeTpE6ypr, 22-24 OKTЯбР 2019 r). CП6.: CBoe n3daTeJIbCTBO, 2019.C.68-70. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,805,897,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KoXeBnKOB B.И. ApxeIckne 3eJIeHOKaMeHHbIe IOra Ca KapelbCKOrO KpaToHa kak aKKpeUHOHHbIe oporeHbl. ITePo3aBOIDcK: KapHL, PAH, 2000. 223 c. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,843,897,895]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JIo6aay-KyueyHko C. B., CepreeB C. A., JIeByeHKO B. M., OBuHHNkoBA F. B., KOToba J. H., KpbIIOB I. H., JKOBoBeBA C. 3. BoJIo3epckn rHeiCoBbI KOMPJIeKc paHero apxera n erO cTpkyTypHO \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[685,914,705,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[97,923,576,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. N6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[97,85,489,893]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"MeTaMOpΦHuecka ΘBOLIOUry // N3OTOnHa rTeoxpOHOJIoRnДOKeM6pry.J.:Hayka,1989.C.14-45. \\\",\\\"Лубнha H. B., Сларов A. И. Реконструкшия Нeoархейскою сунерковинента Кенил end no napeomamгншьим и геологиеским данhhim // Вecthnik Mockobскою уньерситета. Сер. 4. Галогия. 2011. № 4. C. 23-30. \\\",\\\"MntpofoHOB.П. PaHHeIOKEM6pniCKa rTeOINHAMnka, MaMaTu3m n MetaJILOReHnKa KoJIbCKoI npOBUHcun//BecTHNK MFTY.2009.T.12,N#4.C.567-570. \\\",\\\"ПeТРВСКИМ. H., ПeТРВСКАЛ. C., БaHOBa T. B. ；\\\\nЗВОЛЮЦЯ Магматизma B reOJIoRnueCKо NCTOPmN\\\\nMypMaHcKOrO HeoApXeIckOrO kpaToHa // Marmatn3M\\\\nи MeTamOpФизм В nCTopnN 3eMЛ: XI BcepocciNCKoe\\\\nпeТрографчecкое COBEUaHne: Te3ncbl DOKlaNoB.\\\\nT.2.Ekatepin6bypr,2010.C.130-131. \\\",\\\"IpykoB B. H. TeKToHnKa I reOuHaMnKa TmHaHnD // CtpyKTypHO-BeUeCTBHeHHbIe KOMPJIeKcbl I npo6JIeMbI rEoUHaMnKn DOKem6pRnaHepO30iCKnx oporeHOB: MaT-JbIMeXdYHap. Hayu. KOHΦ. (III tTeHnI naMaTn C. H. IBaHoBa). EkaTepeH6Bypr: IΓnI YpO PAH, 2008. C. 104-109. \\\",\\\"PanhnDIOKEm6pN BaNTuCKOrO uTAt / PoI peI.B.A. TJIe6oBnUcKOrO.CN6.:Hayka,2005.C.711. \\\",\\\"CamcoHOB A. B., CTeNaHOBA A. B., Ap3aMaCueB A. A., CaIbHnKOBa E. B., JApnoHOBa IO. O., JApnoHOB A. I., ErOpOBA C. B. KpyHna MarMaTneCKaJI npOBnUZnB BoCToUHOJ ΦeHHOCKaHdN: napareHeTneCKoe pa3-Hoo6pa3ne B rEoDInHaMnueCKOM eINHCTBe // 3TaIbI φOpMnPOBaHnI N pa3BNTN I pOteP03oNcKoI 3EmHOJ KOpbl: CTpaTnRpaΦn, MeTamOpΦn3M, MaRMAtn3M, rEoDInHaMnka: MaTePnAbl Vl PocsnckoK KOhΦepenuN IIO npObIeMaM rEoIognn I rEoDInHaMnKn DOKeM6pNIA (CaHKT-PeTepe6ypr, 22-24 OKT6pbra 2019r). Cπ6.: CBoe n3daTeJIbCTBO, 2019.C.198-200. \\\",\\\"Cna6yHOB A.И. Apxeckneи n paIeIpoTePO3oIckne oporeHb: cpaBnHTeJIbHb aHaJIu3 reOduHAMUeCKNX npoueeccOB npuix foOpMupOBaHm (Ha npImepe FoHooCKaHINHABCKOTO uNTa) // 3TaIbI foOpMupOBaHm npa3BtNIA npOTepO3oIKo ZemHOJ KOpbl: CtpaTIRpaΦn, MetamOpΦn3M, MaMaTHzM, reOduHAMuKa: MaTePnaJIbVI PocnckO KoHΦepeHcNIO npOboJEMam reOJorN INreOduHAMuK NdoKem6pr (CaHKr-TeTe6Bypr, 22-24 OKT86p8 2019 r.). CPi6.: CBoe n3daTeJIbCTBO, 2019.C.210-212. \\\",\\\"Cna6yHOB A. H. TeoIognI r TeoIINHAMnka apxeiCKnx IOaBnKbIX IORcOB (Ha npImepe BEnOMOpCKoI npO-BHHuNΦeHHOCKaHdINHABCKOrO uNTa). PeTpO3aBOJcK: Kapen. Hayu. cHTp PAH, 2008. 294 c. \\\",\\\"Cna6yHOB A.И.,Ioba-ЖучЕнкO C.Б.,Bn6nKoBa E.B.,BaIarAHcKn B.B.,CopboHeH-BapД П.,BoIooNueB O.II,IIuNaHcKn A.A.CBeTOB C.A.,YeKyJaeb B.II.,ApectOba H.A.CTeNaHOB B.C.Apxei BaIantnCKoro Ⅲnta:reoiJorN, reoxpoHOJIOrN, reoiHaMnueckne o6ctahOBkn // TeOTeKToHnka.2006.N6C.1-29. \\\",\\\"CTeNaHOBA A. B., CamcoHOB A. B., CaJIbHnKOBa E. B., Ap3aMaCseB A. A., ErOpBa C. B., BeCeIobCKn P. B., NapHOBa IO. O., EpoΦeeBa K. Γ., CtaΦeeBa M. B. PaIeONpOtePozOienCKne MaΦuYeCKne DaIkn KapelbCKoN n Kolbcko-MypMaHcCKo N pOBoHNzM ΦEHNOckAhandHbAChKO r OHTa: reOxPOHOJOrN, KoppeLZuN, TEKToHnueCKne CLeIcTBn // 3TaIbI φOpMnPOBaHnY n \\\"]\",\n \"page_idx\": \"9\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[507,85,897,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"pa3BnTna npoTePo3oNcKo 3eMHoN KOpb: cTpaTnrgpA. \\\\nfno, Metamopn3M, MaMaTHn3M, rOOnHaMnka: Ma- \\\\nTepnaJIb VI PocCNIcko KOHpeHcUNI IO npo6JIeMaM \\\\nrEoJIoRnN n rOOnHaMnKn DOKeM6pN (CaHKT-NeTpE \\\\n6ypr, 22-24 OKT86Pra 2019 r). CPi6.: CBoe n3daTeJIbCTBO, 2019.C.221-222. \\\",\\\"XaH B. E., BoKko H. A. NCTOpUeCKa rEOTeKToHnKa. JOKem6pni. M.: HeJa, 1988. 381 c. \\\",\\\"LlykHa E. B., AraueB A. M., TolOBnH H. H., IoxnJeHko H. П. 3KBnurpaHnyIrpHbIe 3KJIoIrntbI n3 KIM6epJIInTOB0I Tpy6Kn IIM. B. Frp6a: CBnIeTeJIbCTBa naJIeONpOteP03oNcKo cy6dyKznn Ha TeppnTOpnApXaHReIbckO aIma3OHocHoi npOBnCUn // DOKnaDbI Akademn Hayk. 2015. T. 462. C. 208-212. doi: 10.7868/S0869565215140248 \\\",\\\"Balagansky V. V., Gorbunov L. A., Mudruk S. V. Paleoproterozoic Lapland-Kola collisional orogen, Northen Fennoscandian. Baltic shield // Precambrian high-grade mobile belts: Extended abstracts. Петрозаюск: KapHLP RAH, 2014. C. 7-10. \\\",\\\"Barley M. E., Bekker A., Krapez B. Late Archean to Early Paleoproterozoic global tectonics, environmental change and the rise of atmospheric oxygen // Earth Planet. Sci. Lett. 2005. Vol. 238. P. 156-171. doi: 10.1016/j.epsl.2005.06.062 \\\",\\\"Bogdanova S. V., Bingen B., Gorbatschev R., Kheraskova T. N., Kozlov V. I., Puchkov V. N., Volozh Yu. A. The East European Craton (Baltica) before and during the assembly of Rodinia // Precambr. Res. 2008. Vol. 160(1). P. 23-45. doi: 10.1016/j.precamres.2007.04.024 \\\",\\\"Buchan K. L., Ernst R. E., Hamilton M. A., Mertanen S., Pesonen L., Elming S.-Å. Rodinia the evidence from integrated palaeomagnetism and U-Pb geochronology// Precambr. Res. 2001. Vol. 110, no. 1-4. P. 99-631. doi: 10.1016/S0301-9268(01)00178-4 \\\",\\\"Cadman A. C., Heaman L., Tarney J., Wardle R., Krogh T. E. U-Pb geochronology and geochemical variation within two Proterozoic mafic dyke swarms, Labrador // Can. J. Earth Sci. 1993. Vol. 30(7). P. 1490-1504. doi: 10.1139/e93-128 \\\",\\\"Connelly J. N. Accretionary growth of the Sveconorwegian province of the Baltic shield between 1,7-1,5 Ga and links to intracontinental magmatism // GSA Annual Meeting, November 5-8, 2001 Sess. 11: Proterozoic tectonic evolution of the Grenville Orogen in Eastern North America I. 2001. Pap. 11. \\\",\\\"Daly J. S., Balagansky V. V., Timmerman M. J., Whitehouse V. J. The Lapland-Cola orogen: Paleoproterozoic collision and accretion of the northern Fennoscandian lithosphere // European Lithosphere Dynamics. Geological Society, London memoirs. 2006. Vol. 32. P. 579-598. doi: 10.1144/GSL.MEM.2006.032.01.35 \\\",\\\"Li Z. X., Bogdanova S. V., Collins A. S., Davidson A., De Waele B., Ernst R. E., Fitzsimons I. C. W., Fuck R. A., Gladkochub D. P., Jacobs J., Karlstrom K. E., Lu S., Natapov L. M., Pease V., Pisarevsky S. A., Thrane K., Vernikovsky V. Assembly, configuration, and break-up history of Rodinia: A synthesis // Precambr. Res. 2008. Vol. 160. P. 179-210. doi: 10.1016/j.precamres.2007.04.021 \\\",\\\"Mansfeld J., Andersen T. Formation of New Crust in Scandinavia Between 1,75 and 1,55 Ga as Evident from the Gothian Units of the stfold - Akershus Sector, \\\"]\",\n \"page_idx\": \"9\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[282,903,329,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[329,923,900,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[97,84,489,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"SE Norway // J. Conf. Abstr. EUG 10. 1999. Vol. 4, no. 1. P. 137. \\\",\\\"Pesonen L. J., Mertanen S., Veikkolainen T. Paleomesoproterozoic supercontinents - A paleomagnetic view // Geophysics. 2012. Vol. 48, no. 1-2. P. 5-47. \\\",\\\"Williams H., Hoffman P. F., Lewry J. F., Monger J. W. H., Rivers T. Anatomy of North America: thematic portrayals of the continent//Tectonophysics. 1991. Vol. 187. P. 117-134. doi: 10.1016/0040-1951(91)90416-P \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[97,212,200,226]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,237,489,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Arestova N. A., Chekulaev V. P., Egorova Yu. S., Kucherovskii G. A. Evolution of the composition and sources of basic and ultrabasic rocks during the transition from the Neoarchean to the Paleoproterozoic in the Karelian province, Baltic Shield, Russia. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 23-25. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,416,489,494]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Arzamastsev A. A., Bea F., Glaznev V. N., Arzamastseva L. V., Montero P. The Kola Alkaline Province in the Paleozoic: an assessment of the composition of primary mantlemelts and magmogeneration conditions. Rossiiiskii zhurnal nauk o Zemle = Russian Journal of Earth Sciences. 2001;3(1):1-35. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,494,489,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Balagansky V. V., Gorbunov L. A., Mudruk S. V. Paleoproterozoic Lapland-Kola collisional orogen, Northen Fennoscandian. Baltic Shield. Precambrian high-grade mobile belts: Extended abstracts. Petrozavodsk: KarRC RAS; 2014. P. 7-10. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,558,489,635]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Balagansky V. V., Gorbunov I. A., Mudruk S. V. Paleoproterozoic Lapland-Kola and Svecofennian orogens (Baltic Shield). Vestnik Kol'skogo nauchnogotsentra RAN = Bulletin of the Kola Scientific Center of the Russian Academy of Sciences. 1916;3(26):5-11. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,635,489,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Baluev A. S. Continental rifting of the north of the East European Platform in the Neogee: geology, history of development, comparative analysis: DSc (Dr. of Geol.-Miner.) thesis. Moscow; 2013. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,686,489,750]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Barley M. E., Bekker A., Krapez B. Late Archean to Early Paleoproterozoic global tectonics, environmental change and the rise of atmospheric oxygen. Earth Planet. Sci. Lett. 2005;238:156-171. doi: 10.1016/j.epsl.2005.06.062 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,751,489,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bogdanova S. V., Bingen B., Gorbatschev R., Kheraskova T. N., Kozlov V. I., Puchkov V. N., Volozh Yu. A. The East European Craton (Baltica) before and during the assembly of Rodinia. Precambrian Res. 2008;160(1): 23-45. doi: 10.1016/j.precamres.2007.04.024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,814,489,866]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bozhko N. A. Supercontinental cyclicity in the history of the Earth. Vestn. Mosk. un-ta. Ser. 4. Geologiya = Moscow University Bulletin. Series 4. Geology. 2009;4(2):13-27. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,866,489,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bozhko N. A., Prusakova N. A. On the prospects of the indigenous diamond content of the Karelian cra \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,84,895,109]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ton. Rudy i metally = Oresand Metals. 2014;4:5-13. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"ref_text\"\n },\n {\n \"bbox\": \"[507,110,895,186]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bozhko N. A., Prusakova N. A., Gromtsev K. V. Features of the tectonic structure of the Lapland-White Sea granulite-gneiss belt and prospects of its indigenous diamond content. Otechestvennaya geologiya = National Geology. 2021;6:45-64. (In Russ.). doi: 10.47765/0869-7175-2021-10031 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,186,895,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Buchan K. L., Ernst R. E., Hamilton M. A., Mertanen S., Pesonen L., Elming S.-A. Rodinia the evidence from integrated palaeomagnetism and U-Pb geochronology. Precambr. Res. 2001;110(1-4):99-631. doi: 10.1016/S0301-9268(01)00178-4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,251,895,314]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cadman A. C., Heaman L., Tarney J., Wardle R., Krogh T. E. U-Pb geochronology and geochemical variation within two Proterozoic mafic dyke swarms, Labrador. Can. J. Earth Sci. 1993;30(7):1490-1504. doi: 10.1139/e93-128 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,315,895,391]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Connelly J. N. Accretionary growth of the Sveconorwegian province of the Baltic shield between 1,7-1,5 Ga and links to intracontinental magmatism. GSA Annual Meeting, November 5-8, 2001 Sess. 11: Proterozoic tectonic evolution of the Grenville Orogen in Eastern North America I. 2001. Pap. 11. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,391,895,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daly J. S., Balagansky V. V., Timmerman M. J., Whitehouse V. J. The Lapland-Cola orogen: Paleoproterozoic collision and accretion of the northen Fennoscandian lithosphere. European Lithosphere Dynamics. Geological Society, London memoirs. 2006;32:579-598. doi: 10.1144/GSL.MEM.2006.032.01.35 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,469,895,648]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dokukina K. A., Konilov A. N., Wang K. V., Bayanova T. B., Sheshukov V. S., Khubanov V. B., Golovanova T. I. Paleoproterozoic granulite metamorphism with an age of $\\\\sim 2.45$ billion years in rocks of the White Sea eclogite province of the Fennoscandian Shield, Russia. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 68-70. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,648,895,674]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Glebovitskii V. A. (ed.). Early Precambrian of the Baltic Shield. St. Petersburg: Nauka; 2005. P. 711. 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Archean greenstone belts of the Karelian craton as accretion orogenes. Petrozavodsk: KarRC RAS; 2000. 223 p. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,738,895,840]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li Z. X., Bogdanova S. V., Collins A. S., Davidson A., De Waele B., Ernst R. E., Fitzsimons I. C. W., Fuck R. A., Gladkochub D. P., Jacobs J., Karlstrom K. E., Lu S., Natapov L. M., Pease V., Pisarevsky S. A., Thrane K., Vernikovsky V. Assembly, configuration, and break-up history of Rodinia: A synthesis. Precambr. Res. 2008;160:179-210. doi: 10.1016/j.precamres.2007.04.021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,840,895,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lobach-Zhuchenko S. B., Sergeev S. A., Levchenkov G. M., Ovchinnikova G. V., Kotova L. N., Krylov I. N., Yakovleva S. Z. Vodlozersky gneiss complex of the Early Archean an dits structural and metamorphic evolution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[685,914,705,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[97,923,576,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tpybl Kapelbckoro HayuHoro zentpa Pocsncko akaedmn hayk. 2024. 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Reconstruction of the Neoarchean supercontinent Kenorland based on paleomagnetic and geological data. Vestnik Moskovskogo universiteta. Ser. 4. Geologiya = Moscow University Bulletin. Series 4. Geology. 2011;4(4):23-30. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,187,487,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Mansfeld J., Andersen T. Formation of New Crust in Scandinavia Between 1,75 and 1,55 Ga as Evident from the Gothic Units of the stfold - Akershus Sector, SE Norway. J. Conf. Abstr. EUG 10. 1999;4(1):137. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,238,487,290]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Mitrofanov F. P. Early Precambrian geodynamics, magmatism and metallogeny of the Kola province. Vestnik MGTU = Bulletin of the Moscow State Technical University. 2009;12(4):567-570. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,290,487,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pesonen L. J., Mertanen S., Veikkolainen T. Paleomesoproterozoic supercontinents - A paleomagnetic view. Geophysics. 2012;48(1-2):5-47. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,328,487,429]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Petrovsky M. N., Petrovskaya L. S., Bayanova T. B. Evolution of magmatism in the geological history of the Murmansk Neoarchean craton. Magmatizm i metamorfizm vistorii Zemli: XI Vserossiiskoe petrograficheskoe soveshchanie: Tezisy dokladov = Magmatism and metamorphism in the history of the Earth. Proceed. XI All-Russian petrographic meeting. Vol. 2. Ekaterinburg; 2010. P. 130-131. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,431,487,546]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Puchkov V. N. Tectonics and geodynamics of ti manides. Strukturo-veshchestvennye kompleksey i problemy geodinamiki dokembriya fanerozoiskikh orogenov: Mat-ly mezhdunar. nauch. konf. (III chteniya pamyati S. N. Ivanova) = Structural-material complexes and problems of geodynamics of the Precambrian Phanerozoic orogens. Proceed. Scientific conference (III Readings in memory of S. N. Ivanov). Ekaterinburg: IGiG UrO RAN; 2008. P. 104-109. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,547,487,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Samsonov A. V., Stepanova A. V., Arzamastsev A. A., Sal'nikova E. B., Larionova Yu. O., Larionov A. I., Egorova S. V. The large magmatic province of Eastern Fennoscandia: paragenetic diversity in geodynamic unity. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemmag geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 198-200. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,713,487,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Shchukina E. V., Agashev A. M., Pokhilenko N. P., Golovin N. N. Equipgranular eclogites from the V. Grib \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,84,895,135]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"kimberlite pipe: evidence for Paleoproterozoic subduction on the territory of the Arkhangelsk diamondiferous province. Doklady Earth Sciences. 2015;462(1):497-501. doi: 10.1134/S1028334X15050165 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,136,895,302]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Slabunov A. I. Archaean and Paleoproterozoic orogens: a comparative analysis of geodynamic processes during their formation (on the example of the Fennoscandian Shield). Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 210-212. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,302,895,353]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Slabunov A. I. Geology and geodynamics of Archean mobile belts (on the example of the White Sea province of the Fennoscandian Shield). Petrozavodsk: KarRC RAS; 2008. 294 p. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,353,895,442]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Slabunov A. I., Lobach-Zhuchenko S. B., Bibikova E. V., Balagansky V. V., Soryonen-Ward P., Volodichev O. I., Shchipansky A. A., Svetov S. A., Chekulaev V. P., Arestova N. A., Stepanov V. S. Archaean of the Baltic Shield: geology, geochronology, geodynamic conditions. Geotektonika = Geotectonics. 2006;6:1-29. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,442,895,635]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Stepanova A. V., Samsonov A. V., Sal'nikova E. B., Arzamastsev A. A., Egorova S. V., Veselovskii R. V., Larionova Yu. O., Erofeeva K. G., Stafeeva M. V. Paleoproterozoic mafic dykes of the Karelian and Kola-Murmansk provinces of the Fennoscandian Shield: geochronology, correlation, tectonic consequences. Etapy formirovaniya i razvitiya proterozoiskoi zemnoi kory: stratigrafiya, metamorfizm, magmatizm, geodinamika: Materialy VI Rossiiskoi konferentsii po problemam geologii i geodinamiki dokembriya = Stages of formation and development of the Proterozoic crust: stratigraphy, metamorphism, magmatism, geodynamics. Proceed. VI Russian conference on Precambrian geology and geodynamics. St. Petersburg: Svoe izdatel'stvo; 2019. P. 221-222. (In Russ.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,636,895,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Volodichev O. I., Slabunov A. I., Bibikova E. V., Konilov A. N., Kuzenko T. I. Archean eclogites of the White Sea Mobile Belt (Baltic Shield). Petrologiya = Petrology. 2004;12(6):609-631. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,687,895,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Williams H., Hoffman P. F., Lewry J. F., Monger J. W. H., Rivers T. Anatomy of North America: thematic portrayals of the continent. Tectonophysics. 1991; 187:117-134. doi: 10.1016/0040-1951(91)90416-P \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[152,760,838,786]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IocTynna B peJaKuio / received: 28.03.2024; npinra T K nybIkaun / accepted: 23.09.2024. ABTOp 3aBnT o6 OTCyTCTBn KOHfLkTa HHTepecoB / The author declares no conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,820,307,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CBEDEHNOOBATOPE: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,840,289,853]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Божко Нikuолай Аndрeeвч \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,856,465,877]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Д-р reOl.-MnH. HayK, npofoeccop KafoepbI DInHaMnueckoI reOJOrn \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[121,883,290,894]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"e-mail: bozhko@yandex.ru \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,820,643,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CONTRIBUTOR: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,840,616,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bozhko, Nikolai \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,855,710,866]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dr. Sci. (Geol.-Miner.), Professor \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[295,914,317,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[329,923,900,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Transactions of the Karelian Research Centre of the Russian Academy of Sciences. 2024. No. 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.17076/geo1887"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Earth and Atmospheric Sciences"},"sha256":{"kind":"string","value":"803732029475de1e2825d4e7c3f3c18e17e80ac6c49e01005d1e6ebc91291c75"},"title":{"kind":"string","value":"Geodynamic evolution of the Еastern part of the Baltic shield against the background of supercontinental cyclicity"}}},{"rowIdx":163,"cells":{"abstract":{"kind":"string","value":"The data set collected during the night of the discovery of a minor body constitutes a too-short arc (TSA), resulting in failure of the differential correction procedure. This makes it necessary to recover the object during subsequent nights to gather more observations that will allow a preliminary orbit to be calculated. In this work, we present a recovery technique based on sampling the admissible region (AdRe) by the constrained Delaunay triangulation. We construct the AdRe in its topocentric and geocentric variants, using logarithmic and exponential metrics, for the following near-Earth-asteroids: (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5;and the main-belt asteroids: (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. Using our sampling technique, we established the ephemeris region for these objects, using intervals of observation from 25 minutes up to 2 hours, with propagation times from 1 up to 47 days. All these objects were recoverable in a field of vision of 95' x 72', except for (3122) Florence and (3200) Phaethon, since they were observed during their closest approach to the Earth. In the case of 2006 SO375, we performed an additional test with only two observations separated by 2 minutes, achieving a recovery of up to 28 days after its discovery, which demonstrates the potential of our technique."},"author":{"kind":"string","value":"Espitia, Daniela|Quintero, Edwin A.|Parra, Miguel A."},"content_list":{"kind":"list like","value":[{"bbox":"[94,153,813,208]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Recovery of Asteroids from Observations of Too-Short Arcs by Triangulating Their Admissible Regions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[94,220,542,238]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia†, Edwin A. Quintero, Miguel A. Parra ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[94,240,902,269]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Grupo de Investigación en Astroingeniería Alfa Orión, Observatorio Astrónomico, Universidad Tecnológica de Pereira, Complejo Educativo La Julita, 660003 Pereira, Colombia ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[92,316,905,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The data set collected during the night of the discovery of a minor body constitutes a too-short arc (TSA), resulting in failure of the differential correction procedure. This makes it necessary to recover the object during subsequent nights to gather more observations that will allow a preliminary orbit to be calculated. In this work, we present a recovery technique based on sampling the admissible region (AdRe) by the constrained Delaunay triangulation. We construct the AdRe in its topocentric and geocentric variants, using logarithmic and exponential metrics, for the following near-Earth-astereoids: (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5; and the main-belt asteroids: (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. Using our sampling technique, we established the ephemeris region for these objects, using intervals of observation from 25 minutes up to 2 hours, with propagation times from 1 up to 47 days. All these objects were recoverable in a field of vision of $95' \\times 72'$ , except for (3122) Florence and (3200) Phaethon, since they were observed during their closest approach to the Earth. In the case of 2006 SO375, we performed an additional test with only two observations separated by 2 minutes, achieving a recovery of up to 28 days after its discovery, which demonstrates the potential of our technique. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[94,514,502,528]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: admissible region, asteroids, astrometry, ephemerides ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[94,569,238,583]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[92,602,480,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Orbital dynamics of minor bodies of the solar system is a current area of interest in astronomy, especially when these are newly discovered objects, i.e., there are no previous records. Different observatories around the world report the finding of these objects on a daily basis, but due to the short interval of observation (too-short arcs, TSA), the astrometric data collected are not sufficient to establish a preliminary orbit (Gronchi 2004). This is because the classic methods of initial orbit determination fail in this type of case (Milani & Knezevic 2005; Espitia et al. 2020). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[94,767,480,829]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to establish a preliminary orbit for new objects, it is necessary to ensure their re-observation following the nights after the discovery. This task requires anticipating their predicted location in the celestial sphere, a procedure ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,569,905,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"known as recovery (Milani 2001; Milani & Gronchi 2009). The utility available online known as New Object Ephemerides (http://www.minorplanetcenter.net/iau/MPEph/NewObjEphems.html) is a service offered by the Minor Planet Center (MPC) for the follow-up of new objects. However, this service is based on ephemeris calculation via the orbit-fitting procedure by Väisälä (Gwyn et al. 2012), which is a classic method that provides acceptable results for main-belt asteroids (MBAs) but not for near-Earth asteroids (NEAs; http://www.cadc-ccda.hia-iha.nrc-cnrc.gc.ca/en/ssois/documentation.html#ephem). In addition, this fitting applies the approximation of assuming that the object is observed at its perihelion (Väisälä 1939; Kristensen 2006). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,799,904,829]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In contrast to classical methods, Milani et al. (2004) use the concept of the admissible region (AdRe) to delimit the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[92,74,250,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Research Paper ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[92,95,339,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J.Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[92,109,354,119]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[717,74,904,119]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JASS Journal of Astronomy and Space Sciences ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[94,849,480,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\langle \\widehat{\\mathbb{C}}\\rangle$ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[517,849,899,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received 03 OCT 2020 Revised 28 MAY 2021 Accepted 28 MAY 2021 ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[517,866,652,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"†Corresponding Author ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[517,881,801,892]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tel: +57-3163873180, E-mail: daesmo95@utp.edu.co ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[517,896,774,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORCID: https://orcid.org/0000-0002-7730-3494 ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[94,945,342,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright © The Korean Space Science Society ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[487,945,510,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"119 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[631,945,904,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr pISSN: 2093-5587 eISSN: 2093-1409 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[87,90,480,319]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"location region of an asteroid seen from Earth, followed by triangulation sampling within this region to anticipate the follow-up. While in the literature, there are different applications of this technique in the study of space (Tommei et al. 2007; Maruskin et al. 2009; Farnocchia et al. 2010; DeMars et al. 2012), and in the study of Earth impactors (Valk & Lemaitre 2006; Spoto et al. 2018), the only examples of the method of Milani et al. (2004) being applied for follow-up purposes are NEA 2003 BH84 (Milani et al. 2004) and the centaur (60558) Echeclus (Farnocchia et al. 2015). Given the above, in Espitia Mosquera & Quintero Salazar (2019), we extend this sample by applying the method to delimit the region of space in which a set of 6 asteroids (3 NEA, 2 MBA, and 1 Hilda) were at a given date. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,322,480,433]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this article, we present an AdRe sampling method based on the constrained Delaunay triangulation, which can establish a region of possible orbits of a minor body determined from a TSA observation. This set of orbits can determine the search area of the object in the celestial sphere for follow-up purposes. Our technique does not require mesh smoothing, which reduces the computational cost. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,437,480,515]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition, we extend the application sample of the technique of Milani et al. (2004) by determining the AdRe and applying our triangulation in the follow-up of a set of 12 asteroids (6 NEA, 2 MBA, 1 Hungaria, 2 Hilda, and 1 Jupiter trojan). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,519,480,549]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the results obtained in this work, we discuss the capabilities and limitations of the method. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,552,480,616]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We implement our follow-up technique in a web service available at http://observatoriooenlinea.utm.edu.co/recoveryservice/. The source code of the algorithm is available in that same link under an open-source license. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,651,331,667]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. MATERIALS AND METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[90,684,290,698]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1 Admissible Region (AdRe) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,717,480,781]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"According to Milani et al. (2004), based on an attribute (Milani 2001) given by the expression (1), the AdRe of an object is defined as the set of all possible $(\\pmb {\\rho},\\dot{\\pmb{\\rho}})$ that satisfy the following conditions: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[92,799,480,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"I. The object belongs to the solar system and is not a long-orbital-period celestial body. This implies considering elliptical orbits with heliocentric energies $E_{\\\\odot}$ less than $-k^2 / 2a_{max}$ , with $a_{max} = 100$ au and $k = 0.01720209895$ (Gaussian gravitational constant). \",\"II. The object is not immersed in the Earth's gravitational field; that is, it has a geocentric energy $E_{\\\\oplus} \\\\geq 0$ while it is \"]","page_idx":"1","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[537,92,902,105]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"within the Earth's radius of influence $(R_{SI} = 0.010044\\mathrm{au})$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[584,132,904,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nA = \\left(\\alpha , \\delta , \\dot {\\alpha}, \\dot {\\delta}\\right) \\in \\left[ - \\pi , \\pi\\right) \\times \\left(- \\frac {\\pi}{2}, \\frac {\\pi}{2}\\right) \\times \\mathbb {R} ^ {2} \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,191,905,402]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Condition (1) establishes the upper limit of the AdRe, which can have at most two connected components, in the extreme case in which asteroids with a perihelion greater than 28 au are studied (Spoto et al. 2018). Regarding the lower limit, according to condition (2), it is given by the curve of geocentric energy equal to zero (if $0 < \\rho < R_{SI}$ ), or by a straight-line segment $\\rho = R_{SI}$ and two arcs corresponding to the geocentric energy. It is even possible to constrain the lower limit further by ignoring the orbits belonging to meteoroids that are too small to be considered sources of meteorites. This is achieved by invoking the condition $H \\leq H_{max}$ (Spoto et al. 2018), with $H_{max} = 34.5$ , corresponding to the threshold for meteors (Milani et al. 2004). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,404,907,716]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Espitia Mosquera & Quintero Salazar (2019), we determine the AdRe's of a sample of 6 asteroids from the sets of observations that constitute TSAs, using the geocentric and topocentric variants and the logarithmic and exponential metrics. We find that the topocentric variant considerably reduces the search area of the AdRe's since it involves additional constraints, such as the exclusion of meteors. Furthermore, we find that the AdRe's that were generated from a topocentric variant have simpler geometries compared with their geocentric counterparts. Regarding the metrics, we conclude that the logarithmic metric is adequate for analyzing the regions near the lower limit of the AdRe because this scale allows us to see the characteristics at the values in the distance near to the observer, whereas the exponential metric is adequate for the regions near the upper limit. The AdRe's obtained not only excluded those bodies dominated by Earth's gravity but also considerably reduced the search area, thus optimizing the subsequent sampling from a triangulation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,750,732,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. SAMPLING OF THE ADRE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,783,905,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The diagram shown in Fig. 1 summarizes the triangulation and follow-up process that we implement in this work. First, we sampled the AdRe boundary through a sampling algorithm for a rectifiable curve (blue block) proposed in Milani et al. (2004). Then, we introduced a sampling strategy for the interior of the AdRe based on the constrained Delaunay triangulation (purple block). Next, we propagated all possible orbits to a later date (red block). Finally, we ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,44,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,943,326,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"120 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[221,90,774,174]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. General scheme of the recovery procedure. \"]","image_footnote":"[]","img_path":"images/0317/c27b327218acab5d360fbe6b70c63789d7e575786bed4608396c20ae6d5c5aeb.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,223,482,287]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"calculated the ephemerides for each of the propagated orbits; that is, we found the region of location of the body under study in the celestial sphere for a specific date (yellow block). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,306,332,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1 Sampling of the AdRe Boundary ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,339,482,435]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"According to Milani et al. (2004), the AdRe has an upper limit given by the arcs of the curve $E_{\\odot}(\\rho, \\dot{\\rho}) = 0$ or the curve $E_{\\odot}(\\rho, \\dot{\\rho}) = -k^2 / 2a_{max}$ (symmetric with respect to the line $\\dot{\\rho} = -c_1 / 2$ ). In addition, the lower limit is given by the arcs of the curve $E_{\\oplus}(\\rho, \\dot{\\rho}) = 0$ (symmetric with respect to $\\dot{\\rho} = 0$ ) and the segments of the lines $\\rho = \\rho_{H}, \\rho = R_E$ and $\\rho = R_{SI}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,437,482,469]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The sampling of these AdRe boundaries consists of choosing points that are equispaced at the boundary; that is, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,223,905,435]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"if the boundary is parametrized by the arc length $\\mathbf{s}$ , then the distance of each pair of consecutive points corresponds to a fixed increment of $\\mathbf{s}$ . In order to avoid the calculation of $\\mathbf{s}$ , Milani et al. (2004) propose an algorithm that, from a large number of points equispaced on one of the two abscissas, applies an elimination rule that is iterated until the desired number of points at the boundary are left. The points thus obtained are close to the ideal distribution, equispaced along the arc length. The symmetry with respect to $\\dot{\\rho} = -c_{1}/2$ allows sampling the upper curve of $E_{\\odot}(\\rho, \\dot{\\rho})$ from $\\rho_{H}$ to the maximum value $\\rho_{max}$ . Likewise, for the sampling of the lower limit, we apply the same procedure using the symmetry with respect to $\\dot{\\rho} = 0$ of the curve $E_{\\oplus} = 0$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,437,905,469]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 2 presents the algorithm that we implement for sampling the AdRe boundary. The algorithm starts with ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[226,491,771,887]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2. Algorithm for sampling the boundary of the AdRe. AdRe, admissible region. \"]","image_footnote":"[]","img_path":"images/0053/b668a78c3b6dcda50d85c9cdfe570eda72d68d986f2079d44f46a0f5bc574bb3.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[376,45,905,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,510,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"121 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,905,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[89,90,482,240]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$n$ points of a rectifiable curve $\\gamma$ , with unitary length (The algorithm is designed for any length). The central goal of the algorithm consists of selecting $m$ points $(m < n)$ such that the distance along the curve between 2 consecutive points is as close as possible to $1 / (m - 1)$ (Milani et al. 2004). To avoid the calculation of the arc length $\\mathbf{s}$ , we assume that $\\gamma$ is the unit interval $[0,1] \\subset \\mathbb{R}$ . We then define it as $(P_k)_{k=1,\\dots,n}$ the set of ordered points in $[0,1]$ with $P_1 = 0$ , $P_n = 1$ , and establish $(Q_j)_{j=1,\\dots,m}$ , the sequence of ideal equispaced points with: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[181,266,482,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nQ _ {j + 1} - Q _ {j} = \\frac {1}{m - 1} = h \\quad i d e a l s t e p \\tag {2}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[89,321,484,404]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Considering $d_{k} = P_{k} - P_{k-1}$ and $\\delta_{k,j} = |Q_{j} - P_{k}|$ , note that for each $P_{k}$ there is an ideal point $Q_{j}$ , such that $\\delta_{k,j} \\leq h/2$ . In order to discard a point from the set $(P_{k})_{k=1,\\dots,n}$ , we established an elimination rule, which seeks to eliminate the point such that $\\bar{k}$ minimizes the following function: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[174,427,482,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nf (k) = \\frac {\\min \\left\\{d _ {k} , d _ {k + 1} \\right\\}}{1 + \\min _ {j = 1 \\dots m} \\delta_ {k , j}} k = 2, \\dots , n - 1 \\tag {3}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[89,486,482,602]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The process above is applied $(n - m)$ times. In each iteration, the values of $d_{k}$ change due to the elimination rule of points in the set $\\left(P_k\\right)_{k = 1,\\dots,n}$ given by (3). Finally, we denote by $\\hat{P}_j)_{j = 1,\\dots,m}$ the subset of points selected along the AdRe boundary. We implemented the algorithm described above in a Matlab function. Fig. 3 presents the result obtained when applying this algorithm in the sampling of the AdRe ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,92,774,105]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"boundary of asteroid (1738) Oosterhoff. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,124,742,139]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2 Internal Sampling of the AdRe ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,157,907,370]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"After the sampling of the AdRe boundary, it is necessary to sample the internal region. (Milani et al. 2004), and (Milani & Gronchi 2009) claim that an optimum method for improving this task consists of performing a triangulation followed by mesh smoothing. We propose a strategy based on the constrained Delaunay triangulation, which operates as follows. Given the domain of a polynomial $\\tilde{D} \\subset D$ defined by the connection with the edges of the sample of boundary points (obtained in subsection 3.1) of the AdRe $D$ , the triangulation of the polygonal domain $\\tilde{D}$ is the pair $(\\Pi, \\tau)$ with $\\Pi = \\{P_1, \\dots, P_N\\}$ as the set of nodes of the domain, and $\\tau = \\{T_1, \\dots, T_2\\}$ as the set of triangles $T_i$ whose vertexes are in $\\Pi$ . This triangulation has to fulfill the following conditions: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[529,387,905,436]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. $\\\\cup_{i = 1,k}T_{i} = \\\\tilde{D}$ \",\"2. For each $i \\\\neq j$ , the set $T_i \\\\cap T_j$ is empty, or a vertex is empty, or a side of the triangle, or one of its edges. \"]","page_idx":"3","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[512,453,905,534]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"If in addition to the set of points $\\Pi$ , some edges $P_{i}P_{j}$ are entered as inputs (for example, the boundary edges of $\\tilde{D}$ ; The input is referred to as a planar straight line graph [PSLG]), the triangulation that contains the prescribed edges is called a constrained triangulation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,535,905,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For each triangulation $(\\Pi, \\tau)$ , we can associate the minimum angle, which is defined as the minimum between the angles of all the triangles $T_{i}$ . Among other possible triangulations of a convex domain, there is a construction called the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,633,489,847]","code_body":null,"code_caption":null,"image_caption":"[\"(a) AdRe using exponential metric \"]","image_footnote":"[]","img_path":"images/0651/f8d1780a2a78628ab7c8b0afd88e2b3609da51783c41f51c0dcc2080e68f5df7.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[510,634,885,849]","code_body":null,"code_caption":null,"image_caption":"[\"(b) AdRe sampled at its boundary \",\"Fig. 3. Sampling of boundary of the AdRe for asteroid (1738) Oosterhoff. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. AdRe, admissible region. \"]","image_footnote":"[]","img_path":"images/0866/0b6ac5e613edd9191417c735fa5234eb955692890e00a3b00eb01a2ac99e3368.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,44,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,943,326,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"122 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[89,92,485,126]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Delaunay triangulation (Bern & Eppstein 1995), which is characterized by the following properties: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[105,141,482,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"i. It maximizes the minimum angle. \",\"ii. It minimizes the circumscribed circle. \",\"iii. For each triangle $T_{ij}$ the internal part of its circumscribed circumference does not contain any node of the triangulation (Risler 1992). \"]","page_idx":"4","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[89,239,484,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When they are convex domains, the previous properties are equivalent. If the domain is a convex quadrangle whose vertexes $\\Pi$ are not on the same circle, there are two possible triangulations $(\\Pi, \\tau_1)$ , $(\\Pi, \\tau_2)$ . According to property (iii), only one of this triangulation is a Delaunay triangulation. In this case, the Delaunay triangulation is obtained through a first triangulation using a technique called edge-flipping (Milani & Gronchi 2009). Note that the AdRe domain, $\\tilde{D}$ is not generally convex. In this scenario, there is still a triangulation that maximizes the minimum angle, known as the constrained Delaunay triangulation, but the property (iii) is not guaranteed. For each triangle $T_i$ A procedure is iterated over the adjacent triangles. If the common edge with the adjacent triangle is not Delaunay, the edge-flipping technique is applied. This procedure is repeated until all edges of the structure in the triangulation are Delaunay or are the edges of the boundary $\\tilde{D}$ . In each repetition, the minimum angle increases, and the triangulation that maximizes the minimum angle is obtained at the end (Delaunay 1934). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,569,482,733]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to implement the triangulation described in the previous paragraphs, we develop an algorithm that begins by generating a constrained Delaunay triangulation $(\\Pi_0,\\tau_0)$ with the boundary points (generated as shown in 3.1) and the boundary edges. Once the initial triangulation is obtained, it is refined by adding internal points to the domain, maintaining the Delaunay property at each intersection. In each case, a new point is added, which extends to the internal part of the discrete density domain defined in the boundary point for the quantities: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[226,746,347,769]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\rho P _ {j} = \\min _ {l \\neq j} \\left| P _ {l} - P _ {j} \\right|,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[107,799,327,814]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With the corresponding densities ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,839,339,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\tilde {\\rho} G _ {i} = \\frac {1}{3} \\sum_ {m = 1} ^ {3} \\rho P _ {i m},\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[107,897,482,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Where $G_{i}$ corresponds to the barycenters of the triangles ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,92,905,220]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$T_{i}$ and the barycenter $G_{\\bar{k}}$ is added as a new point, which maximizes the minimum distance (weighted by its density $\\tilde{\\rho} G_{\\bar{k}})$ from the triangulation nodes $(P_{im},m = 1,\\dots,3,$ belong to the same triangle $T_{i})$ . Then, the corresponding triangle $T_{k}$ is removed, and the triangles obtained by joining the edges of $T_{k}$ with the new point are added to $\\tau$ . Consequently, the optimum property of the Delaunay triangulation is conserved in each insertion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,223,907,305]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The flow diagram in Fig. 4 shows the procedure used for triangulating the AdRe as a domain, which is generally not convex. It begins with a number of points resulting from the sampling of the boundary (for example, $N = 25$ ), out of which the repeated data are removed (the result of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,330,907,878]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4. Constrained Delaunay triangulation algorithm for sampling inside the boundary of AdRe. \"]","image_footnote":"[]","img_path":"images/0380/e8afbb97c63767aa2726acb2c2bf199a5e74ced50f233d0886fca4bb46bc32d8.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[376,45,905,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,512,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"123 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,907,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[87,92,480,172]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"sampling the curves at its points of intersection). Then, a first triangulation is performed to identify the triangles outside the AdRe. Then, the domain is constrained, and a first constrained Delaunay triangulation is performed (the outer triangles are removed again). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,174,480,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The following step consists of calculating the barycenters of each triangle $T_{i}$ and with them performing a constrained Delaunay triangulation again. This last step is performed twice. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,240,484,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The algorithm in question was implemented as a MATLAB function. Fig. 5 presents the results obtained when applying our algorithm for sampling inside the AdRe boundary of asteroid (1738) Oosterhoff. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,322,416,337]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3 Propagation of Orbits and Ephemeris Region ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,355,484,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Once the boundary and the internal region of the AdRe are sampled, it is necessary to propagate the established points to define the possible orbits that belong to the object under study. In fact, this object corresponds to a minor body $\\mathfrak{B}$ that belongs to the solar system and that moves around the sun with heliocentric position $\\mathbf{r}$ , which is observed from Earth $\\varepsilon$ with a radius vector $\\mathbf{R}$ , known for a given instant of time. As is evident, the vector between the Earth and the minor body $\\pmb{\\rho}$ is the unknown that was solved in the previous sections. This process gives, as a result, a set of possible values $(\\pmb{\\rho},\\dot{\\pmb{\\rho}})$ for the average time of the observations ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,92,905,139]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"collected from a TSA. Each of these points defines a virtual asteroid determined by a set of six quantities of the following form: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[643,155,778,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nX = \\left[ \\alpha , \\delta , \\dot {\\alpha}, \\dot {\\delta}, \\rho , \\dot {\\rho} \\right]\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,191,905,271]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"That set is known as *attributable orbital elements* (Milani & Gronchi 2009). The following step is consists of replacing each point $(\\rho, \\dot{\\rho})$ or the node of the triangulation (after going back to its original metric) in the state vector expression defined by equation (4). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[678,290,739,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf {r} = \\mathbf {R} + \\rho \\hat {\\boldsymbol {\\rho}}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[636,303,904,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\dot {\\mathbf {r}} = \\dot {\\mathbf {R}} + \\dot {\\rho} \\hat {\\boldsymbol {p}} + \\rho (\\dot {\\alpha} \\hat {\\boldsymbol {p}} _ {\\alpha} + \\dot {\\delta} \\hat {\\boldsymbol {p}} _ {\\delta}) \\tag {4}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,339,905,403]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Where $\\hat{\\rho}$ is the unit vector in the direction of observation and $\\mathbf{R},\\dot{\\mathbf{R}}$ is the state vector of the Earth, a parameter that is obtained from the collection times of the TSA (Espitia Mosquera & Quintero Salazar 2019), with: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[606,419,791,436]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\hat {\\rho} = (\\cos \\alpha \\cos \\delta , \\sin \\alpha \\cos \\delta , \\sin \\delta)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[608,437,904,452]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\hat {\\boldsymbol {\\rho}} _ {a} = (- \\sin \\alpha \\cos \\delta , \\cos \\alpha \\cos \\delta , 0) \\tag {5}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[608,453,800,469]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\hat {\\boldsymbol {\\rho}} _ {\\delta} = (- \\cos \\alpha \\sin \\delta , - \\sin \\alpha \\sin \\delta , \\cos \\delta)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[512,486,905,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As a result of this process, a set of initial state vectors $(\\mathbf{r},\\dot{\\mathbf{r}})$ in the heliocentric-equatorial system is obtained. We used a two-body integrator based on the functions $f$ and $g$ (Danby ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,564,284,679]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0510/4d02746e9180990008c99435df06767ad49ac9e964263fc3f9c18c73c949c069.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[295,566,487,679]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0666/33fac27a109ed3c16a777fb73890f145b122977f5e4aac0adfd5defe578d1407.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[500,566,695,680]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0648/d72f6fe6d55bab9212a202df432d9a241b2a384abdd784e5557144c41dcb4399.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[707,566,902,679]","code_body":null,"code_caption":null,"image_caption":"[\"(d) \"]","image_footnote":"[]","img_path":"images/0102/30990771b08f5c7564d4a83b8bf947d1f7b85edd70829ad34e1a9ef4cd067ea6.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,706,282,819]","code_body":null,"code_caption":null,"image_caption":"[\"(e) \"]","image_footnote":"[]","img_path":"images/0687/60f43f6e15723ce94e3701074f9345786339a31fad36065a228e857c8417e6a9.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[292,707,487,818]","code_body":null,"code_caption":null,"image_caption":"[\"(f) \"]","image_footnote":"[]","img_path":"images/0208/50a38fa5fa1fdcf168a884432d4355fdb1eab462a44046b5fc17c9f01bd0c264.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[500,707,695,818]","code_body":null,"code_caption":null,"image_caption":"[\"(g) \"]","image_footnote":"[]","img_path":"images/0599/b4df3515093bf549e90d43f9e930f1a758cec98f7580836dbb4cff1997e27ca1.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[710,709,900,818]","code_body":null,"code_caption":null,"image_caption":"[\"(h) \",\"Fig. 5. Results of applying our triangulation algorithm for sampling inside the AdRe boundary for asteroid (1738) Oosterhoff under the exponential metric. (a) Selection of points on the boundary. (b) First triangulation and identification of outer triangles. (c) Constraint of the AdRe domain. (d) Removal of triangles outside the domain. (e) First computation of barycenters. (f) Triangulation with the new set of points and subsequent constraint of the boundary. (g) New computation of barycenters inside the boundary of the AdRe. (h) Final result of both the boundary sampling process and constrained Delaunay triangulation. The red dot in (h) shows the asteroid real position. AdRe, admissible region. \"]","image_footnote":"[]","img_path":"images/0328/54c2c5d9a6054024971f34cfc8d82db325d1d46126df28712fa9b1cfd831c0a3.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,44,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,943,327,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"124 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[89,90,484,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1962; Boulet 1991) to obtain the set of final state vectors $(\\mathbf{r}_t,\\dot{\\mathbf{r}}_t)$ . In order to simulate the propagation for a few days we use this dynamic model because its implementation is relatively simple to implement. Fig. 6 presents this set for the case of asteroid (1738) Oosterhoff. From this set, we calculate the ephemerides, that is, the right ascension and declination coordinates for each of the points propagated for a specific date after the observation of the object under ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,92,702,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"study (ephemerides region). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,142,606,157]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,174,905,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We applied our follow-up strategy to the set of the 12 asteroids listed in the first column of Table 1, whose types are reported in the fourth column (6 NEA, 2 MBA, 1 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[97,245,364,399]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0661/d98d257006dbd815ea554d443b8390a22ddcb014c45168ab2fb5d66dec301787.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[371,245,633,399]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0569/b79956e8534272841713a5ef4585709b172ee7907fae8cbfd10936c690e2517f.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[638,245,894,399]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0514/32ba03b6d7f77bdbdfc82b9223477fb8116251189089779c53821337fa06c147.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[97,435,361,588]","code_body":null,"code_caption":null,"image_caption":"[\"(d) \"]","image_footnote":"[]","img_path":"images/0285/a42d0c8a30896d8133dc4da896e65eadfa89e08f9cd4488fa755f032d67c0091.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[374,435,630,588]","code_body":null,"code_caption":null,"image_caption":"[\"(e) \"]","image_footnote":"[]","img_path":"images/0325/a8c9956ec863d6f64ecf4fca3d57abd66fba941451972b18999a1112d835e8bf.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[636,435,895,590]","code_body":null,"code_caption":null,"image_caption":"[\"(f) \",\"Fig. 6. Components of heliocentric position and velocity vectors for asteroid (1738) Oosterhoff. Top row: vectors at the average time of initial observation. Bottom row: vectors at the recovery time. The cyan and red dots show the components of the real asteroid. \"]","image_footnote":"[]","img_path":"images/0915/a7f765cf21b809517c7bbb0ab916f00b7c05afa5bf737f1d55a9f1df60809060.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,698,905,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0311/520b64092ba044b84a5ef75d66ccd390ad3a09aae399f04e47b54e2387259a8a.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td>Asteroid</td><td>MPC code</td><td>TSA (Δt)</td><td>Type</td><td>Smax(au) Topocen.</td><td>η(°/day)</td><td>Real Pos. ρ (au)</td><td>Propagation aprox.</td><td>Recovery</td></tr><tr><td>(3122) Florence</td><td>W63</td><td>1 h 44 min</td><td>NEA/PHA</td><td>0.0849</td><td>9.3920</td><td>0.0475</td><td>12 d</td><td>no</td></tr><tr><td>(3200) Phaethon</td><td>W63</td><td>2 h 04 min</td><td>NEA/PHA</td><td>0.2157</td><td>10.0720</td><td>0.0859</td><td>11 d 19 h</td><td>no</td></tr><tr><td>2003 GW</td><td>608</td><td>1 h 31 min</td><td>NEA/Apollo</td><td>1.7344</td><td>0.7996</td><td>0.9479</td><td>10 d 18 h</td><td>yes</td></tr><tr><td>(1864) Daedalus</td><td>703</td><td>25 min 29 s</td><td>NEA/Apollo</td><td>3.5840</td><td>0.3026</td><td>1.4658</td><td>15 d 20 h</td><td>yes</td></tr><tr><td>2003 BH84</td><td>809</td><td>1 h 37 min</td><td>NEA/Apollo</td><td>4.4617</td><td>0.3498</td><td>1.9928</td><td>11 d 22 h</td><td>yes</td></tr><tr><td>1977 QQ5</td><td>F51</td><td>1 h 47 min</td><td>NEA/Amor</td><td>3.3697</td><td>0.2664</td><td>2.1336</td><td>13 d 16 h</td><td>yes</td></tr><tr><td>(1738) Oosterhoff</td><td>W63</td><td>1 h 24 min</td><td>MBA</td><td>1.7940</td><td>0.2378</td><td>1.0104</td><td>15 d</td><td>yes</td></tr><tr><td>(4690) Strasbourg</td><td>W63</td><td>48 min 40 s</td><td>Hungaria</td><td>2.1182</td><td>0.2916</td><td>1.3425</td><td>16 d 23 h</td><td>yes</td></tr><tr><td>(555) Norma</td><td>W63</td><td>1 h 34 min</td><td>MBA</td><td>3.2767</td><td>0.1051</td><td>2.2395</td><td>12 d</td><td>yes</td></tr><tr><td>2006 SO375</td><td>705</td><td>1 h 23 min</td><td>Hilda</td><td>7.5199</td><td>0.1654</td><td>2.2756</td><td>27 d 20 h</td><td>yes</td></tr><tr><td>2003 GE55</td><td>291</td><td>59 min 04 s</td><td>Hilda</td><td>8.8767</td><td>0.1576</td><td>3.3645</td><td>47 d 21 h</td><td>yes</td></tr><tr><td>(32811) Apisaon</td><td>T05</td><td>2 h 18 min</td><td>Jupiter Trojan</td><td>6.8280</td><td>0.0776</td><td>4.3549</td><td>18 d 15 h</td><td>yes</td></tr></table>","table_caption":"[\"Table 1. Table of sample asteroids recovery. The observatory code, the interval of the initial observations, the orbit type, the $S_{max}$ value, the proper motion, the propagated days interval and the possibility of a recovery are shown \"]","table_footnote":"[\"MPC, minor planet center; TSA, too-short arc; NEA, near-Earth asteroid; MBA, main-belt asteroid. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[376,45,905,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,512,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"125 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,905,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[89,90,480,139]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Hungaria, 2 Hilda, and 1 Jupiter trojan). In order to achieve this goal, we use our new web recovery service available at http://observatoriooenlinea.utp.edu.co/recoveryservice/. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,141,480,336]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As input data, we used the observations reported to the MPC (https://www.minorplanetcenter.net/db_search) by the observatories listed in the second column within the intervals of observation presented in the third column (in all cases, the interval of observation used constitutes a TSA). For minor bodies reported by the W63 observatory, they are registries performed by us from the Astronomical Observatory of the Technological University of Pereira, Colombia (from here on, OAUTP) exclusively for this work. The complete tables of data of the observations used in this work are available at https://www.utp.edu.co/ observatorioiastronomico/astrometria/recovery. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,337,480,418]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"First, we established the AdRe's for the minor bodies under study following the procedure described in Espitia Mosquera & Quintero Salazar (2019), using the geocentric and topocentric approximations and the exponential and logarithmic metrics. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[92,421,482,680]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The performed tests showed that for the 12 asteroids analyzed, the most adequate version for performing an optimum sampling process was the version with topocentric correction and based on the exponential metric. This is because the topocentric approximation gives, in all cases, AdRe's with much simpler shapes than their geocentric equivalents, and the exponential metric presents a higher density of points around the asteroid's real position. Figs. 7 and 8 present the AdRe's computed for the objects under study. However, we observed that the logarithmic metric describes regions of the AdRe's near the Earth with more detail, so it would be useful in the study of near meteoroids and artificial satellites. For those readers interested in these types of objects, we report the AdRe's obtained using logarithmic metrics at https://www.utm.edu.co/ observatorioiaastronomico/astrometria/recovery. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,684,480,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Regarding the AdRe's calculated under the topocentric approximation and under exponential metrics, we applied the sampling technique described in section 3. Figs. 9 and 10 present the results of this process. In all cases, our sampling method generated at least one node of the triangulation in the proximities of the asteroid's real position. This indicates that at least one of the ephemeris points corresponds to a value close to the asteroid's real position in the celestial sphere. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,815,480,911]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We transformed each node provided by the triangulation into a heliocentric-equatorial state vector $(\\rho, \\dot{\\rho})$ . Then, we performed the calculation of the set of vectors for the position and velocity in the heliocentric-equatorial system $(r_{i}, \\dot{r}_{i})$ . The graphs of each component for the initial times of each asteroid show that the metric that offers ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,92,904,238]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"a cleaner sampling was the exponential one (https:// observatorioastronomico.utm.edu.co/astrometria/recovery.html). Subsequently, we performed propagation of each of these vectors to a date after the observation (column 8, Table 1), the date at which the follow-up of the asteroids in question was performed. For that purpose, we used our 2-body propagation algorithm through functions $f$ and $g$ . The propagation of these vectors showed that there are deformations of the AdRe's for the spatial components. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,239,904,368]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The most significant change occurred for asteroids (3200) Phaethon and (3122) Florence, whose input data were collected when they were at their points of closest approach to the Earth (the real position of the objects within their orbit at the moment of their observation is listed in column 7 of Table 1). The changes in the shape of the AdRe's, after the propagation, become less abrupt when the asteroid is farther away from the observer. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,370,904,781]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, we calculated the ephemerides for each of the points obtained from the previous process for observation times after the observations listed in column 8 of Table 1. The recovery times are calculated from the location of the OAUTP (W63). Figs. 11 and 12 present the results of this process. As a reference, the figures include, indicated within the blue dotted-line box, the field of the vision given by the instrumental assembly of the OAUTP $(95^{\\prime} \\times 72^{\\prime})$ . Our approach is to slew the telescope near the region with the highest density of points, i.e., the region with more ephemeris grouped. The asteroid's real position is also included; it was obtained from the HORIZONS Web-Interface of NASA's JPL (identified by a red dot; https:// ssd.jpl.nasa.gov/horizons.cgi) and the recovery by Väisälä provided by the New Object Ephemerides service of the MPC (identified by a blue dot; http://www.minorplanetcenter. net/iau/MPEph/NewObjEphems.html). We tested our methodology by implementing a Laplacian mesh smoothing filter. However, as our purpose was to point the telescope towards the region of the sky with the highest number of points (i.e., ephemeris), the difference when we applied the filter did not show a more significant advantage in the results shown in Figs. 11 and 12. So we concluded that our method eliminates the need for smoothing as proposed by Milani et al. (2004), thus increasing the computational efficiency. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,783,904,911]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As can be observed from Figs. 11 and 12, except for asteroids (3122) Florence and (3200) Phaethon, all asteroids were recoverable since they presented a higher density of possible location coordinates within the visual field of the OAUTP and near the asteroids' real position (red dot). In some cases, it is sufficient to recover the object again by panning the sky with a telescope that covers three fields of vision. Even in the cases of asteroids 2003 BH84 and 2006 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,45,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,944,326,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"126 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,90,465,281]","code_body":null,"code_caption":null,"image_caption":"[\"(a) (3122) Florence $\\\\bar{t}_i$ UT $= 20170902.23046$ \"]","image_footnote":"[]","img_path":"images/0481/4d4f2cb639f2ca2b204b9af00cddff168b717a7b4c2d49fcafa5743696b9f552.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[521,90,855,279]","code_body":null,"code_caption":null,"image_caption":"[\"(b) (3200) Phaethon $\\\\bar{t}_i(\\\\mathrm{UT}) = 2017$ 12 14.17371 \"]","image_footnote":"[]","img_path":"images/0898/ad50b849d1f9e0e60bcfb7863b27b8770605ae5a1bf8322053c62c1c4af37055.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[117,312,455,503]","code_body":null,"code_caption":null,"image_caption":"[\"(c) 2003 GW $\\\\bar{t}_i$ (UT) = 2003 04 04.31379 \"]","image_footnote":"[]","img_path":"images/0867/74d61e35033a5a9c9afbf49089d4a80fdf74a4462ea3c6cd914be4d466be9d14.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[524,317,850,505]","code_body":null,"code_caption":null,"image_caption":"[\"(d) (1864) Daedalus $\\\\bar{t}_i$ (UT) = 2018 03 06.20089 \"]","image_footnote":"[]","img_path":"images/0394/95c430c3a8113a72db56d0a9f293ea04f05aea3b7aaa2556ea25070706ed83d7.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[121,540,453,731]","code_body":null,"code_caption":null,"image_caption":"[\"(e) 2003 BH84 $\\\\bar{\\\\tau}_i$ (UT) $= 20030125.11890$ \"]","image_footnote":"[]","img_path":"images/0890/a073beafbab8d3df7e56365c0da33c24fbe82abcb6311a3fcc644abf5ad34e08.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,539,850,728]","code_body":null,"code_caption":null,"image_caption":"[\"(f) 1977QQ5 $\\\\bar{t}_i(\\\\mathrm{UT}) = 20141126.62712$ \",\"Fig. 7. AdRe's for asteroids (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5, with topocentric correction using the exponential metric. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. \"]","image_footnote":"[]","img_path":"images/0935/5c8381dafd6d542c8f277c71510595939c3dc0a4b17e28d18d470fb87068617c.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,815,482,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SO375, our recovery was better than that provided by the New Object Ephemerides service since our triangulated ephemerides have a higher density closer to the real position than that given by the MPC. In addition, column 8 of Table 1 shows that the follow-up times range from 10 days (in the case of asteroid 2003 GW) up to 47 days (for ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,815,905,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the case of asteroid 2003 GE55) after the observations, from intervals of observation that do not exceed 3 hours, which demonstrates the potential of our follow-up method of newly discovered objects. Our method also reduces the number of objects that inflate the lists of lost objects, since the follow-up strategy would enable locating an object up ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[376,45,905,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"127 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,905,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[124,88,468,281]","code_body":null,"code_caption":null,"image_caption":"[\"(a) (1738) Oosterhoff $\\\\bar{t}_i$ UT=2017 09 27.14048 \"]","image_footnote":"[]","img_path":"images/0797/8f2d1e90c6a97459c3c90cdc0c9750129a2d59c9f4b45cc4a5f34a9a4d744aa7.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[507,88,843,281]","code_body":null,"code_caption":null,"image_caption":"[\"(b) (4690) Strasbourg $\\\\bar{t}_i$ (UT)=2018 03 11.10067 \"]","image_footnote":"[]","img_path":"images/0221/fabdbb4f785be88840b15384fb97c5ae489d56b603aa7f94e21a500f59cc5418.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[126,305,465,501]","code_body":null,"code_caption":null,"image_caption":"[\"(c) (555) Norma $\\\\bar{\\\\tau}_i(\\\\mathrm{UT}) = 20180417.15633$ \"]","image_footnote":"[]","img_path":"images/1010/46cb7f063087cfae33fcb6bf9831d22ea4533eb1911e397be326fbcb0af9a66e.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[507,303,842,504]","code_body":null,"code_caption":null,"image_caption":"[\"(d) 2006 SO375 $\\\\bar{t}_i(\\\\mathrm{UT}) = 20060917.39025$ \"]","image_footnote":"[]","img_path":"images/0944/441d65de129d2b98ac6da349d9574704519a0591153b5f41a67c6382e2fc9a52.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[126,532,463,738]","code_body":null,"code_caption":null,"image_caption":"[\"(e) 2003 GE55 $\\\\bar{t}_i$ (UT)=2002 02 13.27846 \"]","image_footnote":"[]","img_path":"images/0758/f9f872995fab9eeba4b855b23f46b783ca601cf4855aaecf1767ab70caa94d1e.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[510,542,842,738]","code_body":null,"code_caption":null,"image_caption":"[\"(f) (32811) Apisao $\\\\bar{t}_i(\\\\mathrm{UT}) = 20180513.43080$ \",\"Fig. 8. AdRe's for asteroids (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon, with topocentric correction using the exponential metric. The red dot shows the real position of the asteroid obtained from the HORIZONS. AdRe, admissible region. \"]","image_footnote":"[]","img_path":"images/0124/cc702cd3498538cb739348b9b2044e3adece2ee01e4770eb98d337d64b32d7c4.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[87,832,480,862]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"to 47 days after their discovery, using an interval of the observation of just 3 hours. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,863,482,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the case of asteroids (3122) Florence and (3200) Phaethon, our method was not able to anticipate a recovery (last column of Table 1). In fact, the New Object Ephemerides ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,832,907,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"service of the MPC was not able to either (see the top row of Fig. 11). This was because the input observations correspond to one of the moments of closest approach to the Earth (in this case, of the order of $10^{-2}$ au), and therefore their apparent motion was large (column 6 of Table 1). In ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,44,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,943,327,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"128 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[144,90,463,273]","code_body":null,"code_caption":null,"image_caption":"[\"(a) (3122) Florence \"]","image_footnote":"[]","img_path":"images/0335/988d63e8de66f20af4bf5434c6a53a7ef979e8283a49f89d48d2b5dd26b3fcf9.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[527,90,855,276]","code_body":null,"code_caption":null,"image_caption":"[\"(b) (3200) Phaethon \"]","image_footnote":"[]","img_path":"images/0469/79963e2c0ef18980307ede158991bb75e31e615169219efb663b14437ca462cf.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[142,295,460,477]","code_body":null,"code_caption":null,"image_caption":"[\"(c) 2003 GW \"]","image_footnote":"[]","img_path":"images/0206/ef95f42c4a4f8f35a43fcd4b9c6300e503d926f4d2d7f3de2b258c16740a8a64.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[527,297,850,480]","code_body":null,"code_caption":null,"image_caption":"[\"(d) (1864) Daedalus \"]","image_footnote":"[]","img_path":"images/0330/0f4924a95283dbc2e48c7d9bf5d6e2ca198e8f8e117d3e8d408c353abeab074a.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[142,501,465,688]","code_body":null,"code_caption":null,"image_caption":"[\"(e) 2003 BH84 \"]","image_footnote":"[]","img_path":"images/0007/8da90d15051a9f4648574d261cb7314c3f750a238489451c2ac237580209b132.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[526,505,847,688]","code_body":null,"code_caption":null,"image_caption":"[\"(f) 1977 QQ5 \",\"Fig. 9. Triangulated AdRe's for asteroids (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. AdRe, admissible region. \"]","image_footnote":"[]","img_path":"images/0707/48cad9ed64d9b496ed971e6f92a958efded1a935d26b304d366d4d2206f2064a.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,766,482,846]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the recording of a close pass by the Earth, the gravitational field can affect our propagation model based on a two-body integrator, so we conclude that in these cases, it is necessary to consider the gravity of the Earth as a perturbation in our dynamical model. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,848,482,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to identify the scope of our method, we repeat the follow-up of asteroid 2006 SO375, but now with just two input data separated by less than 2 minutes, corresponding to the night of their discovery (Table 2). Fig. 13 presents ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,766,907,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the ephemeris region of the asteroid for 28 days after its observation. Note how the higher density of possible positions of the asteroid provided by our algorithm (black crosses) is within the field of the vision given by the instrumental assembly of the OAUTP and closer to the real position given by the JPL's HORIZONS Web- Interface (red dot), than the recovery provided by the New Object Ephemerides service of the MPC (blue dot). This demonstrates the scopes of our technique, in addition to its application in the follow-up of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[376,45,905,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,512,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"129 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,905,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[152,90,472,273]","code_body":null,"code_caption":null,"image_caption":"[\"(a) (1738) Oosterhoff \"]","image_footnote":"[]","img_path":"images/0047/2e875b5a7982c5c5c9d5894ddee27a330a28498dd6a065870959fb687f688d12.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[497,90,830,274]","code_body":null,"code_caption":null,"image_caption":"[\"(b) (4690) Strasbourg \"]","image_footnote":"[]","img_path":"images/0469/2802ed0be548e970100d40a823714c6b214d856baf5d6f2f4b5ce6dc401906a4.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[152,305,473,489]","code_body":null,"code_caption":null,"image_caption":"[\"(c) (555) Norma \"]","image_footnote":"[]","img_path":"images/0181/a5015dc9ceaecd81caac418d050866dedecb3209bd7b0ff87d7c562f4419ec74.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[512,305,833,496]","code_body":null,"code_caption":null,"image_caption":"[\"(d) 2006 SO375 \"]","image_footnote":"[]","img_path":"images/0491/f41b6765fee532ac153b5e6ed52d1cda7e3f6ea824a1f7e6023d89987f052bae.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[154,518,475,709]","code_body":null,"code_caption":null,"image_caption":"[\"(e) 2003 GE55 \"]","image_footnote":"[]","img_path":"images/0998/05994d2fb70280f680db22b0ae6fe86fa3a604fefdb53fa92f14a3819930bf97.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[507,524,830,713]","code_body":null,"code_caption":null,"image_caption":"[\"(f) (32811) Apisaon \",\"Fig. 10. Triangulated AdRe's for asteroids (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. AdRe, admissible region. \"]","image_footnote":"[]","img_path":"images/0266/3974431121425971ed18b17fe832d7fbf1cc3191f79c7f212d3e33465478492b.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,799,307,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"recently discovered minor bodies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,849,364,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.DISCUSSION AND CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,881,480,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Literature review showed that the AdRe sampling technique is an important tool for the study of objects ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,799,905,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(eespecially with short intervals of observation) that is widely applied to space debris. However, despite its versatility, we found in our review that the use of AdRe has only been applied for the following minor bodies in two cases: 2003 BH84 and (60558) Echeclus. In this paper, we extend the field of application of the AdRe sampling follow-up technique by applying it to a group of 12 asteroids: 6 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,44,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Astron. Space Sci. 38(2), 119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,943,324,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"130 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[131,100,472,293]","code_body":null,"code_caption":null,"image_caption":"[\"(a) (3122) Florence $\\\\bar{t}_f(\\\\mathrm{UT}) = 20170914.23046$ \"]","image_footnote":"[]","img_path":"images/0804/be56e05002439d7cd193e7e62d75bf7a502d27f1b43ca5f64331f83c2db9a0ab.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[512,100,857,296]","code_body":null,"code_caption":null,"image_caption":"[\"(b) (3200) Phaethon $\\\\bar{t}_t(\\\\mathrm{UT}) = 20171225.99749$ \"]","image_footnote":"[]","img_path":"images/0274/f88ba35d35329cb24fb485e5617778735f47a64e2ea4e2c4493daac175ac2441.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[127,327,480,524]","code_body":null,"code_caption":null,"image_caption":"[\"(c) 2003 GW $\\\\bar{t}_f(\\\\mathrm{UT}) = 20030415.10099$ \"]","image_footnote":"[]","img_path":"images/0829/ff9baf97c9bc7a3662e60b2c8134641ca16145148a690ab2a381a7baefa70c5c.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[522,329,868,523]","code_body":null,"code_caption":null,"image_caption":"[\"(d) (1864) Daedalus $\\\\bar{t}_f(\\\\mathrm{UT}) = 20180322.05026$ \"]","image_footnote":"[]","img_path":"images/0712/0c1938892a4827ec24b946a4627ec7ca9ed7863192302176178298857a33ec50.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[129,559,485,757]","code_body":null,"code_caption":null,"image_caption":"[\"(e) 2003 BH84 $\\\\bar{t}_f$ (UT) = 2003 02 06.07308 \"]","image_footnote":"[]","img_path":"images/0341/fa8f54ce18a109186d1edeb37cd4c5340f17ac7aec92a7a44015128ac1340a67.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[519,559,868,754]","code_body":null,"code_caption":null,"image_caption":"[\"(f) 1977 QQ5 $\\\\bar{t}_r(\\\\mathrm{UT}) = 2014$ 12 10.33445 \",\"Fig. 11. Ephemerides region for final date $t_f$ for asteroids (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5. The blue dotted lines box corresponds to the field of vision ( $95' \\\\times 72'$ ) given by the OAUTP instrumental assembly. \"]","image_footnote":"[]","img_path":"images/0456/639faf7e76128f83c9ede9fe49a7ea5bf8c1086cc5d33020cfc7379a4918a102.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,832,482,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NEAs and 6 MBAs. Regarding the sampling strategy, we proposed a technique based on the constrained Delaunay triangulation, which does not require the subsequent application of a mesh smoother. In addition, we implement our follow-up algorithm in a web service under an open-","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,832,905,895]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"source license. We constructed the AdRe's for the twelve asteroids from the geocentric approximation and, with topocentric correction, implementing the logarithmic and exponential metrics. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[529,897,905,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The results showed that the AdRe's based on topocentric ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[376,45,905,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,510,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"131 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,905,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[131,97,480,293]","code_body":null,"code_caption":null,"image_caption":"[\"(a) (1738) Oosterhoff $\\\\tilde{t}_f(\\\\mathrm{UT}) = 20171012.14047$ \"]","image_footnote":"[]","img_path":"images/0331/c43f2fca13db5a8aa437053a10d21cb88c2d73f1b9cae40bbbebcee52e6e142d.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[502,97,863,293]","code_body":null,"code_caption":null,"image_caption":"[\"(b) (4690) Strasbourg $\\\\bar{t}_f(\\\\mathrm{UT}) = 20180328.06564$ \"]","image_footnote":"[]","img_path":"images/0736/3b629e502ef08aa470574fdfa56e0160b8e3bb3c281456555848e049e49cb1dc.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[132,327,475,523]","code_body":null,"code_caption":null,"image_caption":"[\"(c) (555) Norma $\\\\bar{t}_t(\\\\mathrm{UT}) = 20180429.15633$ \"]","image_footnote":"[]","img_path":"images/0154/1b0f6f4b0661b164bb39a324b75aa0d9b61848ce89f7ce36e627b7db35cf4b71.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[504,325,858,523]","code_body":null,"code_caption":null,"image_caption":"[\"(d) 2006 SO375 $\\\\bar{t}_f(\\\\mathrm{UT}) = 20061015.22358$ \"]","image_footnote":"[]","img_path":"images/0903/6293a03629befe8103784f456786d964d0ceb0d87c745871edebd45d5ea05cb9.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[132,557,480,752]","code_body":null,"code_caption":null,"image_caption":"[\"(e) 2003 GE55 $\\\\bar{t}_t$ (UT) = 2002 04 02.16270 \"]","image_footnote":"[]","img_path":"images/0239/c9090ae9f8b8201dfae81f1a66f747ed995f9b9d4fd125f10a11b590237b40db.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[504,556,858,752]","code_body":null,"code_caption":null,"image_caption":"[\"(f) (32811) Apisaon $\\\\bar{\\\\tau}_{f}(\\\\mathrm{UT}) = 20180601.08888$ \",\"Fig. 12. Ephemerides region for final date $t_f$ for asteroids (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. The box comprised of blue dotted lines corresponds to the field of vision ( $95' \\\\times 72'$ ) given by the OUTFP instrumental assembly. \"]","image_footnote":"[]","img_path":"images/0733/af2defd4a06273ac4ccd2e89fa29a87b83af883929f924089f04685a2fe283be.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[159,857,836,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0025/b9cc3cd5d36ee74ec5c41d526868b290cee907351b92eb6e413b13f68feade60.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":"<table><tr><td>Data number</td><td>TSA (Δt)</td><td>Initial date (UT)</td><td>Final date (UT)</td><td>η (°/day)</td><td>Smax(au) Topocentric</td></tr><tr><td>2</td><td>1 min 44 s</td><td>2006 09 17.36278</td><td>2006 10 15.22358</td><td>0.1420</td><td>8.2914</td></tr></table>","table_caption":"[\"Table 2. Table of recovery for asteroid 2006 SO375 using an interval of $\\\\Delta t = 1\\\\mathrm{\\\\;{min}}{11.712}\\\\mathrm{\\\\;s}$ . The initial date of observation,the recovery final date, the proper motion and the ${S}_{max}$ value are shown \"]","table_footnote":"[\"TSA, too-short arc. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[90,45,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J.Astron.Space Sci.382),119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,944,326,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"132 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[92,95,475,313]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 13. Ephemerides region for asteroid 2006 SO375 from 2 spaced data $\\\\Delta t = 1$ min 11.712 s. \"]","image_footnote":"[]","img_path":"images/0593/b47a2198284cfbcb6814e77c68c17f2ecd320f9d4b79c44e410dcfb8d92c0602.jpg","list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[87,370,482,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"correction and using the exponential metric were better adapted to our sampling technique, since they presented a greater geometric simplicity and a higher density of possible orbits around the asteroids' real position. In addition, we observed that the AdRe's presented common elements within each family of asteroids, such that they could be used in future work to delimit the possible families to which a newly discovered object belongs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[90,504,482,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the 12 asteroids, we propagated the ephemeris region using the field of vision of the OAUTP (W63). We observed that 10 out of the 12 asteroids were recoverable, with observation times between approximately 25 minutes and 2 hours (TSA), and with propagations for follow-up of up to 47 days. We even observed how with an interval of the observation of just 2 minutes, it was possible to recover asteroid 2006 SO375 for approximately 28 days, which demonstrates the potential of our triangulation technique. The fact that our methodology can perform the follow-up of an object, even several weeks after its observation, makes it possible for observatories exposed to changing climate conditions, as in the case of the OAUTP, to observe the object again. This enables gathering more data, which would make it possible to construct a preliminary orbit, avoiding addition of the object to the list of lost objects. In the case of asteroids (3122) Florence and (3200) Phaethon, we could not perform the recovery from the observations used as input. We concluded that this was due to these objects being at the nearest point to Earth within their orbit at the moment of observation. As can be observed from Table 1, these minor bodies had a position $\\rho$ of the order $10^{-1}$ au and an average motion $\\eta$ much faster than the other asteroids. To validate our hypothesis, we simulated observations for this same pair of objects but at a distance greater than 1 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,92,905,238]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"au. In this case, our method did allow the follow-up of the objects. The follow-up that we obtained for asteroid 2003 GW $(\\rho \\cong 1$ au) allows us to infer that the closer the object under study is from the Earth at the moment of observation, the more dispersed will be its ephemeris region (center-left, Fig. 11). This effect could be due to its proximity to the Earth, explained by the gravitational field has a more drastic influence, which is why it would be necessary to implement a three-body model in this type of case. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,240,907,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Currently, there are two web services JPL's Scout system (https://cneos.jpl.nasa.gov/scout) and NEOScan (https:// newton.spacedys.com/neodys/NEOScan/), which allow obtaining ephemeris from short-arc observation by using sophisticated methods. However, both services have a common disadvantage which is the fact that they only allow calculating ephemeris of existing objects in the Near-Earth Object Confirmation Page database (https:// minorplanetcenter.net//iau/NEO/toconfirm_tabular.html). In contrast, our services allow obtaining ephemeris from the coordinates resulting from the astrometric reduction made directly by the observer. In this way, if an observed object is suspected of being a discovery, the observer has the possibility of planning its future observations using our service without the need to wait for the provisional pre-registration of the object in the Near-Earth Object Confirmation database. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,553,692,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,585,905,665]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We are grateful for financial support provided by the \"Vicerrectoría de Investigaciones, Innovación y Extensa\" of the Universidad Tecnológica de Pereira, Colombia. This research has made use of NASA's Astrophysics Data System Bibliographic Services. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,701,571,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORCID ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[529,733,900,747]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia https://orcid.org/0000-0002-7730-3494 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[532,750,655,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Edwin A. Quintero ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,767,900,780]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://orcid.org/0000-0002-0974-4650 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[532,783,900,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Miguel A. Parra https://orcid.org/0000-0001-9108-3187 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,832,621,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,865,905,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bern N, Eppstein D, Mesh generation and optimal triangulation, in Computing in Euclidean Geometry, eds. Du D, Hwang F (World Scientific, Singapore, 1995), 47-123. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[376,45,905,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[485,945,512,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"133 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[828,944,905,957]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"http://janss.kr ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[92,92,480,665]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Boulet DL, Methods of Orbit Determination for the Microcomputer (Willmann-Bell, Richmond, NA, 1991). \",\"Danby DMA, Fundamentals of Celestial Mechanics (Macmillan, London, 1962). \",\"Delaunay B, Sur la sphere vide, Izv. Akad. Nauk SSSR, Otdelenie Matematicheskii i Estestvennyka Nauk 7, 6, 793-800 (1934). \",\"DeMars KJ, Jah MK, Schumacher PW, Initial orbit determination using short-arc angle and angle rate data, IEEE Trans. Aerosp. Electron. Syst. 48, 2628-2637 (2012). https://doi.org/10.1109/TAES.2012.6237613 \",\"Espitia D, Quintero EA, Arellano-Ramirez ID, Determination of orbital elements and ephemerides using the geocentric Laplace's method, J. Astron. Space Sci. 37, 171-185 (2020). https://doi.org/10.5140/JASS.2020.37.3.171 \",\"Espitia Mosquera D, Quintero Salazar EA, Determination of the admissible region of asteroids with data from one night of observation, J. Phys. Conf. Ser. 1247, 012038 (2019). https://doi.org/10.1088/1742-6596/1247/1/012038 \",\"Farnocchia D, Chesley SR, Milani A, Gronchi GF, Chodas PW, Orbits, Long-Term Predictions, and Impact Monitoring, Asteroids IV, eds. Michel P, DeMeo FE, Bottke WF (University of Arizona Press, Tucson, AZ, 2015), 815-834. \",\"Farnocchia D, Tommei G, Milani A, Rossi A, Innovative methods of correlation and orbit determination for space debris, Celest. Mech. Dyn. Astron. 107, 169-185 (2010). https://doi.org/10.1007/s10569-010-9274-6 \",\"Gronchi GF, Classical and modern orbit determination for asteroids, Proc. Int. Astron. Union. 2004, 293-303 (2004). https://doi.org/10.1017/S174392130500147X \",\"Gwyn SDJ, Hill N, Kavelaars JJ, SSOS: a moving-object image search tool for asteroid precovery, Publ. Astron. Soc. Pac. 124, 579-585 (2012). https://doi.org/10.1086/666462 \",\"Kristensen LK, Initial linking methods and their classification, Proc. Int. Astron. Union. 2, 301-308 (2006). https://doi.org/10.1017/S1743921307003365 \"]","page_idx":"15","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[515,92,905,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Maruskin JM, Scheeres DJ, Alfriend KT, Correlation of optical observations of objects in Earth orbit, J. Guid. Control Dyn. 32, 194-209 (2009). https://doi.org/10.2514/1.36398 \",\"Milani A, The asteroid identification problem IV: attributions, Icarus. 151, 150-159 (2001). https://doi.org/10.1006/icar:2001.6594 \",\"Milani A, Gronchi G, Theory of Orbit Determination (Cambridge University Press, Cambridge, 2009). \",\"Milani A, Gronchi GF, Vitturi MDM, Knežević Z, Orbit determination with very short arcs. I Admissible regions, Celest. Mech. Dyn. Astron. 90, 57-85 (2004). https://doi.org/10.1007/s10569-004-6593-5 \",\"Milani A, Knežević Z, From astrometry to celestial mechanics: orbit determination with very short arcs, Celest. Mech. Dyn. Astron. 92, 1-18 (2005). https://doi.org/10.1007/s10569-004-6593-5 \",\"Risler JJ, Mathematical Methods for CAD (Cambridge University Press, Cambridge, 1992). \",\"Spoto F, Del Vigna A, Milani A, Tommei G, Tanga P, et al., Short arc orbit determination and imminent impactors in the Gaia era, Astron. Astrophys. 614, A27 (2018). https://doi.org/10.1051/0004-6361/201732104 \",\"Tommei G, Milani A, Rossi A, Orbit determination of space debris: admissible regions, Celest. Mech. Dyn. Astron. 97, 289-304 (2007). https://doi.org/10.1007/s10569-007-9065-x \",\"Väisälä Y, Eine einfache Methode der Bahnbestimmung (Suomalaisen Tiedeakatemian Kustantama, Helsinki, 1939). \",\"Valk S, Lemaitre A, Admissible regions for too short arcs: nodal distances and elongations, Proceedings of the International Astronomical Union, Prague, 24 Aug 2006. https://doi.org/10.1017/S1743921307003572 \"]","page_idx":"15","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[90,45,312,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J.Astron.Space Sci.382),119-134 (2021) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,944,326,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.5140/JASS.2021.38.2.119 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,945,512,955]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"134 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[94,153,813,208]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Recovery of Asteroids from Observations of Too-Short Arcs by Triangulating Their Admissible Regions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,220,542,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia†, Edwin A. Quintero, Miguel A. Parra \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,240,902,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Grupo de Investigación en Astroingeniería Alfa Orión, Observatorio Astrónomico, Universidad Tecnológica de Pereira, Complejo Educativo La Julita, 660003 Pereira, Colombia \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[92,316,905,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The data set collected during the night of the discovery of a minor body constitutes a too-short arc (TSA), resulting in failure of the differential correction procedure. This makes it necessary to recover the object during subsequent nights to gather more observations that will allow a preliminary orbit to be calculated. In this work, we present a recovery technique based on sampling the admissible region (AdRe) by the constrained Delaunay triangulation. We construct the AdRe in its topocentric and geocentric variants, using logarithmic and exponential metrics, for the following near-Earth-astereoids: (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5; and the main-belt asteroids: (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. Using our sampling technique, we established the ephemeris region for these objects, using intervals of observation from 25 minutes up to 2 hours, with propagation times from 1 up to 47 days. All these objects were recoverable in a field of vision of $95' \\\\times 72'$ , except for (3122) Florence and (3200) Phaethon, since they were observed during their closest approach to the Earth. In the case of 2006 SO375, we performed an additional test with only two observations separated by 2 minutes, achieving a recovery of up to 28 days after its discovery, which demonstrates the potential of our technique. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,514,502,528]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: admissible region, asteroids, astrometry, ephemerides \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,569,238,583]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[92,602,480,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Orbital dynamics of minor bodies of the solar system is a current area of interest in astronomy, especially when these are newly discovered objects, i.e., there are no previous records. Different observatories around the world report the finding of these objects on a daily basis, but due to the short interval of observation (too-short arcs, TSA), the astrometric data collected are not sufficient to establish a preliminary orbit (Gronchi 2004). This is because the classic methods of initial orbit determination fail in this type of case (Milani & Knezevic 2005; Espitia et al. 2020). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,767,480,829]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to establish a preliminary orbit for new objects, it is necessary to ensure their re-observation following the nights after the discovery. This task requires anticipating their predicted location in the celestial sphere, a procedure \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,569,905,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"known as recovery (Milani 2001; Milani & Gronchi 2009). The utility available online known as New Object Ephemerides (http://www.minorplanetcenter.net/iau/MPEph/NewObjEphems.html) is a service offered by the Minor Planet Center (MPC) for the follow-up of new objects. However, this service is based on ephemeris calculation via the orbit-fitting procedure by Väisälä (Gwyn et al. 2012), which is a classic method that provides acceptable results for main-belt asteroids (MBAs) but not for near-Earth asteroids (NEAs; http://www.cadc-ccda.hia-iha.nrc-cnrc.gc.ca/en/ssois/documentation.html#ephem). In addition, this fitting applies the approximation of assuming that the object is observed at its perihelion (Väisälä 1939; Kristensen 2006). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,799,904,829]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In contrast to classical methods, Milani et al. (2004) use the concept of the admissible region (AdRe) to delimit the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[92,74,250,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Research Paper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[92,95,339,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J.Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[92,109,354,119]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[717,74,904,119]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JASS Journal of Astronomy and Space Sciences \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[94,849,480,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\langle \\\\widehat{\\\\mathbb{C}}\\\\rangle$ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[517,849,899,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received 03 OCT 2020 Revised 28 MAY 2021 Accepted 28 MAY 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[517,866,652,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"†Corresponding Author \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[517,881,801,892]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tel: +57-3163873180, E-mail: daesmo95@utp.edu.co \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[517,896,774,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORCID: https://orcid.org/0000-0002-7730-3494 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[94,945,342,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright © The Korean Space Science Society \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[487,945,510,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[631,945,904,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr pISSN: 2093-5587 eISSN: 2093-1409 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[87,90,480,319]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"location region of an asteroid seen from Earth, followed by triangulation sampling within this region to anticipate the follow-up. While in the literature, there are different applications of this technique in the study of space (Tommei et al. 2007; Maruskin et al. 2009; Farnocchia et al. 2010; DeMars et al. 2012), and in the study of Earth impactors (Valk & Lemaitre 2006; Spoto et al. 2018), the only examples of the method of Milani et al. (2004) being applied for follow-up purposes are NEA 2003 BH84 (Milani et al. 2004) and the centaur (60558) Echeclus (Farnocchia et al. 2015). Given the above, in Espitia Mosquera & Quintero Salazar (2019), we extend this sample by applying the method to delimit the region of space in which a set of 6 asteroids (3 NEA, 2 MBA, and 1 Hilda) were at a given date. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,322,480,433]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this article, we present an AdRe sampling method based on the constrained Delaunay triangulation, which can establish a region of possible orbits of a minor body determined from a TSA observation. This set of orbits can determine the search area of the object in the celestial sphere for follow-up purposes. Our technique does not require mesh smoothing, which reduces the computational cost. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,437,480,515]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition, we extend the application sample of the technique of Milani et al. (2004) by determining the AdRe and applying our triangulation in the follow-up of a set of 12 asteroids (6 NEA, 2 MBA, 1 Hungaria, 2 Hilda, and 1 Jupiter trojan). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,519,480,549]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the results obtained in this work, we discuss the capabilities and limitations of the method. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,552,480,616]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We implement our follow-up technique in a web service available at http://observatoriooenlinea.utm.edu.co/recoveryservice/. The source code of the algorithm is available in that same link under an open-source license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,651,331,667]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. MATERIALS AND METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,684,290,698]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1 Admissible Region (AdRe) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,717,480,781]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"According to Milani et al. (2004), based on an attribute (Milani 2001) given by the expression (1), the AdRe of an object is defined as the set of all possible $(\\\\pmb {\\\\rho},\\\\dot{\\\\pmb{\\\\rho}})$ that satisfy the following conditions: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[92,799,480,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"I. The object belongs to the solar system and is not a long-orbital-period celestial body. This implies considering elliptical orbits with heliocentric energies $E_{\\\\\\\\odot}$ less than $-k^2 / 2a_{max}$ , with $a_{max} = 100$ au and $k = 0.01720209895$ (Gaussian gravitational constant). \\\",\\\"II. The object is not immersed in the Earth's gravitational field; that is, it has a geocentric energy $E_{\\\\\\\\oplus} \\\\\\\\geq 0$ while it is \\\"]\",\n \"page_idx\": \"1\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[537,92,902,105]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"within the Earth's radius of influence $(R_{SI} = 0.010044\\\\mathrm{au})$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[584,132,904,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nA = \\\\left(\\\\alpha , \\\\delta , \\\\dot {\\\\alpha}, \\\\dot {\\\\delta}\\\\right) \\\\in \\\\left[ - \\\\pi , \\\\pi\\\\right) \\\\times \\\\left(- \\\\frac {\\\\pi}{2}, \\\\frac {\\\\pi}{2}\\\\right) \\\\times \\\\mathbb {R} ^ {2} \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,191,905,402]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Condition (1) establishes the upper limit of the AdRe, which can have at most two connected components, in the extreme case in which asteroids with a perihelion greater than 28 au are studied (Spoto et al. 2018). Regarding the lower limit, according to condition (2), it is given by the curve of geocentric energy equal to zero (if $0 < \\\\rho < R_{SI}$ ), or by a straight-line segment $\\\\rho = R_{SI}$ and two arcs corresponding to the geocentric energy. It is even possible to constrain the lower limit further by ignoring the orbits belonging to meteoroids that are too small to be considered sources of meteorites. This is achieved by invoking the condition $H \\\\leq H_{max}$ (Spoto et al. 2018), with $H_{max} = 34.5$ , corresponding to the threshold for meteors (Milani et al. 2004). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,404,907,716]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Espitia Mosquera & Quintero Salazar (2019), we determine the AdRe's of a sample of 6 asteroids from the sets of observations that constitute TSAs, using the geocentric and topocentric variants and the logarithmic and exponential metrics. We find that the topocentric variant considerably reduces the search area of the AdRe's since it involves additional constraints, such as the exclusion of meteors. Furthermore, we find that the AdRe's that were generated from a topocentric variant have simpler geometries compared with their geocentric counterparts. Regarding the metrics, we conclude that the logarithmic metric is adequate for analyzing the regions near the lower limit of the AdRe because this scale allows us to see the characteristics at the values in the distance near to the observer, whereas the exponential metric is adequate for the regions near the upper limit. The AdRe's obtained not only excluded those bodies dominated by Earth's gravity but also considerably reduced the search area, thus optimizing the subsequent sampling from a triangulation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,750,732,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. SAMPLING OF THE ADRE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,783,905,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The diagram shown in Fig. 1 summarizes the triangulation and follow-up process that we implement in this work. First, we sampled the AdRe boundary through a sampling algorithm for a rectifiable curve (blue block) proposed in Milani et al. (2004). Then, we introduced a sampling strategy for the interior of the AdRe based on the constrained Delaunay triangulation (purple block). Next, we propagated all possible orbits to a later date (red block). Finally, we \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,44,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,943,326,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"120 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[221,90,774,174]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. General scheme of the recovery procedure. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0317/c27b327218acab5d360fbe6b70c63789d7e575786bed4608396c20ae6d5c5aeb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,223,482,287]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"calculated the ephemerides for each of the propagated orbits; that is, we found the region of location of the body under study in the celestial sphere for a specific date (yellow block). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,306,332,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1 Sampling of the AdRe Boundary \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,339,482,435]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"According to Milani et al. (2004), the AdRe has an upper limit given by the arcs of the curve $E_{\\\\odot}(\\\\rho, \\\\dot{\\\\rho}) = 0$ or the curve $E_{\\\\odot}(\\\\rho, \\\\dot{\\\\rho}) = -k^2 / 2a_{max}$ (symmetric with respect to the line $\\\\dot{\\\\rho} = -c_1 / 2$ ). In addition, the lower limit is given by the arcs of the curve $E_{\\\\oplus}(\\\\rho, \\\\dot{\\\\rho}) = 0$ (symmetric with respect to $\\\\dot{\\\\rho} = 0$ ) and the segments of the lines $\\\\rho = \\\\rho_{H}, \\\\rho = R_E$ and $\\\\rho = R_{SI}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,437,482,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The sampling of these AdRe boundaries consists of choosing points that are equispaced at the boundary; that is, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,223,905,435]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"if the boundary is parametrized by the arc length $\\\\mathbf{s}$ , then the distance of each pair of consecutive points corresponds to a fixed increment of $\\\\mathbf{s}$ . In order to avoid the calculation of $\\\\mathbf{s}$ , Milani et al. (2004) propose an algorithm that, from a large number of points equispaced on one of the two abscissas, applies an elimination rule that is iterated until the desired number of points at the boundary are left. The points thus obtained are close to the ideal distribution, equispaced along the arc length. The symmetry with respect to $\\\\dot{\\\\rho} = -c_{1}/2$ allows sampling the upper curve of $E_{\\\\odot}(\\\\rho, \\\\dot{\\\\rho})$ from $\\\\rho_{H}$ to the maximum value $\\\\rho_{max}$ . Likewise, for the sampling of the lower limit, we apply the same procedure using the symmetry with respect to $\\\\dot{\\\\rho} = 0$ of the curve $E_{\\\\oplus} = 0$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,437,905,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 2 presents the algorithm that we implement for sampling the AdRe boundary. The algorithm starts with \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[226,491,771,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2. Algorithm for sampling the boundary of the AdRe. AdRe, admissible region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0053/b668a78c3b6dcda50d85c9cdfe570eda72d68d986f2079d44f46a0f5bc574bb3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[376,45,905,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,510,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"121 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,905,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[89,90,482,240]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$n$ points of a rectifiable curve $\\\\gamma$ , with unitary length (The algorithm is designed for any length). The central goal of the algorithm consists of selecting $m$ points $(m < n)$ such that the distance along the curve between 2 consecutive points is as close as possible to $1 / (m - 1)$ (Milani et al. 2004). To avoid the calculation of the arc length $\\\\mathbf{s}$ , we assume that $\\\\gamma$ is the unit interval $[0,1] \\\\subset \\\\mathbb{R}$ . We then define it as $(P_k)_{k=1,\\\\dots,n}$ the set of ordered points in $[0,1]$ with $P_1 = 0$ , $P_n = 1$ , and establish $(Q_j)_{j=1,\\\\dots,m}$ , the sequence of ideal equispaced points with: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[181,266,482,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nQ _ {j + 1} - Q _ {j} = \\\\frac {1}{m - 1} = h \\\\quad i d e a l s t e p \\\\tag {2}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[89,321,484,404]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Considering $d_{k} = P_{k} - P_{k-1}$ and $\\\\delta_{k,j} = |Q_{j} - P_{k}|$ , note that for each $P_{k}$ there is an ideal point $Q_{j}$ , such that $\\\\delta_{k,j} \\\\leq h/2$ . In order to discard a point from the set $(P_{k})_{k=1,\\\\dots,n}$ , we established an elimination rule, which seeks to eliminate the point such that $\\\\bar{k}$ minimizes the following function: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[174,427,482,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nf (k) = \\\\frac {\\\\min \\\\left\\\\{d _ {k} , d _ {k + 1} \\\\right\\\\}}{1 + \\\\min _ {j = 1 \\\\dots m} \\\\delta_ {k , j}} k = 2, \\\\dots , n - 1 \\\\tag {3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[89,486,482,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The process above is applied $(n - m)$ times. In each iteration, the values of $d_{k}$ change due to the elimination rule of points in the set $\\\\left(P_k\\\\right)_{k = 1,\\\\dots,n}$ given by (3). Finally, we denote by $\\\\hat{P}_j)_{j = 1,\\\\dots,m}$ the subset of points selected along the AdRe boundary. We implemented the algorithm described above in a Matlab function. Fig. 3 presents the result obtained when applying this algorithm in the sampling of the AdRe \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,92,774,105]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"boundary of asteroid (1738) Oosterhoff. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,124,742,139]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2 Internal Sampling of the AdRe \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,157,907,370]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"After the sampling of the AdRe boundary, it is necessary to sample the internal region. (Milani et al. 2004), and (Milani & Gronchi 2009) claim that an optimum method for improving this task consists of performing a triangulation followed by mesh smoothing. We propose a strategy based on the constrained Delaunay triangulation, which operates as follows. Given the domain of a polynomial $\\\\tilde{D} \\\\subset D$ defined by the connection with the edges of the sample of boundary points (obtained in subsection 3.1) of the AdRe $D$ , the triangulation of the polygonal domain $\\\\tilde{D}$ is the pair $(\\\\Pi, \\\\tau)$ with $\\\\Pi = \\\\{P_1, \\\\dots, P_N\\\\}$ as the set of nodes of the domain, and $\\\\tau = \\\\{T_1, \\\\dots, T_2\\\\}$ as the set of triangles $T_i$ whose vertexes are in $\\\\Pi$ . This triangulation has to fulfill the following conditions: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[529,387,905,436]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. $\\\\\\\\cup_{i = 1,k}T_{i} = \\\\\\\\tilde{D}$ \\\",\\\"2. For each $i \\\\\\\\neq j$ , the set $T_i \\\\\\\\cap T_j$ is empty, or a vertex is empty, or a side of the triangle, or one of its edges. \\\"]\",\n \"page_idx\": \"3\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[512,453,905,534]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"If in addition to the set of points $\\\\Pi$ , some edges $P_{i}P_{j}$ are entered as inputs (for example, the boundary edges of $\\\\tilde{D}$ ; The input is referred to as a planar straight line graph [PSLG]), the triangulation that contains the prescribed edges is called a constrained triangulation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,535,905,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For each triangulation $(\\\\Pi, \\\\tau)$ , we can associate the minimum angle, which is defined as the minimum between the angles of all the triangles $T_{i}$ . Among other possible triangulations of a convex domain, there is a construction called the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,633,489,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) AdRe using exponential metric \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0651/f8d1780a2a78628ab7c8b0afd88e2b3609da51783c41f51c0dcc2080e68f5df7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[510,634,885,849]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) AdRe sampled at its boundary \\\",\\\"Fig. 3. Sampling of boundary of the AdRe for asteroid (1738) Oosterhoff. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. AdRe, admissible region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0866/0b6ac5e613edd9191417c735fa5234eb955692890e00a3b00eb01a2ac99e3368.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,44,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,943,326,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"122 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[89,92,485,126]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Delaunay triangulation (Bern & Eppstein 1995), which is characterized by the following properties: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[105,141,482,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"i. It maximizes the minimum angle. \\\",\\\"ii. It minimizes the circumscribed circle. \\\",\\\"iii. For each triangle $T_{ij}$ the internal part of its circumscribed circumference does not contain any node of the triangulation (Risler 1992). \\\"]\",\n \"page_idx\": \"4\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[89,239,484,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When they are convex domains, the previous properties are equivalent. If the domain is a convex quadrangle whose vertexes $\\\\Pi$ are not on the same circle, there are two possible triangulations $(\\\\Pi, \\\\tau_1)$ , $(\\\\Pi, \\\\tau_2)$ . According to property (iii), only one of this triangulation is a Delaunay triangulation. In this case, the Delaunay triangulation is obtained through a first triangulation using a technique called edge-flipping (Milani & Gronchi 2009). Note that the AdRe domain, $\\\\tilde{D}$ is not generally convex. In this scenario, there is still a triangulation that maximizes the minimum angle, known as the constrained Delaunay triangulation, but the property (iii) is not guaranteed. For each triangle $T_i$ A procedure is iterated over the adjacent triangles. If the common edge with the adjacent triangle is not Delaunay, the edge-flipping technique is applied. This procedure is repeated until all edges of the structure in the triangulation are Delaunay or are the edges of the boundary $\\\\tilde{D}$ . In each repetition, the minimum angle increases, and the triangulation that maximizes the minimum angle is obtained at the end (Delaunay 1934). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,569,482,733]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to implement the triangulation described in the previous paragraphs, we develop an algorithm that begins by generating a constrained Delaunay triangulation $(\\\\Pi_0,\\\\tau_0)$ with the boundary points (generated as shown in 3.1) and the boundary edges. Once the initial triangulation is obtained, it is refined by adding internal points to the domain, maintaining the Delaunay property at each intersection. In each case, a new point is added, which extends to the internal part of the discrete density domain defined in the boundary point for the quantities: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[226,746,347,769]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\rho P _ {j} = \\\\min _ {l \\\\neq j} \\\\left| P _ {l} - P _ {j} \\\\right|,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[107,799,327,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With the corresponding densities \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,839,339,873]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\tilde {\\\\rho} G _ {i} = \\\\frac {1}{3} \\\\sum_ {m = 1} ^ {3} \\\\rho P _ {i m},\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[107,897,482,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Where $G_{i}$ corresponds to the barycenters of the triangles \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,92,905,220]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$T_{i}$ and the barycenter $G_{\\\\bar{k}}$ is added as a new point, which maximizes the minimum distance (weighted by its density $\\\\tilde{\\\\rho} G_{\\\\bar{k}})$ from the triangulation nodes $(P_{im},m = 1,\\\\dots,3,$ belong to the same triangle $T_{i})$ . Then, the corresponding triangle $T_{k}$ is removed, and the triangles obtained by joining the edges of $T_{k}$ with the new point are added to $\\\\tau$ . Consequently, the optimum property of the Delaunay triangulation is conserved in each insertion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,223,907,305]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The flow diagram in Fig. 4 shows the procedure used for triangulating the AdRe as a domain, which is generally not convex. It begins with a number of points resulting from the sampling of the boundary (for example, $N = 25$ ), out of which the repeated data are removed (the result of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,330,907,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4. Constrained Delaunay triangulation algorithm for sampling inside the boundary of AdRe. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0380/e8afbb97c63767aa2726acb2c2bf199a5e74ced50f233d0886fca4bb46bc32d8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[376,45,905,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,512,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"123 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,907,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[87,92,480,172]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"sampling the curves at its points of intersection). Then, a first triangulation is performed to identify the triangles outside the AdRe. Then, the domain is constrained, and a first constrained Delaunay triangulation is performed (the outer triangles are removed again). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,174,480,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The following step consists of calculating the barycenters of each triangle $T_{i}$ and with them performing a constrained Delaunay triangulation again. This last step is performed twice. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,240,484,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The algorithm in question was implemented as a MATLAB function. Fig. 5 presents the results obtained when applying our algorithm for sampling inside the AdRe boundary of asteroid (1738) Oosterhoff. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,322,416,337]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3 Propagation of Orbits and Ephemeris Region \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,355,484,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Once the boundary and the internal region of the AdRe are sampled, it is necessary to propagate the established points to define the possible orbits that belong to the object under study. In fact, this object corresponds to a minor body $\\\\mathfrak{B}$ that belongs to the solar system and that moves around the sun with heliocentric position $\\\\mathbf{r}$ , which is observed from Earth $\\\\varepsilon$ with a radius vector $\\\\mathbf{R}$ , known for a given instant of time. As is evident, the vector between the Earth and the minor body $\\\\pmb{\\\\rho}$ is the unknown that was solved in the previous sections. This process gives, as a result, a set of possible values $(\\\\pmb{\\\\rho},\\\\dot{\\\\pmb{\\\\rho}})$ for the average time of the observations \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,92,905,139]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"collected from a TSA. Each of these points defines a virtual asteroid determined by a set of six quantities of the following form: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[643,155,778,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nX = \\\\left[ \\\\alpha , \\\\delta , \\\\dot {\\\\alpha}, \\\\dot {\\\\delta}, \\\\rho , \\\\dot {\\\\rho} \\\\right]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,191,905,271]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"That set is known as *attributable orbital elements* (Milani & Gronchi 2009). The following step is consists of replacing each point $(\\\\rho, \\\\dot{\\\\rho})$ or the node of the triangulation (after going back to its original metric) in the state vector expression defined by equation (4). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[678,290,739,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf {r} = \\\\mathbf {R} + \\\\rho \\\\hat {\\\\boldsymbol {\\\\rho}}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[636,303,904,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\dot {\\\\mathbf {r}} = \\\\dot {\\\\mathbf {R}} + \\\\dot {\\\\rho} \\\\hat {\\\\boldsymbol {p}} + \\\\rho (\\\\dot {\\\\alpha} \\\\hat {\\\\boldsymbol {p}} _ {\\\\alpha} + \\\\dot {\\\\delta} \\\\hat {\\\\boldsymbol {p}} _ {\\\\delta}) \\\\tag {4}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,339,905,403]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Where $\\\\hat{\\\\rho}$ is the unit vector in the direction of observation and $\\\\mathbf{R},\\\\dot{\\\\mathbf{R}}$ is the state vector of the Earth, a parameter that is obtained from the collection times of the TSA (Espitia Mosquera & Quintero Salazar 2019), with: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[606,419,791,436]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\hat {\\\\rho} = (\\\\cos \\\\alpha \\\\cos \\\\delta , \\\\sin \\\\alpha \\\\cos \\\\delta , \\\\sin \\\\delta)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[608,437,904,452]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\hat {\\\\boldsymbol {\\\\rho}} _ {a} = (- \\\\sin \\\\alpha \\\\cos \\\\delta , \\\\cos \\\\alpha \\\\cos \\\\delta , 0) \\\\tag {5}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[608,453,800,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\hat {\\\\boldsymbol {\\\\rho}} _ {\\\\delta} = (- \\\\cos \\\\alpha \\\\sin \\\\delta , - \\\\sin \\\\alpha \\\\sin \\\\delta , \\\\cos \\\\delta)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[512,486,905,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As a result of this process, a set of initial state vectors $(\\\\mathbf{r},\\\\dot{\\\\mathbf{r}})$ in the heliocentric-equatorial system is obtained. We used a two-body integrator based on the functions $f$ and $g$ (Danby \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,564,284,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0510/4d02746e9180990008c99435df06767ad49ac9e964263fc3f9c18c73c949c069.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[295,566,487,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0666/33fac27a109ed3c16a777fb73890f145b122977f5e4aac0adfd5defe578d1407.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[500,566,695,680]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0648/d72f6fe6d55bab9212a202df432d9a241b2a384abdd784e5557144c41dcb4399.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[707,566,902,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0102/30990771b08f5c7564d4a83b8bf947d1f7b85edd70829ad34e1a9ef4cd067ea6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,706,282,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0687/60f43f6e15723ce94e3701074f9345786339a31fad36065a228e857c8417e6a9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[292,707,487,818]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0208/50a38fa5fa1fdcf168a884432d4355fdb1eab462a44046b5fc17c9f01bd0c264.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[500,707,695,818]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(g) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0599/b4df3515093bf549e90d43f9e930f1a758cec98f7580836dbb4cff1997e27ca1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[710,709,900,818]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(h) \\\",\\\"Fig. 5. Results of applying our triangulation algorithm for sampling inside the AdRe boundary for asteroid (1738) Oosterhoff under the exponential metric. (a) Selection of points on the boundary. (b) First triangulation and identification of outer triangles. (c) Constraint of the AdRe domain. (d) Removal of triangles outside the domain. (e) First computation of barycenters. (f) Triangulation with the new set of points and subsequent constraint of the boundary. (g) New computation of barycenters inside the boundary of the AdRe. (h) Final result of both the boundary sampling process and constrained Delaunay triangulation. The red dot in (h) shows the asteroid real position. AdRe, admissible region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0328/54c2c5d9a6054024971f34cfc8d82db325d1d46126df28712fa9b1cfd831c0a3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,44,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,943,327,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"124 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[89,90,484,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1962; Boulet 1991) to obtain the set of final state vectors $(\\\\mathbf{r}_t,\\\\dot{\\\\mathbf{r}}_t)$ . In order to simulate the propagation for a few days we use this dynamic model because its implementation is relatively simple to implement. Fig. 6 presents this set for the case of asteroid (1738) Oosterhoff. From this set, we calculate the ephemerides, that is, the right ascension and declination coordinates for each of the points propagated for a specific date after the observation of the object under \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,92,702,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"study (ephemerides region). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,142,606,157]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,174,905,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We applied our follow-up strategy to the set of the 12 asteroids listed in the first column of Table 1, whose types are reported in the fourth column (6 NEA, 2 MBA, 1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[97,245,364,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0661/d98d257006dbd815ea554d443b8390a22ddcb014c45168ab2fb5d66dec301787.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[371,245,633,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0569/b79956e8534272841713a5ef4585709b172ee7907fae8cbfd10936c690e2517f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[638,245,894,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0514/32ba03b6d7f77bdbdfc82b9223477fb8116251189089779c53821337fa06c147.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[97,435,361,588]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0285/a42d0c8a30896d8133dc4da896e65eadfa89e08f9cd4488fa755f032d67c0091.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[374,435,630,588]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0325/a8c9956ec863d6f64ecf4fca3d57abd66fba941451972b18999a1112d835e8bf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[636,435,895,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) \\\",\\\"Fig. 6. Components of heliocentric position and velocity vectors for asteroid (1738) Oosterhoff. Top row: vectors at the average time of initial observation. Bottom row: vectors at the recovery time. The cyan and red dots show the components of the real asteroid. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0915/a7f765cf21b809517c7bbb0ab916f00b7c05afa5bf737f1d55a9f1df60809060.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,698,905,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0311/520b64092ba044b84a5ef75d66ccd390ad3a09aae399f04e47b54e2387259a8a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Asteroid</td><td>MPC code</td><td>TSA (Δt)</td><td>Type</td><td>Smax(au) Topocen.</td><td>η(°/day)</td><td>Real Pos. ρ (au)</td><td>Propagation aprox.</td><td>Recovery</td></tr><tr><td>(3122) Florence</td><td>W63</td><td>1 h 44 min</td><td>NEA/PHA</td><td>0.0849</td><td>9.3920</td><td>0.0475</td><td>12 d</td><td>no</td></tr><tr><td>(3200) Phaethon</td><td>W63</td><td>2 h 04 min</td><td>NEA/PHA</td><td>0.2157</td><td>10.0720</td><td>0.0859</td><td>11 d 19 h</td><td>no</td></tr><tr><td>2003 GW</td><td>608</td><td>1 h 31 min</td><td>NEA/Apollo</td><td>1.7344</td><td>0.7996</td><td>0.9479</td><td>10 d 18 h</td><td>yes</td></tr><tr><td>(1864) Daedalus</td><td>703</td><td>25 min 29 s</td><td>NEA/Apollo</td><td>3.5840</td><td>0.3026</td><td>1.4658</td><td>15 d 20 h</td><td>yes</td></tr><tr><td>2003 BH84</td><td>809</td><td>1 h 37 min</td><td>NEA/Apollo</td><td>4.4617</td><td>0.3498</td><td>1.9928</td><td>11 d 22 h</td><td>yes</td></tr><tr><td>1977 QQ5</td><td>F51</td><td>1 h 47 min</td><td>NEA/Amor</td><td>3.3697</td><td>0.2664</td><td>2.1336</td><td>13 d 16 h</td><td>yes</td></tr><tr><td>(1738) Oosterhoff</td><td>W63</td><td>1 h 24 min</td><td>MBA</td><td>1.7940</td><td>0.2378</td><td>1.0104</td><td>15 d</td><td>yes</td></tr><tr><td>(4690) Strasbourg</td><td>W63</td><td>48 min 40 s</td><td>Hungaria</td><td>2.1182</td><td>0.2916</td><td>1.3425</td><td>16 d 23 h</td><td>yes</td></tr><tr><td>(555) Norma</td><td>W63</td><td>1 h 34 min</td><td>MBA</td><td>3.2767</td><td>0.1051</td><td>2.2395</td><td>12 d</td><td>yes</td></tr><tr><td>2006 SO375</td><td>705</td><td>1 h 23 min</td><td>Hilda</td><td>7.5199</td><td>0.1654</td><td>2.2756</td><td>27 d 20 h</td><td>yes</td></tr><tr><td>2003 GE55</td><td>291</td><td>59 min 04 s</td><td>Hilda</td><td>8.8767</td><td>0.1576</td><td>3.3645</td><td>47 d 21 h</td><td>yes</td></tr><tr><td>(32811) Apisaon</td><td>T05</td><td>2 h 18 min</td><td>Jupiter Trojan</td><td>6.8280</td><td>0.0776</td><td>4.3549</td><td>18 d 15 h</td><td>yes</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Table of sample asteroids recovery. The observatory code, the interval of the initial observations, the orbit type, the $S_{max}$ value, the proper motion, the propagated days interval and the possibility of a recovery are shown \\\"]\",\n \"table_footnote\": \"[\\\"MPC, minor planet center; TSA, too-short arc; NEA, near-Earth asteroid; MBA, main-belt asteroid. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[376,45,905,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,512,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"125 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,905,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[89,90,480,139]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Hungaria, 2 Hilda, and 1 Jupiter trojan). In order to achieve this goal, we use our new web recovery service available at http://observatoriooenlinea.utp.edu.co/recoveryservice/. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,141,480,336]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As input data, we used the observations reported to the MPC (https://www.minorplanetcenter.net/db_search) by the observatories listed in the second column within the intervals of observation presented in the third column (in all cases, the interval of observation used constitutes a TSA). For minor bodies reported by the W63 observatory, they are registries performed by us from the Astronomical Observatory of the Technological University of Pereira, Colombia (from here on, OAUTP) exclusively for this work. The complete tables of data of the observations used in this work are available at https://www.utp.edu.co/ observatorioiastronomico/astrometria/recovery. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,337,480,418]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"First, we established the AdRe's for the minor bodies under study following the procedure described in Espitia Mosquera & Quintero Salazar (2019), using the geocentric and topocentric approximations and the exponential and logarithmic metrics. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[92,421,482,680]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The performed tests showed that for the 12 asteroids analyzed, the most adequate version for performing an optimum sampling process was the version with topocentric correction and based on the exponential metric. This is because the topocentric approximation gives, in all cases, AdRe's with much simpler shapes than their geocentric equivalents, and the exponential metric presents a higher density of points around the asteroid's real position. Figs. 7 and 8 present the AdRe's computed for the objects under study. However, we observed that the logarithmic metric describes regions of the AdRe's near the Earth with more detail, so it would be useful in the study of near meteoroids and artificial satellites. For those readers interested in these types of objects, we report the AdRe's obtained using logarithmic metrics at https://www.utm.edu.co/ observatorioiaastronomico/astrometria/recovery. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,684,480,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Regarding the AdRe's calculated under the topocentric approximation and under exponential metrics, we applied the sampling technique described in section 3. Figs. 9 and 10 present the results of this process. In all cases, our sampling method generated at least one node of the triangulation in the proximities of the asteroid's real position. This indicates that at least one of the ephemeris points corresponds to a value close to the asteroid's real position in the celestial sphere. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,815,480,911]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We transformed each node provided by the triangulation into a heliocentric-equatorial state vector $(\\\\rho, \\\\dot{\\\\rho})$ . Then, we performed the calculation of the set of vectors for the position and velocity in the heliocentric-equatorial system $(r_{i}, \\\\dot{r}_{i})$ . The graphs of each component for the initial times of each asteroid show that the metric that offers \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,92,904,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"a cleaner sampling was the exponential one (https:// observatorioastronomico.utm.edu.co/astrometria/recovery.html). Subsequently, we performed propagation of each of these vectors to a date after the observation (column 8, Table 1), the date at which the follow-up of the asteroids in question was performed. For that purpose, we used our 2-body propagation algorithm through functions $f$ and $g$ . The propagation of these vectors showed that there are deformations of the AdRe's for the spatial components. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,239,904,368]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The most significant change occurred for asteroids (3200) Phaethon and (3122) Florence, whose input data were collected when they were at their points of closest approach to the Earth (the real position of the objects within their orbit at the moment of their observation is listed in column 7 of Table 1). The changes in the shape of the AdRe's, after the propagation, become less abrupt when the asteroid is farther away from the observer. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,370,904,781]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, we calculated the ephemerides for each of the points obtained from the previous process for observation times after the observations listed in column 8 of Table 1. The recovery times are calculated from the location of the OAUTP (W63). Figs. 11 and 12 present the results of this process. As a reference, the figures include, indicated within the blue dotted-line box, the field of the vision given by the instrumental assembly of the OAUTP $(95^{\\\\prime} \\\\times 72^{\\\\prime})$ . Our approach is to slew the telescope near the region with the highest density of points, i.e., the region with more ephemeris grouped. The asteroid's real position is also included; it was obtained from the HORIZONS Web-Interface of NASA's JPL (identified by a red dot; https:// ssd.jpl.nasa.gov/horizons.cgi) and the recovery by Väisälä provided by the New Object Ephemerides service of the MPC (identified by a blue dot; http://www.minorplanetcenter. net/iau/MPEph/NewObjEphems.html). We tested our methodology by implementing a Laplacian mesh smoothing filter. However, as our purpose was to point the telescope towards the region of the sky with the highest number of points (i.e., ephemeris), the difference when we applied the filter did not show a more significant advantage in the results shown in Figs. 11 and 12. So we concluded that our method eliminates the need for smoothing as proposed by Milani et al. (2004), thus increasing the computational efficiency. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,783,904,911]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As can be observed from Figs. 11 and 12, except for asteroids (3122) Florence and (3200) Phaethon, all asteroids were recoverable since they presented a higher density of possible location coordinates within the visual field of the OAUTP and near the asteroids' real position (red dot). In some cases, it is sufficient to recover the object again by panning the sky with a telescope that covers three fields of vision. Even in the cases of asteroids 2003 BH84 and 2006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,45,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,944,326,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"126 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,90,465,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) (3122) Florence $\\\\\\\\bar{t}_i$ UT $= 20170902.23046$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0481/4d4f2cb639f2ca2b204b9af00cddff168b717a7b4c2d49fcafa5743696b9f552.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[521,90,855,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) (3200) Phaethon $\\\\\\\\bar{t}_i(\\\\\\\\mathrm{UT}) = 2017$ 12 14.17371 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0898/ad50b849d1f9e0e60bcfb7863b27b8770605ae5a1bf8322053c62c1c4af37055.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[117,312,455,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) 2003 GW $\\\\\\\\bar{t}_i$ (UT) = 2003 04 04.31379 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0867/74d61e35033a5a9c9afbf49089d4a80fdf74a4462ea3c6cd914be4d466be9d14.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[524,317,850,505]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) (1864) Daedalus $\\\\\\\\bar{t}_i$ (UT) = 2018 03 06.20089 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0394/95c430c3a8113a72db56d0a9f293ea04f05aea3b7aaa2556ea25070706ed83d7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[121,540,453,731]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) 2003 BH84 $\\\\\\\\bar{\\\\\\\\tau}_i$ (UT) $= 20030125.11890$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0890/a073beafbab8d3df7e56365c0da33c24fbe82abcb6311a3fcc644abf5ad34e08.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[515,539,850,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) 1977QQ5 $\\\\\\\\bar{t}_i(\\\\\\\\mathrm{UT}) = 20141126.62712$ \\\",\\\"Fig. 7. AdRe's for asteroids (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5, with topocentric correction using the exponential metric. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0935/5c8381dafd6d542c8f277c71510595939c3dc0a4b17e28d18d470fb87068617c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,815,482,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SO375, our recovery was better than that provided by the New Object Ephemerides service since our triangulated ephemerides have a higher density closer to the real position than that given by the MPC. In addition, column 8 of Table 1 shows that the follow-up times range from 10 days (in the case of asteroid 2003 GW) up to 47 days (for \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,815,905,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the case of asteroid 2003 GE55) after the observations, from intervals of observation that do not exceed 3 hours, which demonstrates the potential of our follow-up method of newly discovered objects. Our method also reduces the number of objects that inflate the lists of lost objects, since the follow-up strategy would enable locating an object up \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[376,45,905,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"127 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,905,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[124,88,468,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) (1738) Oosterhoff $\\\\\\\\bar{t}_i$ UT=2017 09 27.14048 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0797/8f2d1e90c6a97459c3c90cdc0c9750129a2d59c9f4b45cc4a5f34a9a4d744aa7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[507,88,843,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) (4690) Strasbourg $\\\\\\\\bar{t}_i$ (UT)=2018 03 11.10067 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0221/fabdbb4f785be88840b15384fb97c5ae489d56b603aa7f94e21a500f59cc5418.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[126,305,465,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) (555) Norma $\\\\\\\\bar{\\\\\\\\tau}_i(\\\\\\\\mathrm{UT}) = 20180417.15633$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1010/46cb7f063087cfae33fcb6bf9831d22ea4533eb1911e397be326fbcb0af9a66e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[507,303,842,504]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) 2006 SO375 $\\\\\\\\bar{t}_i(\\\\\\\\mathrm{UT}) = 20060917.39025$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0944/441d65de129d2b98ac6da349d9574704519a0591153b5f41a67c6382e2fc9a52.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[126,532,463,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) 2003 GE55 $\\\\\\\\bar{t}_i$ (UT)=2002 02 13.27846 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0758/f9f872995fab9eeba4b855b23f46b783ca601cf4855aaecf1767ab70caa94d1e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[510,542,842,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) (32811) Apisao $\\\\\\\\bar{t}_i(\\\\\\\\mathrm{UT}) = 20180513.43080$ \\\",\\\"Fig. 8. AdRe's for asteroids (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon, with topocentric correction using the exponential metric. The red dot shows the real position of the asteroid obtained from the HORIZONS. AdRe, admissible region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0124/cc702cd3498538cb739348b9b2044e3adece2ee01e4770eb98d337d64b32d7c4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[87,832,480,862]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"to 47 days after their discovery, using an interval of the observation of just 3 hours. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,863,482,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the case of asteroids (3122) Florence and (3200) Phaethon, our method was not able to anticipate a recovery (last column of Table 1). In fact, the New Object Ephemerides \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,832,907,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"service of the MPC was not able to either (see the top row of Fig. 11). This was because the input observations correspond to one of the moments of closest approach to the Earth (in this case, of the order of $10^{-2}$ au), and therefore their apparent motion was large (column 6 of Table 1). In \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,44,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,943,327,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"128 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[144,90,463,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) (3122) Florence \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0335/988d63e8de66f20af4bf5434c6a53a7ef979e8283a49f89d48d2b5dd26b3fcf9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[527,90,855,276]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) (3200) Phaethon \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0469/79963e2c0ef18980307ede158991bb75e31e615169219efb663b14437ca462cf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[142,295,460,477]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) 2003 GW \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0206/ef95f42c4a4f8f35a43fcd4b9c6300e503d926f4d2d7f3de2b258c16740a8a64.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[527,297,850,480]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) (1864) Daedalus \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0330/0f4924a95283dbc2e48c7d9bf5d6e2ca198e8f8e117d3e8d408c353abeab074a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[142,501,465,688]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) 2003 BH84 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0007/8da90d15051a9f4648574d261cb7314c3f750a238489451c2ac237580209b132.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[526,505,847,688]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) 1977 QQ5 \\\",\\\"Fig. 9. Triangulated AdRe's for asteroids (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. AdRe, admissible region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0707/48cad9ed64d9b496ed971e6f92a958efded1a935d26b304d366d4d2206f2064a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,766,482,846]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the recording of a close pass by the Earth, the gravitational field can affect our propagation model based on a two-body integrator, so we conclude that in these cases, it is necessary to consider the gravity of the Earth as a perturbation in our dynamical model. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,848,482,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to identify the scope of our method, we repeat the follow-up of asteroid 2006 SO375, but now with just two input data separated by less than 2 minutes, corresponding to the night of their discovery (Table 2). Fig. 13 presents \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,766,907,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the ephemeris region of the asteroid for 28 days after its observation. Note how the higher density of possible positions of the asteroid provided by our algorithm (black crosses) is within the field of the vision given by the instrumental assembly of the OAUTP and closer to the real position given by the JPL's HORIZONS Web- Interface (red dot), than the recovery provided by the New Object Ephemerides service of the MPC (blue dot). This demonstrates the scopes of our technique, in addition to its application in the follow-up of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[376,45,905,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,512,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"129 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,905,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[152,90,472,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) (1738) Oosterhoff \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0047/2e875b5a7982c5c5c9d5894ddee27a330a28498dd6a065870959fb687f688d12.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[497,90,830,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) (4690) Strasbourg \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0469/2802ed0be548e970100d40a823714c6b214d856baf5d6f2f4b5ce6dc401906a4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[152,305,473,489]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) (555) Norma \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0181/a5015dc9ceaecd81caac418d050866dedecb3209bd7b0ff87d7c562f4419ec74.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,305,833,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) 2006 SO375 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0491/f41b6765fee532ac153b5e6ed52d1cda7e3f6ea824a1f7e6023d89987f052bae.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[154,518,475,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) 2003 GE55 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0998/05994d2fb70280f680db22b0ae6fe86fa3a604fefdb53fa92f14a3819930bf97.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[507,524,830,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) (32811) Apisaon \\\",\\\"Fig. 10. Triangulated AdRe's for asteroids (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. The red dot shows the real position of the asteroid obtained from the HORIZONS Web-Interface service of NASA's JPL. AdRe, admissible region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0266/3974431121425971ed18b17fe832d7fbf1cc3191f79c7f212d3e33465478492b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,799,307,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"recently discovered minor bodies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,849,364,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.DISCUSSION AND CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,881,480,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Literature review showed that the AdRe sampling technique is an important tool for the study of objects \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,799,905,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(eespecially with short intervals of observation) that is widely applied to space debris. However, despite its versatility, we found in our review that the use of AdRe has only been applied for the following minor bodies in two cases: 2003 BH84 and (60558) Echeclus. In this paper, we extend the field of application of the AdRe sampling follow-up technique by applying it to a group of 12 asteroids: 6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,44,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Astron. Space Sci. 38(2), 119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,943,324,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"130 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[131,100,472,293]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) (3122) Florence $\\\\\\\\bar{t}_f(\\\\\\\\mathrm{UT}) = 20170914.23046$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0804/be56e05002439d7cd193e7e62d75bf7a502d27f1b43ca5f64331f83c2db9a0ab.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,100,857,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) (3200) Phaethon $\\\\\\\\bar{t}_t(\\\\\\\\mathrm{UT}) = 20171225.99749$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0274/f88ba35d35329cb24fb485e5617778735f47a64e2ea4e2c4493daac175ac2441.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[127,327,480,524]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) 2003 GW $\\\\\\\\bar{t}_f(\\\\\\\\mathrm{UT}) = 20030415.10099$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0829/ff9baf97c9bc7a3662e60b2c8134641ca16145148a690ab2a381a7baefa70c5c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[522,329,868,523]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) (1864) Daedalus $\\\\\\\\bar{t}_f(\\\\\\\\mathrm{UT}) = 20180322.05026$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0712/0c1938892a4827ec24b946a4627ec7ca9ed7863192302176178298857a33ec50.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[129,559,485,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) 2003 BH84 $\\\\\\\\bar{t}_f$ (UT) = 2003 02 06.07308 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0341/fa8f54ce18a109186d1edeb37cd4c5340f17ac7aec92a7a44015128ac1340a67.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[519,559,868,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) 1977 QQ5 $\\\\\\\\bar{t}_r(\\\\\\\\mathrm{UT}) = 2014$ 12 10.33445 \\\",\\\"Fig. 11. Ephemerides region for final date $t_f$ for asteroids (3122) Florence, (3200) Phaethon, 2003 GW, (1864) Daedalus, 2003 BH84 and 1977 QQ5. The blue dotted lines box corresponds to the field of vision ( $95' \\\\\\\\times 72'$ ) given by the OAUTP instrumental assembly. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0456/639faf7e76128f83c9ede9fe49a7ea5bf8c1086cc5d33020cfc7379a4918a102.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,832,482,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NEAs and 6 MBAs. Regarding the sampling strategy, we proposed a technique based on the constrained Delaunay triangulation, which does not require the subsequent application of a mesh smoother. In addition, we implement our follow-up algorithm in a web service under an open-\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,832,905,895]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"source license. We constructed the AdRe's for the twelve asteroids from the geocentric approximation and, with topocentric correction, implementing the logarithmic and exponential metrics. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[529,897,905,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The results showed that the AdRe's based on topocentric \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[376,45,905,59]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,510,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"131 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,905,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[131,97,480,293]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) (1738) Oosterhoff $\\\\\\\\tilde{t}_f(\\\\\\\\mathrm{UT}) = 20171012.14047$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0331/c43f2fca13db5a8aa437053a10d21cb88c2d73f1b9cae40bbbebcee52e6e142d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[502,97,863,293]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) (4690) Strasbourg $\\\\\\\\bar{t}_f(\\\\\\\\mathrm{UT}) = 20180328.06564$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0736/3b629e502ef08aa470574fdfa56e0160b8e3bb3c281456555848e049e49cb1dc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[132,327,475,523]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) (555) Norma $\\\\\\\\bar{t}_t(\\\\\\\\mathrm{UT}) = 20180429.15633$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0154/1b0f6f4b0661b164bb39a324b75aa0d9b61848ce89f7ce36e627b7db35cf4b71.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[504,325,858,523]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) 2006 SO375 $\\\\\\\\bar{t}_f(\\\\\\\\mathrm{UT}) = 20061015.22358$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0903/6293a03629befe8103784f456786d964d0ceb0d87c745871edebd45d5ea05cb9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[132,557,480,752]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(e) 2003 GE55 $\\\\\\\\bar{t}_t$ (UT) = 2002 04 02.16270 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0239/c9090ae9f8b8201dfae81f1a66f747ed995f9b9d4fd125f10a11b590237b40db.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[504,556,858,752]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(f) (32811) Apisaon $\\\\\\\\bar{\\\\\\\\tau}_{f}(\\\\\\\\mathrm{UT}) = 20180601.08888$ \\\",\\\"Fig. 12. Ephemerides region for final date $t_f$ for asteroids (1738) Oosterhoff, (4690) Strasbourg, (555) Norma, 2006 SO375, 2003 GE55 and (32811) Apisaon. The box comprised of blue dotted lines corresponds to the field of vision ( $95' \\\\\\\\times 72'$ ) given by the OUTFP instrumental assembly. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0733/af2defd4a06273ac4ccd2e89fa29a87b83af883929f924089f04685a2fe283be.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[159,857,836,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0025/b9cc3cd5d36ee74ec5c41d526868b290cee907351b92eb6e413b13f68feade60.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Data number</td><td>TSA (Δt)</td><td>Initial date (UT)</td><td>Final date (UT)</td><td>η (°/day)</td><td>Smax(au) Topocentric</td></tr><tr><td>2</td><td>1 min 44 s</td><td>2006 09 17.36278</td><td>2006 10 15.22358</td><td>0.1420</td><td>8.2914</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Table of recovery for asteroid 2006 SO375 using an interval of $\\\\\\\\Delta t = 1\\\\\\\\mathrm{\\\\\\\\;{min}}{11.712}\\\\\\\\mathrm{\\\\\\\\;s}$ . The initial date of observation,the recovery final date, the proper motion and the ${S}_{max}$ value are shown \\\"]\",\n \"table_footnote\": \"[\\\"TSA, too-short arc. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[90,45,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J.Astron.Space Sci.382),119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,944,326,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"132 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[92,95,475,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 13. Ephemerides region for asteroid 2006 SO375 from 2 spaced data $\\\\\\\\Delta t = 1$ min 11.712 s. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0593/b47a2198284cfbcb6814e77c68c17f2ecd320f9d4b79c44e410dcfb8d92c0602.jpg\",\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[87,370,482,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"correction and using the exponential metric were better adapted to our sampling technique, since they presented a greater geometric simplicity and a higher density of possible orbits around the asteroids' real position. In addition, we observed that the AdRe's presented common elements within each family of asteroids, such that they could be used in future work to delimit the possible families to which a newly discovered object belongs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[90,504,482,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the 12 asteroids, we propagated the ephemeris region using the field of vision of the OAUTP (W63). We observed that 10 out of the 12 asteroids were recoverable, with observation times between approximately 25 minutes and 2 hours (TSA), and with propagations for follow-up of up to 47 days. We even observed how with an interval of the observation of just 2 minutes, it was possible to recover asteroid 2006 SO375 for approximately 28 days, which demonstrates the potential of our triangulation technique. The fact that our methodology can perform the follow-up of an object, even several weeks after its observation, makes it possible for observatories exposed to changing climate conditions, as in the case of the OAUTP, to observe the object again. This enables gathering more data, which would make it possible to construct a preliminary orbit, avoiding addition of the object to the list of lost objects. In the case of asteroids (3122) Florence and (3200) Phaethon, we could not perform the recovery from the observations used as input. We concluded that this was due to these objects being at the nearest point to Earth within their orbit at the moment of observation. As can be observed from Table 1, these minor bodies had a position $\\\\rho$ of the order $10^{-1}$ au and an average motion $\\\\eta$ much faster than the other asteroids. To validate our hypothesis, we simulated observations for this same pair of objects but at a distance greater than 1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,92,905,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"au. In this case, our method did allow the follow-up of the objects. The follow-up that we obtained for asteroid 2003 GW $(\\\\rho \\\\cong 1$ au) allows us to infer that the closer the object under study is from the Earth at the moment of observation, the more dispersed will be its ephemeris region (center-left, Fig. 11). This effect could be due to its proximity to the Earth, explained by the gravitational field has a more drastic influence, which is why it would be necessary to implement a three-body model in this type of case. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,240,907,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Currently, there are two web services JPL's Scout system (https://cneos.jpl.nasa.gov/scout) and NEOScan (https:// newton.spacedys.com/neodys/NEOScan/), which allow obtaining ephemeris from short-arc observation by using sophisticated methods. However, both services have a common disadvantage which is the fact that they only allow calculating ephemeris of existing objects in the Near-Earth Object Confirmation Page database (https:// minorplanetcenter.net//iau/NEO/toconfirm_tabular.html). In contrast, our services allow obtaining ephemeris from the coordinates resulting from the astrometric reduction made directly by the observer. In this way, if an observed object is suspected of being a discovery, the observer has the possibility of planning its future observations using our service without the need to wait for the provisional pre-registration of the object in the Near-Earth Object Confirmation database. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,553,692,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,585,905,665]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We are grateful for financial support provided by the \\\"Vicerrectoría de Investigaciones, Innovación y Extensa\\\" of the Universidad Tecnológica de Pereira, Colombia. This research has made use of NASA's Astrophysics Data System Bibliographic Services. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,701,571,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORCID \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[529,733,900,747]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia https://orcid.org/0000-0002-7730-3494 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[532,750,655,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Edwin A. Quintero \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,767,900,780]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://orcid.org/0000-0002-0974-4650 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[532,783,900,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Miguel A. Parra https://orcid.org/0000-0001-9108-3187 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,832,621,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,865,905,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bern N, Eppstein D, Mesh generation and optimal triangulation, in Computing in Euclidean Geometry, eds. Du D, Hwang F (World Scientific, Singapore, 1995), 47-123. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[376,45,905,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Daniela Espitia et al. Recovery of Asteroids from Observations of TSA by Triangulating Their AdRe's \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,945,512,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"133 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[828,944,905,957]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"http://janss.kr \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[92,92,480,665]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Boulet DL, Methods of Orbit Determination for the Microcomputer (Willmann-Bell, Richmond, NA, 1991). \\\",\\\"Danby DMA, Fundamentals of Celestial Mechanics (Macmillan, London, 1962). \\\",\\\"Delaunay B, Sur la sphere vide, Izv. 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Control Dyn. 32, 194-209 (2009). https://doi.org/10.2514/1.36398 \\\",\\\"Milani A, The asteroid identification problem IV: attributions, Icarus. 151, 150-159 (2001). https://doi.org/10.1006/icar:2001.6594 \\\",\\\"Milani A, Gronchi G, Theory of Orbit Determination (Cambridge University Press, Cambridge, 2009). \\\",\\\"Milani A, Gronchi GF, Vitturi MDM, Knežević Z, Orbit determination with very short arcs. I Admissible regions, Celest. Mech. Dyn. Astron. 90, 57-85 (2004). https://doi.org/10.1007/s10569-004-6593-5 \\\",\\\"Milani A, Knežević Z, From astrometry to celestial mechanics: orbit determination with very short arcs, Celest. Mech. Dyn. Astron. 92, 1-18 (2005). https://doi.org/10.1007/s10569-004-6593-5 \\\",\\\"Risler JJ, Mathematical Methods for CAD (Cambridge University Press, Cambridge, 1992). \\\",\\\"Spoto F, Del Vigna A, Milani A, Tommei G, Tanga P, et al., Short arc orbit determination and imminent impactors in the Gaia era, Astron. 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Astron. 97, 289-304 (2007). https://doi.org/10.1007/s10569-007-9065-x \\\",\\\"Väisälä Y, Eine einfache Methode der Bahnbestimmung (Suomalaisen Tiedeakatemian Kustantama, Helsinki, 1939). \\\",\\\"Valk S, Lemaitre A, Admissible regions for too short arcs: nodal distances and elongations, Proceedings of the International Astronomical Union, Prague, 24 Aug 2006. https://doi.org/10.1017/S1743921307003572 \\\"]\",\n \"page_idx\": \"15\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[90,45,312,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J.Astron.Space Sci.382),119-134 (2021) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,944,326,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.5140/JASS.2021.38.2.119 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,945,512,955]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"134 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.5140/jass.2021.38.2.119"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Astronomy and Space Sciences"},"sha256":{"kind":"string","value":"a13b8527403c94b6b4134a495abdd9de09778c8b1ac6fe8e009536ee5df5e8d9"},"title":{"kind":"string","value":"Recovery of Asteroids from Observations of Too-Short Arcs by Triangulating Their Admissible Regions"}}},{"rowIdx":164,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Qinhui Huang|Jing Wang"},"content_list":{"kind":"list like","value":[{"bbox":"[60,131,243,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PAPER • OPEN ACCESS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,157,633,226]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tectonic Characteristics and Geological Significance of Joints on the Southwest Bank of Yangzonghai Lake ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,241,626,266]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To cite this article: Qinhui Huang and Jing Wang 2021 IOP Conf. Ser.: Earth Environ. Sci. 668 012006 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,308,391,321]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View the article online for updates and enhancements. 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Engage. Champion. Empower. Accelerate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[159,913,410,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MOVE SCIENCE FORWARD ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[470,802,529,846]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0641/770cf1567cbc2f40756b9f9896b731ab29fc22b0165184e1578d9be4b31fb655.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[534,815,721,831]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Submit your abstract ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[692,771,936,855]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0356/c49623a9fdb4675d856ba59a7d50070dbada24c86973815cf44cb861171cbbf6.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[690,856,936,939]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0492/9a8691cb1c143780f6984b97641bb2b17794d1fa1d7b1ac4c565afdc4becf256.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[60,42,584,58]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conference Series: Earth and Environmental Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,228,870,275]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tectonic Characteristics and Geological Significance of Joints on the Southwest Bank of Yangzonghai Lake ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[233,307,453,324]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Qinhui Huang*, Jing Wang ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,328,653,345]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Yunnan Land and Resources Vocational College, China ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,345,448,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Email: 274959263@qq.com ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,372,880,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract. Affected by the movement of the Xiaojiang Fault Zone, frequent tectonic activities have occurred in the Yangzonghai Lake area, and a large number of joints have developed in the rock formations. The analysis of joints in the study area shows that there are 6 sets dominant joints, of which 4 sets are two conjugate joint systems; the analysis of stereographic projection for conjugate joints shows that the direction of the maximum principal stress indicated by the tectonic stress field in the area has a tendency to turn from NWW to NNW, which is consistent with the tectonic stress field reflected by faults and folds in the study area and and conforms to the characteristics of the tectonic stress field in the middle of the Xiaojiang Fault Zone. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,496,823,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: Conjugated joint, Tectonic stress field, Principal stress, Yangzonghai Lake ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,545,226,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Instruction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,559,882,724]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Xiaojiang Fault Zone, located in the Sichuan-Yunnan area, is a famous active fault zone, and has extremely complex structure with its adjacent areas [1-3]. Yangzonghai Lake, located in the west branch of the middle section of Xiaojiang Fault Zone, is a faulted lake and is closely related to Xiaojiang Fault Zone in its origin. Affected by the movement of the Xiaojiang Fault Zone, frequent tectonic activities have occurred in the Yangzonghai Lake area, and a large number of joints have developed in the rock formations. The rose diagram, pole diagram and isodensity diagram of the joints directly reflect the degree of development of the joints and their dominant direction, which is an important auxiliary basis for restoring palaeotectonic stress field, determining the geometric form, occurrence direction and combination law of the geological structure and its origin and development process. This paper will analyze the regional tectonic stress field by the research on the joint characteristics of the southwest bank of Yangzonghai Lake. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,724,880,831]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study of joints has a long history, including the origin (Gilbert.1882, Becker.1891, Van. Hise 1896), field observations, and experimental studies of joints (Sheldon.1912), joint mechanics formation mechanism, and Bucher's deduction in 1921 of the bisected acute Angle of the maximum principal stress and the bisected obtuse Angle of the minimum principal stress when the joint ruptures. It is proved to be a reliable method to invert the tectonic stress field using joints. Through the inversion of joints to the stress field [4-6], Chen C [7], Qin L M [8], Deng B [9], Zhang Z P [10], Dong L [11], et al. also proved that joints have very good indicative significance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,844,324,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Geological Background ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,859,880,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Xiaojiang Fault Zone can be roughly divided into north section, middle section and south section. The study area is the diamond massif sandwiched by the east and west faults in the middle section, which has developed a series of secondary faults tending to the NNE. The exposed strata dip in this area is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,65,200,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HECE 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,882,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,884,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,913,198,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CC BY ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[198,913,880,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[112,938,371,950]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under licence by IOP Publishing Ltd ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[497,940,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[110,135,885,258]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"relatively steep, such as Canglangpu Formation $(\\in_{1}c)$ , Longwangmiao Formation $(\\in_{1}l)$ , and Douposi Formation $(\\in_{2}d)$ of Cambrian System; Haikou Formation $(\\mathrm{D}_2\\mathrm{h})$ of Middle Devonian Series, Zaige Formation of Upper Devonian $(\\mathrm{D}_3\\mathrm{z})$ ; Datang Formation $(\\mathrm{C}_1\\mathrm{d})$ of Lower Carboniferous Series, Weining Formation $(\\mathrm{C}_2\\mathrm{w})$ of Middle Carboniferous Series; Daoshitou Formation $(\\mathrm{P}_1\\mathrm{d})$ , Yangxin Formation $(\\mathrm{P}_1\\mathrm{y})$ , Emeishan Basalt Formation (Pe) of Lower Permian Series, Lufeng Formation (JI) of Middle Jurassic Series. The structure in this area is relatively complex, with developed folds and faults; the folds axis mainly NE-trending, while the faults are mainly NE, EW, and NS trending faults(as shown in the figure 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,273,359,288]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Joint Development Features ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,302,315,315]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. Geometrical Features ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[110,315,882,423]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"More than 500 joints of 15 observation points are obtained through detailed observation and measurement of the field outcrop joints of the Cambrian System's Douposi Formation, Devonian System's Zaige Formation, Carboniferous System's Datang Formation and Weining Formation, and Jurassic System's Lufeng Formation's formation. In general, the surface deformation in the study area is relatively weak, mainly low-strain brittle fracture deformation, forming outcrop multi-phase joints structures; the joint surface is straight, and the dip angle is steep with good extension (as shown in the table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[305,442,566,625]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Geological Sketch of the Southwest Bank of Yangzonghai Lake. \"]","image_footnote":"[]","img_path":"images/0102/10d295139f4ff818e96344649a2a44ca575d1e9596a2ca5c99f754cab0bd341b.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[329,627,539,647]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig 1: Geological Sketch of the Southwest Bank of Yangzonghai Lake ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[566,444,697,652]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0176/f0bf6401be6e03403dd082e7c05bdb9373b990f33ed7b80af180698ec6037d13.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>J2l</td><td>Liuwan Formation of Middle Jurassic Series</td></tr><tr><td>JL</td><td>Lufeng Group of Lower Jurassic Series</td></tr><tr><td>Pe</td><td>Emeishan Basall Formation of Upper Permian Series</td></tr><tr><td>P1y</td><td>Yangxin Formation of Lower Permian Series</td></tr><tr><td>P1l</td><td>Liangshan Formation of Lower Permian Series</td></tr><tr><td>Ch</td><td>Huanglong Formation of Upper Carboniferous Series</td></tr><tr><td>C1w</td><td>Wanshoushan Formation of Lower Carboniferous Series</td></tr><tr><td>D2z</td><td>Zaige Formation of Upper Devonian Series</td></tr><tr><td>D2h</td><td>Haikou Formation of Middle Devonian Series</td></tr><tr><td>€2d</td><td>Douposi Formation of Middle Cambrian Series</td></tr><tr><td>€1l</td><td>Longwangmiao Formation of Lower Cambrian Series</td></tr><tr><td>€1c2</td><td>Canglangpu Formation of Lower Cambrian Series</td></tr><tr><td colspan=\"2\">Undefined fault</td></tr><tr><td colspan=\"2\">That fault</td></tr><tr><td colspan=\"2\">Reverse fault</td></tr><tr><td colspan=\"2\">Attitude of stratum</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[136,717,858,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0403/ec87d4375e1b3a503f820d40cb897dabd8c7bdd83d1e8b16e7f748b9701dddf3.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>Stratigraphic Age, Position and Lithology</td><td>Occurrence of Stratum</td><td>Joint occurrence</td><td>Joint Mechanical Property</td><td>Density of Joint</td><td>Joint Surface Characteristics and Filling</td></tr><tr><td>Douposi Formation (∈1d)</td><td></td><td>1: 200 °~210 °/60 °~70 °</td><td rowspan=\"2\">shear joint</td><td rowspan=\"2\">35 strip/m</td><td rowspan=\"2\">The joint surface is straight and smooth.</td></tr><tr><td>Thin-bedded yellow-310 °/50 °gray shale, arenaceous shale.</td><td></td><td>2: 140 °~145 °/35 °~40 °</td></tr><tr><td>Zaige Formation (D3z)</td><td></td><td>1: 240 °~255 °/39 °~45 °</td><td rowspan=\"2\">shear joint</td><td rowspan=\"2\">15 strip/m</td><td rowspan=\"2\">The joint surface is straight and smooth.</td></tr><tr><td>Gray-white aplitic dolomite limestone</td><td>105 °/40 °</td><td>2: 70 °~85 °/30 °~40 °</td></tr><tr><td colspan=\"2\">Datang Formation (C1d)</td><td>1: 270 °~285 °∠</td><td></td><td></td><td rowspan=\"3\">The joint surface is straight and smooth.</td></tr><tr><td colspan=\"2\" rowspan=\"2\">Gray-white medium- and thick-bedded calcarenite.</td><td>55 °~68 °</td><td rowspan=\"2\">shear joint</td><td rowspan=\"2\">16 strip/m</td></tr><tr><td>2: 20 °~36 °∠52 °~60 °</td></tr><tr><td colspan=\"2\" rowspan=\"4\">Weining Formation (C2w) Gray-white middle-bedded cumulus crystal limestone</td><td>1: 305 °~315 °∠</td><td></td><td></td><td rowspan=\"4\">The joint surface is straight and smooth.</td></tr><tr><td>38 °~46 °</td><td rowspan=\"3\">shear joint</td><td rowspan=\"3\">10 strip/m</td></tr><tr><td>2: 165 °~173 °∠</td></tr><tr><td>50 °~60 °</td></tr><tr><td colspan=\"2\" rowspan=\"3\">Lufeng Formation(JI) Amaranth sandstone</td><td>1: 55 °~63 °∠68 °~73 °</td><td></td><td></td><td rowspan=\"3\">The joint surface is straight and smooth.</td></tr><tr><td>2: 300 °~310 °∠</td><td rowspan=\"2\">shear joint</td><td rowspan=\"2\">5 strip/m</td></tr><tr><td>33 °~42 °</td></tr></table>","table_caption":"[\"Table 1. Field Observation Record of Joints on the Southwest Bank of Yangzonghai Lake. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[112,65,200,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HECE 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,884,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,940,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[134,131,858,347]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[112,359,421,374]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Control Factors for Joint Formation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,374,878,404]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is basically concluded from the field primary observation that the development degree of joint is mainly controlled by factors such as lithology, formation thickness and stress intensity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,404,880,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The main exposed limestone and sandstone in this area have strong brittle strain characteristics. The comparison of joints in the field shows that the dominant joints in this area are mainly developed in the Zaige Formation $(\\mathrm{D}_3\\mathrm{z})$ and Lufeng Formation (JI); Douposi Formation $(\\in_{1}\\mathrm{d})$ is mainly thin-bedded yellow-gray shale and sandy shale, with thin thickness and high density of joint development. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,480,478,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. Joint Movement and Mechanical Properties ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,496,880,587]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Joint analysis can be performed directly in areas where the rock formation is close to flat, without the need to correct the rock formation to flat; dip correction is first performed when measuring areas where rock formations are dip. Most of the data points in this analysis are from dip stratum, so flat correction is required, and strGraphPrj software is used for flat correction. After flat correction, the Excel is used to draw rose diagram, and the Stereonet (version 10.1) software is used to complete stereographic projection drawing. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[221,602,779,756]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. Strike and Dip Rose Diagrams of Joints on the Southwest Bank of Yangzonghai Lake. (Strike rose diagram radius=55 strips; dip rose diagram radius=41 strips) \"]","image_footnote":"[]","img_path":"images/0893/e8040e4d19daa4dc155e65926bcbe4d71783fc6917dbf2b81b0df49d9e436b13.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[112,811,884,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From the field data and strike and dip rose diagrams of joints (as shown in the figure 2), it can be clearly concluded that there are six sets of joint systems in the study area: set 1: $10^{\\circ} \\sim 20^{\\circ} \\angle 69^{\\circ} \\sim 80^{\\circ}$ , set 2: $30^{\\circ} \\sim 40^{\\circ} \\angle 43^{\\circ} \\sim 57^{\\circ}$ , set 3: $120^{\\circ} \\sim 130^{\\circ} \\angle 84^{\\circ} \\sim 86^{\\circ}$ , set 4: $250^{\\circ} \\sim 260^{\\circ} \\angle 72^{\\circ} \\sim 81^{\\circ}$ , set 5: $290^{\\circ} \\sim 300^{\\circ} \\angle 65^{\\circ} \\sim 73^{\\circ}$ , set 6: $340^{\\circ} \\sim 350^{\\circ} \\angle 54^{\\circ} \\sim 60^{\\circ}$ . Among them, the two sets of strike to NE-SW and dip to SE, and strike close to SN and dip to W have developed more joints, mainly exposed in the gray-white aplitic dolomite limestone of Zagge Formation ( $\\mathrm{D}_{3} \\mathrm{z}$ ) and the amaranth sandstone of Lufeng Formation ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,65,200,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HECE 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,884,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,81,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[110,134,880,163]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(JI), and basically the same as the strike of the Hujiazhuang reverse fault and the Taiyanggou reverse fault exposed in the study area, reflecting that this area was once extruded by the NW-SE trending. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[110,163,882,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the matching principle of conjugate joints and combined with the field intersection relationship of joints, the joints are further analyzed and it is concluded that there are two sets of conjugate joints in the study area (as shown in the table 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[105,243,892,375]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0686/994158f8aa4bcd05d565d8a05db77ceabb436afdd78eee4a440ad92a3a89a45f.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td>Joint System</td><td>Variation Range of Joint occurrence</td><td>Joint Mechanics Relationship</td><td>Direction of Maximum Principal Stress</td><td>Affiliation of Structure</td></tr><tr><td>System 1</td><td>1: 250°~260°∠72°~81°2: 340°~350°∠54°~60°</td><td>Plane conjugate shear joint</td><td>290°~301°∠54°~63°</td><td>NE - SW</td></tr><tr><td>System 2</td><td>1: 30°~40°∠43°~57°2: 290°~300°∠65°~73°</td><td>Plane conjugate shear joint</td><td>330°~346°∠42°~54°</td><td>NE - SW</td></tr></table>","table_caption":"[\"Table 2. Features of the occurrence of Conjugate Joints on the Southwest Bank of Yangzonghai Lake. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[110,385,882,431]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The features of conjugate joints in the System 1: this joint system is mainly developed in the Zaige Formation, with steep dip angles that belong to the plane conjugate joint set; the strike of the two sets of joints are NW-SE, and NE-SW, controlled by the tectonic stress field of NW-SE extrusion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[110,431,882,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The features of conjugate joints in the System 2: the dip angles of this system are slower than that of System 2, which belong to the plane conjugate joint set, controlled by the tectonic stress field of NW-SE extrusion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,491,522,505]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Joint Instructions for Palaeotectonic Stress Field ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[110,505,884,628]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Joints are sensitive signs of micro-stress fields. To explore the history of tectonic deformation and palaeotectonic stress field in this area, joint staging and matching are often carried out. The analysis of the joints in the study area shows that there are 4 sets of shear joint surfaces in the area that are nearly perpendicular to the rock stratum, which are matched with two sets of plane conjugate shear joint systems. Through the stereographical projection on the joints based on the analysis principle that the intersection line of the two sets of shear joint surfaces is $\\sigma_{2}$ , the acute-angle bisector is $\\sigma_{1}$ , and the obtuse-angle bisector is $\\sigma_{3}$ , it is concluded the features of the tectonic stress field of the two sets of conjugate joints in this area as follows (as shown in the figure 3, table 3): ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[236,643,470,795]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0918/f9fa8a3cb1aab38b69ff54a2bf00c2946158e21f71a7cf0566aa17fe6a76860c.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[541,643,766,796]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Stereographic Projection of the Dominant occurrence of the Conjugate Joints. \"]","image_footnote":"[]","img_path":"images/0776/bd94ea871caee9bc70cd16725b85ec62a7ecdb3e1e3ce54a4c5b23477db2c823.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[112,65,200,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HECE 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,882,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[152,154,843,268]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0310/b897876160ef5433ccb0d8ba2f9c43485fc8de3e56ec6baaf230f09f0c5d844a.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Dominant occurrence of conjugate joints</td><td colspan=\"3\">Principal stress axis occurrence</td><td rowspan=\"2\">Corresponding Affiliation conjugate joint of Structure</td></tr><tr><td>σ1</td><td>σ2</td><td>σ3</td></tr><tr><td>255°/76°, 347°/57°</td><td>296°/58°</td><td>54°/55°</td><td>35°/77°</td><td>Set 1</td></tr><tr><td>34°/50°, 296°/70°</td><td>338°/48°</td><td>94°/46°</td><td>80°/77°</td><td>Set 2</td></tr><tr><td></td><td></td><td></td><td></td><td>NE - SW</td></tr></table>","table_caption":"[\"Table 3. Tectonic Analysis of Conjugate Joint. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[112,280,882,340]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The analysis of the changes in the opposite directions of the maximum principal stresses of the two sets of conjugate shows that the direction of the tectonic stress changes from NWW to NNW, which is consistent with the tectonic stress field of Xiaojiang Fault Zone inverted using seismic data by Lin X D [12] and Shen Y H [13]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,353,226,368]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5. Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,370,885,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"(1) There are six sets of joint systems in the study area: 1: $10^{\\\\circ} \\\\sim 20^{\\\\circ}\\\\angle 69^{\\\\circ} \\\\sim 80^{\\\\circ}$ , 2: $30^{\\\\circ} \\\\sim 40^{\\\\circ}\\\\angle 43^{\\\\circ} \\\\sim 57^{\\\\circ}$ , 3: $120^{\\\\circ} \\\\sim 130^{\\\\circ}\\\\angle 84^{\\\\circ} \\\\sim 86^{\\\\circ}$ , 4: $250^{\\\\circ} \\\\sim 260^{\\\\circ}\\\\angle 72^{\\\\circ} \\\\sim 81^{\\\\circ}$ , 5: $290^{\\\\circ} \\\\sim 300^{\\\\circ}\\\\angle 65^{\\\\circ} \\\\sim 73^{\\\\circ}$ , 6: $340^{\\\\circ} \\\\sim 350^{\\\\circ}\\\\angle 54^{\\\\circ} \\\\sim 60^{\\\\circ}$ . \",\"(2) The two sets of conjugate joints in the study area are both controlled by the tectonic stress field of the extrusion in the NW-SE trending in terms of macroscopic characteristics. \",\"(3) The changes in the opposite directions of the maximum principal stresses of the two sets of conjugate joints in the study area show that the direction of tectonic stress changes from NWW to NNW, which is consistent with the tectonic stress field reflected by faults, folds, and joints in this area. \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[112,510,265,524]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgement ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,524,882,555]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This project is supported by Scientific Research Fund Project of Yunnan Provincial Department of Education (2013Y562). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,570,206,583]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,584,882,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] Lin X D, Xu P, Ge H K 2011 Analysis of time variation of stress field in the middle section of Xiaojiang fault zone and its adjacent areas Earthquake Science 33(6): 755-762. \",\"[2] Shen J, Wang Y P, Song F M 1997 NE trending fault and fault block structure in the middle section of Xiaojiang fault zone Seismogeology 19(3): 203-210 \",\"[3] Tang W Q, Liu Y P, Chen Z L 2006 Current activity characteristics of the central-south section of the Xiaojiang fault zone in Yunnan Sedimentaryary Geology and Tethyan Geology 26(2): 21-24. \",\"[4] Engelder T, Geiser P 1980 On the use of regional joint sets as trajectories of paleostree fileds during the development of the Appalachian Plateau, New York Journal of Geophysical Research 85(B11): 6319-6341. \",\"[5] Hancock P L, Engelder T 1989 Neotectnic joints Geological Society of America Bulletin 101: 1197-1208. \",\"[6] Hancock P L 1991 Determining contemporary stress directions from neotectonic jiont systems Philosophical Transactions of Royal Society of London A337: 29-40. \",\"[7] Chen C, Liu Sh, He L, Liang Q L 2010 Joint features and stress analysis in Longgang area, Pingchang county, central Sichuan basin Journal of Mineralogy and Petrology 30(3): 44-51. \",\"[8] Qin L M, Liu Y C, Wu D C 2003 Characteristics and analysis of joint structure in Xiluodu area Sedimentaryary Geology and Tethyan Geology 3(23): 51-54. \",\"[9] Deng B, Liu S G, Yang S 2009 Tentonic characteristics and significance of multi-phase joints in Lintanchang Sedimentary Geology and Tethyan Geology 29(3): 83-90 \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[112,65,200,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HECE 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,882,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,81,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,133,882,283]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[10] Zhang Z P, Wang Q C, The developmental characteristics of Kuqa depression joints and shear fractures and their indication of regional stress field transformation Sci. China Ser. D 34 (supplementary issue 1): 63-73. \",\"[11] Dong L, Tang L J, Lu X M 2008 Joint development characteristics and indication of stress field transformation in Majiang Oil & Gas Journal 26(6): 740-747. \",\"[12] Lin X D, Xu P, Wu M J, Wu A X 2010 Distribution characteristics of tectonic stress field in the middle section of Xiaojiang fault zone and its adjacent areas Earthquake Research in China 26(2): 192-200. \",\"[13] Shen Y H, Zhang J G, Mao Y 2012 Characteristics of tectonic stress field in Xiaojiang fault zone and its surrounding area Journal of Yunnan University (JCR-SCI) 34(3): 308-314. \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[114,65,200,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HECE 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,882,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,940,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[60,131,243,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PAPER • OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,157,633,226]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tectonic Characteristics and Geological Significance of Joints on the Southwest Bank of Yangzonghai Lake \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,241,626,266]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To cite this article: Qinhui Huang and Jing Wang 2021 IOP Conf. Ser.: Earth Environ. Sci. 668 012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,308,391,321]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View the article online for updates and enhancements. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[673,131,836,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"You may also like \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[699,157,931,271]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"- Recent Tectonic Stress Field in Northwest Yunnan Province\\\\nWenjie Fan, Xiuyi Yao and Xiaofeng Cui \\\",\\\"- Influence of tectonic stress on the structural safety of mountain tunnel under the strike-slip faulting \\\\nJ Tang, Y F Qiao, M C He et al. \\\",\\\"- Cracking mechanism of shale cracks during fracturing X J Zhao, Q Zhan, H Fan et al. \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[84,779,156,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0570/a245f14f4cd08598e5ab5af1ec5fe0df4f76167c80361eb4ce322a9cf0900430.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[157,785,410,802]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Electrochemical Society \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[159,801,410,809]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Advancing solid state & electrochemical science & technology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[159,815,410,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"242nd ECS Meeting \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[159,839,440,855]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Oct 9 - 13, 2022 • Atlanta, GA, US \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[157,863,531,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract submission deadline: April 8, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[157,889,583,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Connect. 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\"image\"\n },\n {\n \"bbox\": \"[534,815,721,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Submit your abstract \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[692,771,936,855]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0356/c49623a9fdb4675d856ba59a7d50070dbada24c86973815cf44cb861171cbbf6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[690,856,936,939]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0492/9a8691cb1c143780f6984b97641bb2b17794d1fa1d7b1ac4c565afdc4becf256.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[60,42,584,58]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conference Series: Earth and Environmental Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[115,228,870,275]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tectonic Characteristics and Geological Significance of Joints on the Southwest Bank of Yangzonghai Lake \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,307,453,324]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Qinhui Huang*, Jing Wang \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,328,653,345]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Yunnan Land and Resources Vocational College, China \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,345,448,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Email: 274959263@qq.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,372,880,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract. Affected by the movement of the Xiaojiang Fault Zone, frequent tectonic activities have occurred in the Yangzonghai Lake area, and a large number of joints have developed in the rock formations. The analysis of joints in the study area shows that there are 6 sets dominant joints, of which 4 sets are two conjugate joint systems; the analysis of stereographic projection for conjugate joints shows that the direction of the maximum principal stress indicated by the tectonic stress field in the area has a tendency to turn from NWW to NNW, which is consistent with the tectonic stress field reflected by faults and folds in the study area and and conforms to the characteristics of the tectonic stress field in the middle of the Xiaojiang Fault Zone. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,496,823,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: Conjugated joint, Tectonic stress field, Principal stress, Yangzonghai Lake \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,545,226,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Instruction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,559,882,724]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Xiaojiang Fault Zone, located in the Sichuan-Yunnan area, is a famous active fault zone, and has extremely complex structure with its adjacent areas [1-3]. Yangzonghai Lake, located in the west branch of the middle section of Xiaojiang Fault Zone, is a faulted lake and is closely related to Xiaojiang Fault Zone in its origin. Affected by the movement of the Xiaojiang Fault Zone, frequent tectonic activities have occurred in the Yangzonghai Lake area, and a large number of joints have developed in the rock formations. The rose diagram, pole diagram and isodensity diagram of the joints directly reflect the degree of development of the joints and their dominant direction, which is an important auxiliary basis for restoring palaeotectonic stress field, determining the geometric form, occurrence direction and combination law of the geological structure and its origin and development process. This paper will analyze the regional tectonic stress field by the research on the joint characteristics of the southwest bank of Yangzonghai Lake. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,724,880,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study of joints has a long history, including the origin (Gilbert.1882, Becker.1891, Van. Hise 1896), field observations, and experimental studies of joints (Sheldon.1912), joint mechanics formation mechanism, and Bucher's deduction in 1921 of the bisected acute Angle of the maximum principal stress and the bisected obtuse Angle of the minimum principal stress when the joint ruptures. It is proved to be a reliable method to invert the tectonic stress field using joints. Through the inversion of joints to the stress field [4-6], Chen C [7], Qin L M [8], Deng B [9], Zhang Z P [10], Dong L [11], et al. also proved that joints have very good indicative significance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,844,324,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Geological Background \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,859,880,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Xiaojiang Fault Zone can be roughly divided into north section, middle section and south section. The study area is the diamond massif sandwiched by the east and west faults in the middle section, which has developed a series of secondary faults tending to the NNE. The exposed strata dip in this area is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,65,200,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HECE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,882,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,884,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,913,198,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CC BY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[198,913,880,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[112,938,371,950]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under licence by IOP Publishing Ltd \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[497,940,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[110,135,885,258]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"relatively steep, such as Canglangpu Formation $(\\\\in_{1}c)$ , Longwangmiao Formation $(\\\\in_{1}l)$ , and Douposi Formation $(\\\\in_{2}d)$ of Cambrian System; Haikou Formation $(\\\\mathrm{D}_2\\\\mathrm{h})$ of Middle Devonian Series, Zaige Formation of Upper Devonian $(\\\\mathrm{D}_3\\\\mathrm{z})$ ; Datang Formation $(\\\\mathrm{C}_1\\\\mathrm{d})$ of Lower Carboniferous Series, Weining Formation $(\\\\mathrm{C}_2\\\\mathrm{w})$ of Middle Carboniferous Series; Daoshitou Formation $(\\\\mathrm{P}_1\\\\mathrm{d})$ , Yangxin Formation $(\\\\mathrm{P}_1\\\\mathrm{y})$ , Emeishan Basalt Formation (Pe) of Lower Permian Series, Lufeng Formation (JI) of Middle Jurassic Series. The structure in this area is relatively complex, with developed folds and faults; the folds axis mainly NE-trending, while the faults are mainly NE, EW, and NS trending faults(as shown in the figure 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,273,359,288]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Joint Development Features \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,302,315,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. Geometrical Features \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[110,315,882,423]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"More than 500 joints of 15 observation points are obtained through detailed observation and measurement of the field outcrop joints of the Cambrian System's Douposi Formation, Devonian System's Zaige Formation, Carboniferous System's Datang Formation and Weining Formation, and Jurassic System's Lufeng Formation's formation. In general, the surface deformation in the study area is relatively weak, mainly low-strain brittle fracture deformation, forming outcrop multi-phase joints structures; the joint surface is straight, and the dip angle is steep with good extension (as shown in the table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[305,442,566,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Geological Sketch of the Southwest Bank of Yangzonghai Lake. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0102/10d295139f4ff818e96344649a2a44ca575d1e9596a2ca5c99f754cab0bd341b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[329,627,539,647]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig 1: Geological Sketch of the Southwest Bank of Yangzonghai Lake \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[566,444,697,652]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0176/f0bf6401be6e03403dd082e7c05bdb9373b990f33ed7b80af180698ec6037d13.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>J2l</td><td>Liuwan Formation of Middle Jurassic Series</td></tr><tr><td>JL</td><td>Lufeng Group of Lower Jurassic Series</td></tr><tr><td>Pe</td><td>Emeishan Basall Formation of Upper Permian Series</td></tr><tr><td>P1y</td><td>Yangxin Formation of Lower Permian Series</td></tr><tr><td>P1l</td><td>Liangshan Formation of Lower Permian Series</td></tr><tr><td>Ch</td><td>Huanglong Formation of Upper Carboniferous Series</td></tr><tr><td>C1w</td><td>Wanshoushan Formation of Lower Carboniferous Series</td></tr><tr><td>D2z</td><td>Zaige Formation of Upper Devonian Series</td></tr><tr><td>D2h</td><td>Haikou Formation of Middle Devonian Series</td></tr><tr><td>€2d</td><td>Douposi Formation of Middle Cambrian Series</td></tr><tr><td>€1l</td><td>Longwangmiao Formation of Lower Cambrian Series</td></tr><tr><td>€1c2</td><td>Canglangpu Formation of Lower Cambrian Series</td></tr><tr><td colspan=\\\"2\\\">Undefined fault</td></tr><tr><td colspan=\\\"2\\\">That fault</td></tr><tr><td colspan=\\\"2\\\">Reverse fault</td></tr><tr><td colspan=\\\"2\\\">Attitude of stratum</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[136,717,858,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0403/ec87d4375e1b3a503f820d40cb897dabd8c7bdd83d1e8b16e7f748b9701dddf3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Stratigraphic Age, Position and Lithology</td><td>Occurrence of Stratum</td><td>Joint occurrence</td><td>Joint Mechanical Property</td><td>Density of Joint</td><td>Joint Surface Characteristics and Filling</td></tr><tr><td>Douposi Formation (∈1d)</td><td></td><td>1: 200 °~210 °/60 °~70 °</td><td rowspan=\\\"2\\\">shear joint</td><td rowspan=\\\"2\\\">35 strip/m</td><td rowspan=\\\"2\\\">The joint surface is straight and smooth.</td></tr><tr><td>Thin-bedded yellow-310 °/50 °gray shale, arenaceous shale.</td><td></td><td>2: 140 °~145 °/35 °~40 °</td></tr><tr><td>Zaige Formation (D3z)</td><td></td><td>1: 240 °~255 °/39 °~45 °</td><td rowspan=\\\"2\\\">shear joint</td><td rowspan=\\\"2\\\">15 strip/m</td><td rowspan=\\\"2\\\">The joint surface is straight and smooth.</td></tr><tr><td>Gray-white aplitic dolomite limestone</td><td>105 °/40 °</td><td>2: 70 °~85 °/30 °~40 °</td></tr><tr><td colspan=\\\"2\\\">Datang Formation (C1d)</td><td>1: 270 °~285 °∠</td><td></td><td></td><td rowspan=\\\"3\\\">The joint surface is straight and smooth.</td></tr><tr><td colspan=\\\"2\\\" rowspan=\\\"2\\\">Gray-white medium- and thick-bedded calcarenite.</td><td>55 °~68 °</td><td rowspan=\\\"2\\\">shear joint</td><td rowspan=\\\"2\\\">16 strip/m</td></tr><tr><td>2: 20 °~36 °∠52 °~60 °</td></tr><tr><td colspan=\\\"2\\\" rowspan=\\\"4\\\">Weining Formation (C2w) Gray-white middle-bedded cumulus crystal limestone</td><td>1: 305 °~315 °∠</td><td></td><td></td><td rowspan=\\\"4\\\">The joint surface is straight and smooth.</td></tr><tr><td>38 °~46 °</td><td rowspan=\\\"3\\\">shear joint</td><td rowspan=\\\"3\\\">10 strip/m</td></tr><tr><td>2: 165 °~173 °∠</td></tr><tr><td>50 °~60 °</td></tr><tr><td colspan=\\\"2\\\" rowspan=\\\"3\\\">Lufeng Formation(JI) Amaranth sandstone</td><td>1: 55 °~63 °∠68 °~73 °</td><td></td><td></td><td rowspan=\\\"3\\\">The joint surface is straight and smooth.</td></tr><tr><td>2: 300 °~310 °∠</td><td rowspan=\\\"2\\\">shear joint</td><td rowspan=\\\"2\\\">5 strip/m</td></tr><tr><td>33 °~42 °</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Field Observation Record of Joints on the Southwest Bank of Yangzonghai Lake. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[112,65,200,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HECE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,884,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,940,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[134,131,858,347]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[112,359,421,374]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Control Factors for Joint Formation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,374,878,404]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is basically concluded from the field primary observation that the development degree of joint is mainly controlled by factors such as lithology, formation thickness and stress intensity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,404,880,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The main exposed limestone and sandstone in this area have strong brittle strain characteristics. The comparison of joints in the field shows that the dominant joints in this area are mainly developed in the Zaige Formation $(\\\\mathrm{D}_3\\\\mathrm{z})$ and Lufeng Formation (JI); Douposi Formation $(\\\\in_{1}\\\\mathrm{d})$ is mainly thin-bedded yellow-gray shale and sandy shale, with thin thickness and high density of joint development. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,480,478,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. Joint Movement and Mechanical Properties \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,496,880,587]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Joint analysis can be performed directly in areas where the rock formation is close to flat, without the need to correct the rock formation to flat; dip correction is first performed when measuring areas where rock formations are dip. Most of the data points in this analysis are from dip stratum, so flat correction is required, and strGraphPrj software is used for flat correction. After flat correction, the Excel is used to draw rose diagram, and the Stereonet (version 10.1) software is used to complete stereographic projection drawing. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[221,602,779,756]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. Strike and Dip Rose Diagrams of Joints on the Southwest Bank of Yangzonghai Lake. (Strike rose diagram radius=55 strips; dip rose diagram radius=41 strips) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0893/e8040e4d19daa4dc155e65926bcbe4d71783fc6917dbf2b81b0df49d9e436b13.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[112,811,884,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From the field data and strike and dip rose diagrams of joints (as shown in the figure 2), it can be clearly concluded that there are six sets of joint systems in the study area: set 1: $10^{\\\\circ} \\\\sim 20^{\\\\circ} \\\\angle 69^{\\\\circ} \\\\sim 80^{\\\\circ}$ , set 2: $30^{\\\\circ} \\\\sim 40^{\\\\circ} \\\\angle 43^{\\\\circ} \\\\sim 57^{\\\\circ}$ , set 3: $120^{\\\\circ} \\\\sim 130^{\\\\circ} \\\\angle 84^{\\\\circ} \\\\sim 86^{\\\\circ}$ , set 4: $250^{\\\\circ} \\\\sim 260^{\\\\circ} \\\\angle 72^{\\\\circ} \\\\sim 81^{\\\\circ}$ , set 5: $290^{\\\\circ} \\\\sim 300^{\\\\circ} \\\\angle 65^{\\\\circ} \\\\sim 73^{\\\\circ}$ , set 6: $340^{\\\\circ} \\\\sim 350^{\\\\circ} \\\\angle 54^{\\\\circ} \\\\sim 60^{\\\\circ}$ . Among them, the two sets of strike to NE-SW and dip to SE, and strike close to SN and dip to W have developed more joints, mainly exposed in the gray-white aplitic dolomite limestone of Zagge Formation ( $\\\\mathrm{D}_{3} \\\\mathrm{z}$ ) and the amaranth sandstone of Lufeng Formation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,65,200,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HECE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,884,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,939,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,81,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[110,134,880,163]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(JI), and basically the same as the strike of the Hujiazhuang reverse fault and the Taiyanggou reverse fault exposed in the study area, reflecting that this area was once extruded by the NW-SE trending. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[110,163,882,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the matching principle of conjugate joints and combined with the field intersection relationship of joints, the joints are further analyzed and it is concluded that there are two sets of conjugate joints in the study area (as shown in the table 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[105,243,892,375]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0686/994158f8aa4bcd05d565d8a05db77ceabb436afdd78eee4a440ad92a3a89a45f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Joint System</td><td>Variation Range of Joint occurrence</td><td>Joint Mechanics Relationship</td><td>Direction of Maximum Principal Stress</td><td>Affiliation of Structure</td></tr><tr><td>System 1</td><td>1: 250°~260°∠72°~81°2: 340°~350°∠54°~60°</td><td>Plane conjugate shear joint</td><td>290°~301°∠54°~63°</td><td>NE - SW</td></tr><tr><td>System 2</td><td>1: 30°~40°∠43°~57°2: 290°~300°∠65°~73°</td><td>Plane conjugate shear joint</td><td>330°~346°∠42°~54°</td><td>NE - SW</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Features of the occurrence of Conjugate Joints on the Southwest Bank of Yangzonghai Lake. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[110,385,882,431]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The features of conjugate joints in the System 1: this joint system is mainly developed in the Zaige Formation, with steep dip angles that belong to the plane conjugate joint set; the strike of the two sets of joints are NW-SE, and NE-SW, controlled by the tectonic stress field of NW-SE extrusion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[110,431,882,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The features of conjugate joints in the System 2: the dip angles of this system are slower than that of System 2, which belong to the plane conjugate joint set, controlled by the tectonic stress field of NW-SE extrusion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,491,522,505]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Joint Instructions for Palaeotectonic Stress Field \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[110,505,884,628]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Joints are sensitive signs of micro-stress fields. To explore the history of tectonic deformation and palaeotectonic stress field in this area, joint staging and matching are often carried out. The analysis of the joints in the study area shows that there are 4 sets of shear joint surfaces in the area that are nearly perpendicular to the rock stratum, which are matched with two sets of plane conjugate shear joint systems. Through the stereographical projection on the joints based on the analysis principle that the intersection line of the two sets of shear joint surfaces is $\\\\sigma_{2}$ , the acute-angle bisector is $\\\\sigma_{1}$ , and the obtuse-angle bisector is $\\\\sigma_{3}$ , it is concluded the features of the tectonic stress field of the two sets of conjugate joints in this area as follows (as shown in the figure 3, table 3): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[236,643,470,795]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0918/f9fa8a3cb1aab38b69ff54a2bf00c2946158e21f71a7cf0566aa17fe6a76860c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[541,643,766,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Stereographic Projection of the Dominant occurrence of the Conjugate Joints. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0776/bd94ea871caee9bc70cd16725b85ec62a7ecdb3e1e3ce54a4c5b23477db2c823.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[112,65,200,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HECE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,882,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,939,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[152,154,843,268]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0310/b897876160ef5433ccb0d8ba2f9c43485fc8de3e56ec6baaf230f09f0c5d844a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Dominant occurrence of conjugate joints</td><td colspan=\\\"3\\\">Principal stress axis occurrence</td><td rowspan=\\\"2\\\">Corresponding Affiliation conjugate joint of Structure</td></tr><tr><td>σ1</td><td>σ2</td><td>σ3</td></tr><tr><td>255°/76°, 347°/57°</td><td>296°/58°</td><td>54°/55°</td><td>35°/77°</td><td>Set 1</td></tr><tr><td>34°/50°, 296°/70°</td><td>338°/48°</td><td>94°/46°</td><td>80°/77°</td><td>Set 2</td></tr><tr><td></td><td></td><td></td><td></td><td>NE - SW</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3. Tectonic Analysis of Conjugate Joint. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[112,280,882,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The analysis of the changes in the opposite directions of the maximum principal stresses of the two sets of conjugate shows that the direction of the tectonic stress changes from NWW to NNW, which is consistent with the tectonic stress field of Xiaojiang Fault Zone inverted using seismic data by Lin X D [12] and Shen Y H [13]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,353,226,368]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5. Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,370,885,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"(1) There are six sets of joint systems in the study area: 1: $10^{\\\\\\\\circ} \\\\\\\\sim 20^{\\\\\\\\circ}\\\\\\\\angle 69^{\\\\\\\\circ} \\\\\\\\sim 80^{\\\\\\\\circ}$ , 2: $30^{\\\\\\\\circ} \\\\\\\\sim 40^{\\\\\\\\circ}\\\\\\\\angle 43^{\\\\\\\\circ} \\\\\\\\sim 57^{\\\\\\\\circ}$ , 3: $120^{\\\\\\\\circ} \\\\\\\\sim 130^{\\\\\\\\circ}\\\\\\\\angle 84^{\\\\\\\\circ} \\\\\\\\sim 86^{\\\\\\\\circ}$ , 4: $250^{\\\\\\\\circ} \\\\\\\\sim 260^{\\\\\\\\circ}\\\\\\\\angle 72^{\\\\\\\\circ} \\\\\\\\sim 81^{\\\\\\\\circ}$ , 5: $290^{\\\\\\\\circ} \\\\\\\\sim 300^{\\\\\\\\circ}\\\\\\\\angle 65^{\\\\\\\\circ} \\\\\\\\sim 73^{\\\\\\\\circ}$ , 6: $340^{\\\\\\\\circ} \\\\\\\\sim 350^{\\\\\\\\circ}\\\\\\\\angle 54^{\\\\\\\\circ} \\\\\\\\sim 60^{\\\\\\\\circ}$ . \\\",\\\"(2) The two sets of conjugate joints in the study area are both controlled by the tectonic stress field of the extrusion in the NW-SE trending in terms of macroscopic characteristics. \\\",\\\"(3) The changes in the opposite directions of the maximum principal stresses of the two sets of conjugate joints in the study area show that the direction of tectonic stress changes from NWW to NNW, which is consistent with the tectonic stress field reflected by faults, folds, and joints in this area. \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[112,510,265,524]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgement \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,524,882,555]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This project is supported by Scientific Research Fund Project of Yunnan Provincial Department of Education (2013Y562). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,570,206,583]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,584,882,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] Lin X D, Xu P, Ge H K 2011 Analysis of time variation of stress field in the middle section of Xiaojiang fault zone and its adjacent areas Earthquake Science 33(6): 755-762. \\\",\\\"[2] Shen J, Wang Y P, Song F M 1997 NE trending fault and fault block structure in the middle section of Xiaojiang fault zone Seismogeology 19(3): 203-210 \\\",\\\"[3] Tang W Q, Liu Y P, Chen Z L 2006 Current activity characteristics of the central-south section of the Xiaojiang fault zone in Yunnan Sedimentaryary Geology and Tethyan Geology 26(2): 21-24. \\\",\\\"[4] Engelder T, Geiser P 1980 On the use of regional joint sets as trajectories of paleostree fileds during the development of the Appalachian Plateau, New York Journal of Geophysical Research 85(B11): 6319-6341. \\\",\\\"[5] Hancock P L, Engelder T 1989 Neotectnic joints Geological Society of America Bulletin 101: 1197-1208. \\\",\\\"[6] Hancock P L 1991 Determining contemporary stress directions from neotectonic jiont systems Philosophical Transactions of Royal Society of London A337: 29-40. \\\",\\\"[7] Chen C, Liu Sh, He L, Liang Q L 2010 Joint features and stress analysis in Longgang area, Pingchang county, central Sichuan basin Journal of Mineralogy and Petrology 30(3): 44-51. \\\",\\\"[8] Qin L M, Liu Y C, Wu D C 2003 Characteristics and analysis of joint structure in Xiluodu area Sedimentaryary Geology and Tethyan Geology 3(23): 51-54. \\\",\\\"[9] Deng B, Liu S G, Yang S 2009 Tentonic characteristics and significance of multi-phase joints in Lintanchang Sedimentary Geology and Tethyan Geology 29(3): 83-90 \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[112,65,200,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HECE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,882,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,939,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,81,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Conf. Series: Earth and Environmental Science 668 (2021) 012006 doi:10.1088/1755-1315/668/1/012006 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,133,882,283]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[10] Zhang Z P, Wang Q C, The developmental characteristics of Kuqa depression joints and shear fractures and their indication of regional stress field transformation Sci. China Ser. D 34 (supplementary issue 1): 63-73. \\\",\\\"[11] Dong L, Tang L J, Lu X M 2008 Joint development characteristics and indication of stress field transformation in Majiang Oil & Gas Journal 26(6): 740-747. \\\",\\\"[12] Lin X D, Xu P, Wu M J, Wu A X 2010 Distribution characteristics of tectonic stress field in the middle section of Xiaojiang fault zone and its adjacent areas Earthquake Research in China 26(2): 192-200. \\\",\\\"[13] Shen Y H, Zhang J G, Mao Y 2012 Characteristics of tectonic stress field in Xiaojiang fault zone and its surrounding area Journal of Yunnan University (JCR-SCI) 34(3): 308-314. \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[114,65,200,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HECE 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,882,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,940,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1088/1755-1315/668/1/012006"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"0dc6caaf22c25a6f05e1bbc0fbcbc3e93036e2fc8b47a4fb5f072828d51e4093"},"title":{"kind":"string","value":"Tectonic Characteristics and Geological Significance of Joints on the Southwest Bank of Yangzonghai Lake"}}},{"rowIdx":165,"cells":{"abstract":{"kind":"string","value":"We report the synthesis and characterization of a new family of maltose-derived nonionic surfactants that contain a photocleavable azo-sulfide linker (mAzo). The self-assembly properties of these surfactants were investigated using surface tension measurements to determine the critical micelle concentration (CMC), dynamic light scattering (DLS) to reveal the hydrodynamic radius of their self-assemblies, and transmission electron microscopy (TEM) to elucidate the micelle morphology. Ultraviolet-visible (UV-visible) spectroscopy confirmed the rapid photodegradation of these surfactants, but surface tension measurements of the surfactant solutions before and after degradation showed unusual degradation products. The photodegradation process was further studied using online liquid chromatography coupled with mass spectrometry (LC-MS),which revealed that these surfactants can form another photo-stable surfactant post-degradation. Finally, traditionally challenging proteins from heart tissue were solubilized using the mAzo surfactants to demonstrate their potential in biological applications."},"author":{"kind":"string","value":"Kyle A. Brown|Morgan K. Gugger|David S. Roberts|David Moreno|Pil Seok Chae|Ying Ge|Song Jin"},"content_list":{"kind":"list like","value":[{"bbox":"[80,103,212,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[863,103,904,115]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,135,807,205]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Synthesis, Self-Assembly Properties, and Degradation Characterization of a Nonionic Photocleavable Azo-Sulfide Surfactant Family ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[79,208,883,246]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Kyle A. Brown,\\* Morgan K. Gugger,\\* David S. Roberts, David Moreno, Pil Seok Chae, Ying Ge, and Song Jin\\* ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,253,116,281]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0650/5ce7b9b0551677cfa1a1ad5a6f4ab2314fb6d151af776fe8aa0424844530126c.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[120,261,357,275]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cite This: Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,253,550,281]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0670/c5821aea891cd60f2879f84128c7467f0df30985c58e49439df8912a08045497.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[551,262,635,273]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Read Online ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,300,172,318]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACCESS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[232,305,255,320]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0745/eb78535ec076125403d828e150176d56d9dce5159f2015576b188173b330b2bc.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[260,305,354,317]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Metrics & More ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[449,305,472,320]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0532/f3f8611f94e16a4712977a98693cfd806b11236210eb1f1a764ab09049b0573b.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[474,305,632,317]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article Recommendations ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[706,305,728,320]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0934/c697c7e697fec83d47cecba3b7bd15c1ff48d0150dc5204b6d3d83e76ad0d868.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[731,305,871,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supporting Information ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,335,680,515]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ABSTRACT: We report the synthesis and characterization of a new family of maltose-derived nonionic surfactants that contain a photocleavable azo-sulfide linker (mAzo). The self-assembly properties of these surfactants were investigated using surface tension measurements to determine the critical micelle concentration (CMC), dynamic light scattering (DLS) to reveal the hydrodynamic radius of their self-assemblies, and transmission electron microscopy (TEM) to elucidate the micelle morphology. Ultraviolet-visible (UV-visible) spectroscopy confirmed the rapid photodegradation of these surfactants, but surface tension measurements of the surfactant solutions before and after degradation showed unusual degradation products. The photodegradation process was further studied using online liquid chromatography coupled with mass spectrometry (LC-MS), which revealed that these surfactants can form another photo-stable surfactant post-degradation. Finally, traditionally challenging proteins from heart tissue were solubilized using the mAzo surfactants to demonstrate their potential in biological applications. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[691,333,914,406]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0527/c9f272da1e70c49e7cc9dac1919c19ea6ca5eb77bef2ac9c82b7129af6869239.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[690,410,914,505]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0348/c2320c06aa9666902b9ace7d195aa9725ff41a050432d1bace81aa501570bca2.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,542,230,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,561,482,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Surfactants are molecules that contain both a hydrophobic and hydrophilic component. $^{1-3}$ They can alter the surface tension of the liquid in which they are present and have proven to be valuable across several industries and scientific fields ranging from vessels for chemical reactions to membrane mimics for the characterization of biomolecules. $^{1-6}$ Consequently, it is important to develop and characterize new surfactant compounds with specifically desired attributes. Surfactants have been traditionally categorized as ionic, zwitterionic, or nonionic, and these characteristics have important behavioral implications that make the surfactants suitable for different applications. For example, nonionic surfactants can preserve the native states and biological functions of proteins. $^{7-9}$ They can also act as effective templates to design and synthesize mesoporous solids, a process termed nonionic-surfactant-templating. $^{10}$ More recently, novel surfactants with unique properties, such as cleavable surfactants, multimeric surfactants (e.g., Gemini and trimeric), and surfactants with constituents of biological origin, have been of increasing interest. $^{11,12}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,825,481,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cleavable surfactants, wherein a weakened bond is engineered between the hydrophobic and hydrophilic portions of the molecule, can be especially useful when their surface tension-altering property is initially needed yet is a subsequent nuisance. Several cleavable motifs are labile under various external stimuli including light, acid, alkali, temperature, redox environment, and enzymatic conditions.[12-24] Light offers advantages over other stimuli, as it can be administered at a ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,542,915,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"specific time and location within a larger system, it is relatively inexpensive, and it is noninvasive.[25] Some of the most widely used photocleavable motifs include phenacyl, nitrobenzyl-based, azo-based, and benzyl-based.[18,26-29] For example, our lab recently demonstrated the use of an anionic azobenzene photocleavable surfactant (Azo) for protein extraction and subsequent proteomic analysis following rapid surfactant degradation.[13,30-33] However, the ionic nature of Azo surfactant prevents its biological applications where the proteins cannot be denatured. It is desirable to develop new classes of photocleavable surfactants with milder nonionic head and tail groups for a wide variety of biological applications. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,715,915,830]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Here, we have synthesized and characterized the molecular and supramolecular properties of a novel family of nonionic sugar-derived surfactants containing a photocleavable motif (Figure 1). This surfactant series, which we refer to as mAzo, consists of a hydrophilic head of maltose, $^{34,35}$ a photocleavable azo-sulfide linker, and a phenylalkyl hydrophobic tail with alkyl chains ranging between 6 and 10 carbons to explore how the relative hydrophobicity affects aspects of the compounds and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,847,693,860]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: October 14, 2022 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,861,703,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Revised: December 29, 2022 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,875,688,888]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published: January 13, 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[843,842,914,917]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0015/f90fd87c96fca9a90859b902f7335c6d09debc396e1272061b77407ac92b09f1.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[14,293,31,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ished articles. ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[16,645,32,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"See https://pu ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[80,37,352,72]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LANGMUIR ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,946,121,975]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[123,951,273,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACS Publications ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[304,950,462,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 American Chemical Society ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[484,957,512,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1465 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,948,914,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,960,914,966]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,70,915,201]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Design of a family of nonionic photocleavable surfactants (mAzo) consisting of a maltose head group, azobenzene linker, and tunable alkyl chain, and the hypothesized photodegradation pathway. \"]","image_footnote":"[]","img_path":"images/0894/e5a463aa4551072b176b7d02322caedce3afd8a93bcbc1b697ffe7675b4d8b98.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[133,266,861,350]","code_body":null,"code_caption":null,"image_caption":"[\"Scheme 1. Synthetic Scheme for the mAzo Surfactant Family \"]","image_footnote":"[]","img_path":"images/0538/cd2a7746f6462dead222cc4386f28bd85e0156bb56bad06953ec06e60f162331.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[133,358,828,540]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0414/8f5193d493768871690f315dbddb1ca0ce111bd5f6fb1ddb70a43ce19afd3800.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[77,556,481,695]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"their assemblies. It is expected that, upon ultraviolet (UV) irradiation, the azo-sulfide would homolytically cleave to expel nitrogen gas, leaving behind alkylbenzene and phenolic-derived products as well as thiomaltose based on a previous work on the Azo surfactants (that contain a sulfate head group).[23,26,36] However, detailed characterization of the properties of the surfactant uncovered a secondary degradation pathway leading to the formation of a new surfactant that alters surface tension. These results provide insights into the continued development and application of photocleavable surfactants. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,710,299,725]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"EXPERIMENTAL SECTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,730,482,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reagents and Materials. All chemicals and reagents were obtained commercially and used without further purification. The $\\beta$ -D-maltose octaacetate, ammonium acetate $(\\mathrm{NH}_4\\mathrm{OAc})$ , thiourea, and high-performance liquid chromatography (HPLC)-grade water $(\\mathrm{H}_2\\mathrm{O})$ were purchased from Fischer Scientific. Boron trifluoride diethyl etherate $(\\mathrm{BF}_3\\cdot \\mathrm{Et}_2\\mathrm{O})$ , sodium metabisulfite $(\\mathrm{Na}_2\\mathrm{S}_2\\mathrm{O}_5)$ , magnesium sulfate $(\\mathrm{MgSO}_4)$ , sodium nitrite $(\\mathrm{NaNO}_2)$ , hydrochloric acid (HCl), potassium hydroxide (KOH), dichloromethane (DCM), acetonitrile (MeCN), ethyl acetate (EtOAc), anhydrous methanol (MeOH), anhydrous chloroform $(\\mathrm{CHCl}_3)$ , and silica were all purchased from Sigma-Aldrich. 4-n-Hexylaniline, 4-n-octylaniline, and 4-n-decylaniline were all obtained from TCI America. Protein extraction solutions were made in nanopure water, ammonium bicarbonate $(\\mathrm{NH}_4\\mathrm{HCO}_3)$ , potassium chloride (KCl), sucrose, sodium fluoride (NaF), phenylmethanesulfonyl fluoride (PMSF), L-methionine, ethylenediaminetetraacetic acid (EDTA), and $n$ -dodecyl- $\\beta$ -D-maltoside (DDM) were all purchased from Sigma-Aldrich. Swine ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,556,915,605]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"heart tissue was obtained from healthy Yorkshire domestic pigs and had been flash-frozen in liquid $\\mathbf{N}_2$ and stored at $-80^{\\circ}\\mathrm{C}$ prior to use. The Protein Assay Dye Reagent Concentrate was obtained from BioRad. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,605,914,631]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Surfactant Synthesis. The synthesis of the family of mAzo surfactants followed the multistep process outlined in Scheme 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,630,915,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1-Isothiouronium- $\\beta$ -D-maltose Heptaacetate Fluoride (1). Thiourea $(0.418\\mathrm{g},5.50\\mathrm{mmol},1.10\\mathrm{equiv})$ was added to a stirring solution of $\\beta$ -D-maltose octaacetate $(3.39~\\mathrm{g},5\\mathrm{mmol},1$ equiv) in dry acetonitrile $(10.0~\\mathrm{mL})$ . Then, $\\mathrm{BF}_3\\bullet \\mathrm{Et}_2\\mathrm{O}$ $(1.85~\\mathrm{mL},15.0~\\mathrm{mmol},3$ equiv) was added and the reaction was allowed to proceed under reflux for $20\\mathrm{min}$ All starting material should disappear at this time. The reaction mixture was cooled to room temperature before adding pyridine $(15.0\\mathrm{mmol},1.19\\mathrm{g},1.21\\mathrm{mL},3$ equiv) and concentrating in vacuo to a syrup. The syrup was dissolved in $40~\\mathrm{mL}$ of EtOAc and washed with HPLC-grade water $(3\\times 20~\\mathrm{mL})$ . The organic layer was then dried with anhydrous $\\mathrm{MgSO_4}$ and concentrated in vacuo.37 The isothiouronium salt 1 was obtained as a white amorphous solid and used without further purification. Crude yield, $98\\%$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,791,915,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1-Thio- $\\beta$ -D-maltose Heptaacetate (2). Sodium metabisulfite (7.50 mmol, $1.43\\mathrm{g},$ 1.50 equiv), DCM $(23~\\mathrm{mL})$ , and HPLC-grade water $(13~\\mathrm{mL})$ were added to the isothiouronium intermediate 1 $(3.51\\mathrm{g},$ $5.00\\mathrm{mmol}$ 1.00 equiv), and the reaction mixture was refluxed at $\\sim 60$ $^\\circ C$ for $3.5\\mathrm{h}$ . After the mixture was cooled to room temperature, the aqueous layer was decanted and extracted with DCM $(2\\times 20~\\mathrm{mL})$ The organic layers were then recombined and washed with brine $(1\\times$ $10~\\mathrm{mL})$ , dried over anhydrous $\\mathrm{MgSO_4}$ , and concentrated in vacuo to afford 2 as an amorphous white solid, which was used in the following steps without further purification. Yield, $84\\%$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,915,915,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1-Thio- $\\beta$ -D-maltose Potassium Salt (3). Peracetylated 1-thio- $\\beta$ -DMaltose 2 (1.00 g, 1.53 mmol, 1.00 equiv) was suspended in a ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,46,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[434,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[864,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,952,512,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1466 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[79,70,481,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"solution of anhydrous MeOH (5 mL) containing KOH (100 mg, 1.78 mmol, 1.18 equiv). The deacetylation was allowed to proceed for 30 min to afford a white precipitate before adding EtOAc (5 mL). The reaction mixture was then centrifuged, and the supernatant was discarded. The solid was washed once more with EtOAc (5 mL), isolated via centrifugation, and dried overnight in a desiccator to afford 3 as a white solid in quantitative yield. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,158,481,307]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4-n-Alkyl Diazonium Chloride Salts (4, 5, 6). 4-n-Hexylaniline (C6) (115 mg, 0.649 mmol, 1.0 equiv) was added to a solution of 11 M HCl (215 μL) and HPLC-grade water (630 μL), and the mixture was stirred at $0^{\\circ}\\mathrm{C}$ in an ice bath for 5 min before a cooled solution of $\\mathrm{NaNO}_2$ (63 mg, 0.914 mmol, 1.4 equiv) in HPLC-grade water (630 μL) was added dropwise over 5 min. The same procedure was scaled and repeated for 4-n-octylaniline (C8) (116 mg, 0.568 mmol, 1.0 equiv) and 4-n-decylaniline (C10) (35.2 mg, 0.151 mmol, 1.0 equiv). The reaction mixtures were stirred for 20 min at $0^{\\circ}\\mathrm{C}$ to afford clear, colorless to slightly yellow solutions of diazonium chloride salts 4-6 in assumed quantitative yields, which were used in situ in the following steps.[23] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,307,481,530]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Maltose Azo-Sulfide Surfactants [7 (mAzo 6), 8 (mAzo 8), 9 (mAzo 10)]. To the stirred solution of diazonium salt 4, ice-cold $\\mathrm{NH_4OAc}$ (6 M) was added dropwise until a pH of 6 was attained. This buffered solution was then added dropwise to a stirred, cooled solution of 3 (410 mg, 0.965 mmol, 1.7 equiv) in HPLC-grade water (2.0 mL), and a bright yellow product was immediately observed. The same procedure was scaled and repeated for the solutions of 5 and 6, and supplemental water was added in $200\\mu \\mathrm{L}$ aliquots for ease of stirring. After allowing the reaction to stir for a further $30\\mathrm{min}$ at $0^{\\circ}\\mathrm{C}$ , a volume of chloroform equivalent to the aqueous reaction mixture was added. Methanol was then added in $100\\mu \\mathrm{L}$ aliquots, and the mixture was shaken vigorously until the yellow product was observed to migrate into the organic layer. The organic layer was then removed, dried with anhydrous $\\mathrm{MgSO_4}$ , and the solvent was removed in vacuo without applying heat. The crude solids of 7-9 were purified by silica flash chromatography using ice-cold solvent (DCM:MeOH 80:20; $R_{\\mathrm{f}} = 0.3$ (C6), $R_{\\mathrm{f}} = 0.4$ (C8), $R_{\\mathrm{f}} = 0.45$ (C10)) to afford 7-9 as a bright yellow solid. Yield, 39% (C6), 40% (C8), 34% (C10). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,530,481,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Surfactant Characterization. The mAzo surfactants and the resulting degradation products were characterized using the following methods: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,567,481,630]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"${}^{1}\\mathsf{H}$ NMR. Spectra were recorded on a Bruker Avance-400 MHz spectrometer at room temperature and referenced using residual undetuerated solvent peaks $\\mathrm{(DMSO - d_6}$ $\\delta_{\\mathrm{H}} = 2.50$ ppm; $\\mathrm{D}_2\\mathrm{O}$ $\\delta_{\\mathrm{H}} = 4.79$ ppm). The ${}^{1}\\mathrm{H}$ NMR spectra and associated peak shifts for compounds 1-9 are displayed in Figures S1-S6. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,630,481,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Surface Tension Measurements. Critical micelle concentration (CMC) values were obtained using a Tensimeter Kruss K10T equipped with a Wilhelmy plate. A $1\\%$ wt solution of 7 (mAzo 6) and 8 (mAzo 8) as well as a $0.1\\%$ wt solution of 9 (mAzo 10) was prepared in nanopure water and kept in an ice bath. Small aliquots of each surfactant were added to $10~\\mathrm{mL}$ of ice-cold nanopure water under continuous stirring, and surface tension measurements were taken and plotted as a function of the logarithm of their corresponding concentration. The measurements were repeated three times for each surfactant. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,755,481,853]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dynamic Light Scattering. Dynamic light scattering (DLS) measurements were carried out using a Malvern Zetasizer Nano ZSP. Solutions were prepared for each surfactant at $30\\times$ their measured CMCs in degassed nanopure water. The surfactant solutions were then passed through a $0.2\\mu \\mathrm{m}$ filter and centrifuged at $21,100\\mathrm{g}$ for $10\\mathrm{min}$ at $4^{\\circ}\\mathrm{C}$ . Samples were allowed to equilibrate in the zetasizer for $120\\mathrm{s}$ before DLS measurements were taken. DLS experiments were repeated three times on each sample. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,853,481,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"TEM Imaging. The surfactants were suspended in nanopure deionized water from Milli-Q water (MilliporeSigma) at $30\\times$ their measured CMCs, sonicated for 2 min, and allowed to equilibrate in the dark for 10 min. Transmission electron microscopy (TEM) samples were prepared by mixing surfactant solutions with a $4\\%$ wt aqueous phosphotungstic acid solution $(\\mathrm{pH}7.4)$ (MilliporeSigma) in a 1:1 ratio by volume, and then one drop of the surfactant solution ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,71,915,146]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"was pipetted onto a formvar-coated copper TEM grid with carbon film for negative staining. TEM imaging was conducted on an FEI Tecnai TF 30 TEM instrument operated at $300\\mathrm{kV}$ and equipped with a Gatan K2 direct electron detector for low-dose TEM. Images were collected with a total electron dose of $10\\mathrm{e} / \\mathring{\\mathrm{A}}^2$ , and all images were processed with digital micrograph software program. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,146,915,245]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Photodegradation Analysis by UV-Vis. All UV-visible (UV-vis) absorbance measurements were performed on a PerkinElmer Lambda 10 spectrophotometer. A $0.014\\%$ wt solution of each surfactant was prepared and aliquoted into $1.5~\\mathrm{mL}$ Lo-Bind Eppendorf centrifuge tubes. Samples were then irradiated using a $100\\mathrm{W}$ high-pressure mercury lamp for 0, 30, 120, or $600\\mathrm{s}$ . Samples were then immediately flash-frozen at $-80^{\\circ}\\mathrm{C}$ and thawed at $4^{\\circ}\\mathrm{C}$ before taking absorbance spectra. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,245,915,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LC-MS of the Degradation Products of Surfactants. Liquid chromatography-mass spectrometry (LC-MS) was performed on a Waters nanoACQUITY HPLC coupled to a maXis II ETD Q-TOF (Bruker Daltonics). Surfactant or degraded product $(2\\mu \\mathrm{g})$ was loaded onto a home-packed C2 column $(500~\\mu \\mathrm{M})$ and separated at room temperature with a flow rate of $12~\\mu \\mathrm{L / min}$ using a $35\\mathrm{min}$ gradient from 40 to $95\\%$ B with mobile phases of $0.2\\%$ formic acid in water (A) and $0.2\\%$ formic acid in ACN:IPA (1:1) (B). Compounds eluted from the column were infused and ionized using a capillary voltage of $4500\\mathrm{V}$ and transmitted with an endplate voltage of $500\\mathrm{V}$ . MS scans were collected at $1\\mathrm{Hz}$ from 500 to $2000m / z$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,382,915,670]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Insoluble Protein Extraction and Bradford Assay. The following protein extraction was carried out at $4^{\\circ}\\mathrm{C}$ . Swine heart tissue (230 mg) was cut into small pieces and homogenized for 1 min in 1 mL of a lysis buffer containing 1 mM EDTA, 25 mM $\\mathrm{NH_4HCO_3}$ , 250 mM sucrose, 500 mM KCl, 500 mM NaF, 2 mM L-methionine, and 1 mM PMSF. The homogenate was then centrifuged at 21,100 g for 10 min, and the supernatant was removed and discarded. The tissue pellet was then rehomogenized for 1 min in 1 mL of a washing buffer containing 25 mM $\\mathrm{NH_4HCO_3}$ , 2 mM L-methionine, and 1 mM PMSF, centrifuged for 10 min at 21,100 g, and the supernatant was removed. This washing process was repeated twice more, wherein the homogenate from the final wash was first partitioned into 21 separate 1.5 mL Eppendorf centrifuge tubes. To each tissue pellet was then added 100 μL of 25 mM $\\mathrm{NH_4HCO_3}$ containing no surfactant (NS, control), 1.0% wt mAzo 6, 1.0% wt mAzo 8, 1.0% wt mAzo 10, 1.0% wt DDM, 1.0% wt Azo 6, or a maximally concentrated solution of Azo 8. Each of these seven conditions was tested three times. The insoluble pellets were then resuspended, and the extraction was allowed to proceed for 1 h before centrifuging at 21,100g and collecting the supernatant. The concentration of the protein in the supernatants was determined using a Bradford Assay on a small, diluted sample aliquot and measuring the absorbance at 595 nm after a 5 min incubation period. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,670,915,792]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SDS-PAGE of Extracted Proteins. To $40~\\mu \\mathrm{L}$ of each supernatant, $160~\\mu \\mathrm{L}$ of ice-cold acetone was added, and the samples were allowed to sit overnight at $-20^{\\circ}C.$ After the samples were centrifuged for 10 min at $21,100g$ and the supernatant was removed, the precipitated proteins from each sample were reconstituted in $40~\\mu \\mathrm{L}$ of $1\\times$ Laemmli buffer, of which $5\\mu \\mathrm{L}$ was loaded into a $1\\mathrm{mm}$ 10 well $12.5\\%$ sodium dodecyl sulfate (SDS) polyacrylamide gel made in-house. Proteins were resolved by applying $70\\mathrm{V}$ for $20\\mathrm{min}$ and subsequently $120\\mathrm{V}$ for approximately $80\\mathrm{min}$ and the bands were visualized using Coomassie Brilliant Blue. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,810,752,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS AND DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,830,915,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We report the successful synthesis of a new class of photocleavable, nonionic surfactants (mAzo) derived from the maltose hydrophilic head group, azo-sulfide linker, and hydrophobic 4-n-alkyl anilines. These mAzo compounds represent novel analogues of the previously characterized alkylbenzene azosulfonates[23,26] but have a highly water-soluble maltose head group. This was chosen to mimic the properties of the commercially available nonionic surfactant DDM, which ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,47,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[436,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,952,512,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1467 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[205,83,413,163]","code_body":null,"code_caption":null,"image_caption":"[\"a \"]","image_footnote":"[]","img_path":"images/0965/ec09dd28c8af743ea3ac13922d2dde5f2c8d045935bba1869ec296f103cc6ad8.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[436,75,645,162]","code_body":null,"code_caption":null,"image_caption":"[\"d \",\"g \"]","image_footnote":"[]","img_path":"images/0171/f1fee8dbecded51e28138cfb2afeda4d41e53b44ca360341098d57649a2cf7fe.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[678,73,795,162]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0318/f724c4ebaca21766798ce2df4d7c57e05f3da32caa16b9f7d2906b4a4b5e878d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[205,170,416,251]","code_body":null,"code_caption":null,"image_caption":"[\"b \"]","image_footnote":"[]","img_path":"images/0946/344d30aa5dae396058b380f4363174d2f787b9a6daa194c3b6f5d971133fcd3e.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[436,165,644,251]","code_body":null,"code_caption":null,"image_caption":"[\"e \",\"h \"]","image_footnote":"[]","img_path":"images/0507/101b0ba657a668904fee3ec61a6ac41e37387497ac730fb87bd1a69c1a070199.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[678,165,795,253]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0758/8b495d8ad4cf08a5e22f9160c3a1a25492e3151fb76dea5268e1ef529f677908.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[202,260,413,342]","code_body":null,"code_caption":null,"image_caption":"[\"C \"]","image_footnote":"[]","img_path":"images/0688/b838654c2720c2fadf85d6440d627264683ffd15a16461a28f7cdaa82ab8e2a3.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[436,258,644,345]","code_body":null,"code_caption":null,"image_caption":"[\"f \",\"i \"]","image_footnote":"[]","img_path":"images/0227/e11f69b609b4743276524f13856bdcc8b0e6dfce105949a26e55e2125c8452c5.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[678,258,795,345]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. Characterization of the supramolecular assemblies formed by the mAzo surfactants. (a-c) Surface tension measurements at different surfactant concentrations with linear regression fits to decline and plateau regions for mAzo 6, mAzo 8, and mAzo 10. (d-f) Triplicate trial overlay of hydrodynamic micelle diameters for mAzo 6, mAzo 8, and mAzo 10 as measured by DLS. (g-h) Representative low-dose TEM images of mAzo 6, mAzo 8, and mAzo 10 obtained by negative stain contrast showing micellar structures. The insets show the micelle size distribution histograms. \"]","image_footnote":"[]","img_path":"images/0043/8974bedb5d057d51d579bfacc7507e0acf0fe99e5babf125fba578f98f670611.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[79,418,479,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"has been widely used in biology for protein purification and crystallography. $^{7}$ We envision that additional photodegradable surfactants featuring a variety of head groups (e.g., different sugar moieties, oligoglycerols, etc.) could be developed using a similar process described here, which would have unique properties. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,500,479,788]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The surfactants were synthesized in four total steps (Scheme 1), the first three of which were used to form 1-thio- $\\beta$ -D-maltose (3). Commercially available peracetylated maltose was first taken to its 1-isothiouronium derivative 1 by exploiting the increased electrophilicity of the sugar's anomeric position, using thiourea as a nucleophile in an $\\mathrm{S_N2}$ substitution. The isothiouronium moiety was reduced to thiol 2, which was then subjected to alkaline deacetylation conditions to afford 3 as a potassium salt. Diazonium salts 4-6 were synthesized in aqueous conditions from $4 - n$ -hexylaniline (C6, mAzo 6), $4 - n$ octylaniline (C8, mAzo 8), or $4 - n$ -decyaniline (C10, mAzo 10), respectively. The final coupling step between 3 and diazonium salts 4-6 afforded amphiphiles 7 (mAzo 6), 8 (mAzo 8), and 9 (mAzo 10), respectively. At $4^{\\circ}\\mathrm{C},$ both mAzo 6 and mAzo 8 are soluble at or above $10\\%$ wt in nanopure water, whereas mAzo 10 is soluble at up to $2\\%$ wt. Successful synthesis was confirmed by NMR spectra of the individual mAzo compounds (Figures S1-S6). A family of surfactants was made using the same approach with a glucose head group; however, they suffered from poor water solubility $(< 0.5\\%)$ wt for all). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,790,481,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The solution stability of these new surfactants (7-9) was tested using UV absorbance for up to $24\\mathrm{h}$ . The mAzo surfactant solutions in water appear to be unstable when maintained at room temperature in the dark, as the UV-vis absorbance spectra show substantial degradation at $6\\mathrm{h}$ and almost complete degradation by $24\\mathrm{h}$ (Figure S7). The previously studied Azo surfactants were found to be stable in water at room temperature and higher.[13,23] When the mAzo surfactant solutions were stored at $4^{\\circ}\\mathrm{C}$ in the dark, minimal degradation was observed even after $24\\mathrm{h}$ . Due to the labile nature of this surfactant family, the proceeding characterization ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,418,915,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"experiments were carried out at colder temperatures (4-10 $^\\circ \\mathrm{C}$ ) instead of at room temperature. However, thermally labile molecules have been reported to be beneficial in drug delivery and in green chemistry, which both rely on biodegradability; thus, this property could be advantageous in select applications.[39] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,500,915,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The self-assembly of surfactants into structures like micelles or vesicles is a key property of these materials. Micelles are the simplest of amphiphile supramolecular assemblies, and their formation is driven by the hydrophobic effect.[40] We monitored changes in the surface tension as a function of the mAzo surfactant concentration as there is a linear dependency with respect to the logarithm of surfactant concentration until the critical micelle concentration (CMC) is reached, and little or no change is then observed (Figure 2a-c). By averaging three trials of such surface tension measurements (additional results shown in Figure S8), we determined the CMCs to be $(5.1 \\pm 0.5) \\times 10^{-6}$ , $(2.6 \\pm 0.1) \\times 10^{-5}$ , and $(2.5 \\pm 0.2) \\times 10^{-4} \\mathrm{~mol/L}$ for mAzo 10, mAzo 8, and mAzo 6, respectively. A decrease in CMC with the addition of two carbons on the tail follows the trend observed with the Azo surfactants.[26] For mAzo 10, a slight uncharacteristic decrease in surface tension was observed after the CMC was reached (Figure 2c), which could be caused by impurities (such as a small amount of thermally degraded surfactant, which will be discussed later). Because mAzo 10 has the lowest CMC, it is likely the most affected by any impurity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,776,915,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Next, we measured the micellar size and size distribution using dynamic light scattering (DLS). Because the measurement is made based on particle diffusion in a fluid, the micellar size measured is referred to as its hydrodynamic diameter.41 Intensity percentage as a function of the hydrodynamic micelle diameter distributions of mAzo 6 $(7\\pm 1\\mathrm{nm})$ ,mAzo $8(9\\pm 2$ nm), and mAzo $10(19\\pm 5\\mathrm{nm})$ can be seen as a set of three separate trials (Figure 2d-f). Typical hydrodynamic micelle diameters of surfactants are less than $50~\\mathrm{nm},$ and commonly used commercially available nonionic surfactants such as DDM, Triton X-100, and Tween 20 fall at the lower end of this range,43 as do the values obtained for the mAzo surfactants ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,46,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[436,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[484,952,512,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1468 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[723,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[200,73,392,181]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/1010/b510356a3ee402c57add1732fdfd0780f40a3efeb2c24b25abceb7b0bca94716.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[401,72,594,180]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0160/6dd090cfcc16b56fbe76a273853d5fe6b2b6096823729e65aa3cd12ca88bb399.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[604,72,797,180]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0389/ea4076fa0793d6e950965a6ed8d17a791a51b51be865ba89bf914e84fb9f550a.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[258,193,482,272]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0100/d60e46da543730a9909eb0e86e16bc12540ea6a5c15dc98292035bed2f438ce9.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[507,193,728,272]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. (a-c) UV-visible absorbance spectra for mAzo 6, mAzo 8, and mAzo 10 (0.014% wt, 4 °C) after 0, 30, 120, and 600 s of photoirradiation. (d, e) Photographs of the solutions of mAzo 6, mAzo 8, and mAzo 10 before and after photoirradiation. \"]","image_footnote":"[]","img_path":"images/0999/c8252c3791e49bdd27e53cfaf031f1f2e4df8d1f3af9022449fc682ff3701490.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[77,320,481,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Figure 2d-f). As the aliphatic chain length increases among the mAzo surfactants, the hydrodynamic diameter increases as expected. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,361,481,513]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Negative stain low-dose TEM imaging was used to further corroborate the size and distribution measurements obtained from DLS, as well as to reveal micellar morphology and other properties. In general, the mAzo surfactant family showed slightly elongated spherical micelle morphologies (Figure 2g-i) with increasing average sizes moving from mAzo 6 $(5.8 \\pm 0.5 \\mathrm{~nm})$ to mAzo 8 $(7.4 \\pm 0.7 \\mathrm{~nm})$ and to mAzo 10 $(9.0 \\pm 1.0 \\mathrm{~nm})$ . This increase in TEM average size as a function of increased aliphatic chain length for the mAzo surfactants agrees with the trend of increasing hydrodynamic diameter of mAzo 6 to mAzo 10 observed above in the DLS results. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,513,479,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We next used UV-visible spectroscopy to examine the photodegradation of the mAzo surfactants. For each variant, a $\\lambda_{\\mathrm{max - abs}}$ was observed at $322~\\mathrm{nm}$ (Figure 3a-c), and the largest contribution to this absorbance is from the azo chromophore, which also gives these surfactants their characteristic bright yellow hue. Specifically, the electronic transition that takes place to create this absorbance maximum is $\\pi_{\\mathrm{N = N}}\\rightarrow \\pi^{*}_{\\mathrm{N = N}}$ and the absence of this transition can be used to monitor the photodegradation process (Figure 3a-c). This photodegradation can also be visualized when the color changes from bright yellow before degradation (Figure 3d) to slightly darker after degradation (Figure 3e). When comparing across UV-visible absorbance spectra, the degradation time appears to be correlated with the aliphatic chain length. After $120~\\mathrm{s}$ , mAzo 6 is completely degraded, whereas mAzo 8 or mAzo 10 takes around $600~\\mathrm{s}$ for complete degradation. The second absorbance maximum, corresponding to the aromatic region of the surfactants, also disappears post-photodegradation and is replaced by a smaller band at $\\sim 255~\\mathrm{nm}$ , congruent with the changes in ring electronics post-degradation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,790,481,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To further characterize the photodegradation products of the surfactants, we took surface tension measurements of the whole surfactant solutions after photodegradation. A $0.1\\%$ solution of each surfactant was irradiated for $10\\mathrm{min}$ and diluted as previously described to perform the series of surface tension measurements. Surprisingly, surface tension still decreased linearly with increasing surfactant concentration (Figure 4), instead of remaining constant around the level of water, as would be expected with the complete destruction of the surfactant. This behavior was unexpected based on the anticipated degradation products (illustrated in Scheme 1) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[563,320,864,445]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0208/59db4e301e14e125886172c774ff86116d5a5690db073afb98e38eda69bf30f3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[563,462,864,601]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0035/2ca4fa083c9bcdd66c853da863ffbce55b7cca74b0b068758e692a6a1f020514.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[568,612,866,740]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Whole-solution surface tension measurements as a function of surfactant concentration before (black) and after (red) photoirradiation $(10\\\\mathrm{min})$ of $0.1\\\\%$ (a) mAzo 6, (b) mAzo 8, and (c) mAzo 10. \"]","image_footnote":"[]","img_path":"images/0528/4a046ad63332c4e5b3694ff224265eeab6d77fa23250e22d10596788a340a839.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[512,817,915,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"because they are not likely to alter surface tension to this extent.[26] Thus, we hypothesize that a new, surfactant-like species could form from the recombination of the hydrophilic and hydrophobic fragments after the photodegradation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,873,915,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To investigate the surfactant degradation mechanism, we performed liquid chromatography (LC)-MS analysis to identify the photodegradation products, which differ from the previously established photodegradation mechanism of azobenzene-containing surfactants.[26] Before photodegradation, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,46,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[434,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[864,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,952,512,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1469 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[250,73,479,175]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0937/4640d9ff38d55bb90b369d0be78779c0d94f31bb41ce6a39726124cbec1bce45.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[517,72,749,175]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/1003/0919442aa107c9b415502f226e472ab7029f89987a34e9798767b51c42a01836.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[250,195,510,255]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0610/6fae3c90d6693653f80cf2affa631432fa19a7ba6d532336176515d77c684c20.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[518,177,749,240]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0177/d284a1a8376002d17257f07073173321d5475eaff0a932c492912c5381f8a5e1.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[248,260,749,466]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. Representative extracted ion chromatograms and the corresponding mass peaks before (a, black) and after (b, red) photoirradiation for mAzo 6 obtained via LC-MS. ESI-MS for mAzo 6 $\\\\left(\\\\mathrm{C}_{24}\\\\mathrm{H}_{39}\\\\mathrm{N}_2\\\\mathrm{O}_{10}\\\\mathrm{S}\\\\right)$ , $[\\\\mathrm{M} + \\\\mathrm{H}]^{+}$ , calcd $m/z$ : 547.2325, exptl $m/z$ : 547.2300, error: $-4.6$ ppm. ESI-MS for maltose disulfide $\\\\left(\\\\mathrm{C}_{24}\\\\mathrm{H}_{43}\\\\mathrm{O}_{20}\\\\mathrm{S}_2\\\\right)$ , $[\\\\mathrm{M} + \\\\mathrm{H}]^{+}$ , calcd $m/z$ : 715.1789, exptl $m/z$ : 715.1751, error: $-5.3$ ppm. ESI-MS for the thioether degradation product $\\\\left(\\\\mathrm{C}_{48}\\\\mathrm{H}_{77}\\\\mathrm{O}_{20}\\\\mathrm{S}_2\\\\right)$ , $[2\\\\mathrm{M} + \\\\mathrm{H}]^{+}$ , calcd $m/z$ : 1037.4450, exptl $m/z$ : 1037.4399, error: $-4.9$ ppm. (c) Proposed surfactant degradation scheme based on LC-MS results. \"]","image_footnote":"[]","img_path":"images/0556/11e0fd9510e048b37cfc24547566d8e63f924006a143bd16207fe5abdfe39c5c.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[148,552,500,697]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0255/2a5a8758a6c32de9b091e59410fafcb4060648453351f8f14e193dc01de0a244.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,562,846,835]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0653/37029213062c5886695dfb03fb41747a271b5c4cf65026aa1422fd0120b269e2.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[148,686,492,847]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 6. Insoluble protein extraction performance of mAzo surfactants. (a) Tissue extraction workflow: (i) cell lysis and homogenization, (ii) centrifugation and removal of supernatant, (iii) extraction using a surfactant, (iv) sample analysis of soluble proteins via Bradford assay or SDS-PAGE. (b) Bradford assay results from triplicate insoluble protein extracts using either no surfactant (NS), DDM, mAzo 6, mAzo 8, mAzo 10, Azo 6, or Azo 8. (c) $12\\\\%$ SDS-PAGE of insoluble protein extracts using the same sets of surfactants. \"]","image_footnote":"[]","img_path":"images/0159/d9f2b804f6a46f3416b13e2f130c03eed00edc4963c1a3e8726b7189753d2e1d.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,46,154,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[436,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[864,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,951,512,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1470 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,71,479,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the chromatograms for each surfactant were dominated by one large peak that corresponds to a mixture of surfactant monomer, dimer, and trimer, which are typical association patterns in the gas phase for molecules containing a sugar motif. After photodegradation, two species prevailed in each chromatogram, one of which was consistent with a disulfide compound formed from the oxidation of two thiomaltose fragments (Y) and eluted earlier in the gradient relative to the intact surfactant (X; Figure 5a). The second compound, Z, eluted close to the original surfactant peak and had a mass that corresponds to a compound consisting of a maltose head group and an alkylbenzene tail that were linked through a thioether bond. This amphiphilic product is likely to alter surface tension, which explains the observed decrease in surface tension as a function of surfactant concentration even after irradiation (Figure 4a-c). These photodegradation products were consistent across mAzo surfactants with different surfactant chain lengths (Figures S9 and S10). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,321,479,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on these results, we propose that the surfactant degrades upon irradiation by two pathways as illustrated in Figure 5c. The first is the traditional (and original anticipated) pathway wherein the surfactant undergoes homolytic cleavage to form maltose (which in turn forms a disulfide bond with another free molecule of thiomaltose yielding Y), phenol, and alkylbenzene byproducts. We note that the phenolic and benzene-derived degradation products in pathway 1 were not observed likely because of the poor ionization efficiency of these species using electrospray ionization (ESI)-MS analysis. The amphiphilic product Z from pathway 2 forms because of the recombination of thiomaltose and alkylbenzyl radicals (Figure S11). Interestingly, when surfactant solutions were allowed to degrade under nonphotolytic conditions (i.e., allowed to remain in the dark in room temperature water), this amphiphilic product still formed as evidenced by LC-MS (Figure S12), albeit to a lesser extent. The formation of this new product under nonphotolytic conditions could proceed via an alternative mechanism (Figure S13). Overall, the formation of a new surfactant (Z) explains the continued decrease in surface tension observed in Figure 4 even after photodegradation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,625,479,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, we explored the use of the mAzo surfactants for protein extraction, as surfactants are widely used throughout biology to solubilize proteins from cells and tissues.[6,44,45] To examine this property of the mAzo surfactants, heart tissue was homogenized and washed in $\\mathrm{NH_4HCO_3}$ extraction and washing buffers to remove water-soluble proteins and obtain an insoluble tissue pellet (Figure 6a). Depleting the soluble species allows us to better evaluate the surfactants' ability to extract challenging, insoluble proteins such as membrane proteins. The pellet was then treated with the mAzo surfactants $(1\\% \\mathrm{w / v})$ , DDM $(1\\% \\mathrm{w / v})$ , no surfactant (NS), or the Azo surfactants $(1\\% \\mathrm{w / v}$ or $0.2\\% \\mathrm{w / v}$ , based on maximum solubility in water), which have been previously shown to facilitate protein extraction (Figure 6b,c).[13] The concentration of surfactants used is in great excess of their CMC to achieve high protein solubilization.[44,46] All steps were performed at $4^{\\circ}\\mathrm{C}$ to prevent surfactant degradation as well as to reduce proteolytic activity and preserve protein integrity. Thus, the mAzo surfactants can serve as a cleavable alternative to common biological surfactants when this functionality is desirable (e.g., detergent exchange).[17,47] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,913,479,942]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Overall, all extraction conditions using various surfactants, including the mAzo surfactants, show an improved protein ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,71,914,180]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"extraction efficacy relative to using no surfactant. The Bradford assay results in Figure 6b as well as the SDS-polyacrylamide gel electrophoresis (SDS-PAGE) gel in Figure 6c show that mAzo 8 provides the best protein solubility, while mAzo 6, mAzo 10, and DDM were slightly less effective. The results suggest a chain length of 8 provides the best hydrophilic-lipophilic balance to enable protein solubilization for the mAzo surfactants. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,182,914,430]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Not surprisingly, anionic surfactants like Azo 6 and Azo 8 appear to be more effective at solubilizing proteins compared to the nonionic surfactants,[6,13,35,45] even though they contain the same hydrophobic and photocleavable components as the mAzo surfactants. Ionic head groups destabilize lipid membranes and denature proteins by disturbing noncovalent interaction (e.g., hydrogen bonding), enabling more effective protein extraction and solubilization relative to surfactants with nonionic head groups.[48,49] Although the mAzos were less efficient than the anionic Azos at extracting membrane proteins in the current study, these surfactants presumably are superior to the original surfactants in stabilizing extracted membrane proteins.[6,8] Therefore, they could be amenable to techniques requiring nondenaturing conditions such as crystallography or native MS.[29,50,51] Moreover, cleavable surfactants are generally useful in proteomics for protein solubilization and then detergent removal before MS analysis[13,15,16,19,30-32,52,53] or in detergent exchange before biophysical characterization.[17,47] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,442,657,455]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CONCLUSIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,460,914,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We have successfully synthesized and characterized a new family of nonionic photocleavable surfactants (mAzo) derived from maltose, azo-sulfide benzenelinker, and a variable hydrophobic alkyl chain. Surface tension measurements, dynamic light scattering, and transmission electron microscopy show that these mAzo surfactants are able to form supramolecular assemblies. UV-visible spectroscopy shows the rapid photodegradation of the mAzo surfactants, and surface tension measurements of the whole post-degradation solutions suggest an unexpected degradation pathway. LC-MS studies of the photodegradation products reveal that the mAzo surfactants could undergo a recombination event after nitrogen expulsion to nonquantitatively form another photo-stable surfactant. Moreover, we have demonstrated that these surfactants are capable of solubilizing proteins in a comparable way to a commercially available nonionic surfactant analogue (DDM), which is widely used for protein purification and crystallography. Despite the complexity of their photodegradation processes, these new nonionic cleavable mAzo surfactants provide another set of tools for the applications of mild and switchable surfactants in chemical synthesis, green chemistry, drug delivery, characterization of insoluble biomolecules, and more. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,790,721,803]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ASSOCIATED CONTENT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[517,808,708,823]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supporting Information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,823,914,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.langmuir.2c02820. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[551,855,914,940]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"${}^{1}\\mathrm{H}$ NMR spectra of 1-isothiouronium- $\\beta$ -D-maltose heptaacetate fluoride; ${}^{1}\\mathrm{H}$ NMR spectra of 1-thio- $\\beta$ -D maltose heptaacetate; ${}^{1}\\mathrm{H}$ NMR spectra of 1-thio- $\\beta$ -D maltose potassium salt; ${}^{1}\\mathrm{H}$ NMR spectra of mAzo 6; ${}^{1}\\mathrm{H}$ NMR of mAzo 8; ${}^{1}\\mathrm{H}$ NMR spectra of mAzo 10; solution stability determination of mAzo 6, mAzo 8, and mAzo ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,47,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[436,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,952,512,961]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1471 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[118,73,482,225]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 at room temperature and $4^{\\circ}\\mathrm{C}$ ; surface tension measurements for replicate CMC trials for mAzo 6, mAzo 8, and mAzo 10; dynamic light scattering curves for mAzo 6, mAzo 8, and mAzo 10 after photodegradation; EICs of photodegradation products from mAzo 8 and mAzo 10; proposed photodegradation mechanism; EICs of thermal degradation products from mAzo 6, mAzo 8, and mAzo 10; proposed thermal degradation mechanism; and particle size, standard deviation, and PDI for triplicate DLS trials before photodegradation (PDF) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,240,293,255]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHOR INFORMATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,260,245,273]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Corresponding Authors ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[98,275,464,411]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Kyle A. Brown - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; orcid.org/0000-0003-1255-9146; Email: kbrown33@wisc.edu \",\"Song Jin - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; orcid.org/0000-0001-8693-7010; Email: jin@chem.wisc.edu \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,420,138,432]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Authors ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[98,435,482,695]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Morgan K. Gugger - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States \",\"David S. Roberts - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; orcid.org/0000-0002-0478-4987 \",\"David Moreno - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States \",\"Pil Seok Chae - Department of Bionano Engineering, Hanyang University, Ansan 15588, South Korea; orcid.org/0000-0003-1799-3304 \",\"Ying Ge - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; Department of Cell and Regenerative Biology and Human Proteomics Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States; $\\\\oplus$ orcid.org/0000-0001-5211-6812 \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,700,413,730]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Complete contact information is available at: https://pubs.acs.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,741,230,753]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author Contributions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,755,426,770]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{\\#}$ K.A.B. and M.K.G. contributed equally to this work. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,772,123,783]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Notes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,786,418,800]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare no competing financial interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,812,276,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,830,481,940]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This research was supported by National Institutes of Health (NIH) R01 GM117058 (to both S.J. and Y.G.). The authors acknowledge funding from the HL096971, HL109810, GM125085, and S10 OD018475 (to Y.G.). K.A.B. acknowledges the Vascular Surgery Research Training Program Grant T32 HL110853. D.S.R. acknowledges the support from the American Heart Association Predoctoral Fellowship Grant No. 832615/David S. Roberts/2021. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[517,71,640,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[515,91,915,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"(1) Chowdhury, S.; Shrivastava, S.; Kakati, A.; Sangwai, J. S. Comprehensive Review on the Role of Surfactants in the Chemical Enhanced Oil Recovery Process. Ind. Eng. Chem. Res. 2022, 61, 21-64. \",\"(2) De, S.; Malik, S.; Ghosh, A.; Saha, R.; Saha, B. A review on natural surfactants. RSC Adv. 2015, 5, 65757-65767. \",\"(3) Song, T.; Gao, F.; Guo, S.; Zhang, Y.; Li, S.; You, H.; Du, Y. A review of the role and mechanism of surfactants in the morphology control of metal nanoparticles. Nanoscale 2021, 13, 3895-3910. \",\"(4) Raffa, P.; Wever, D. A. Z.; Picchioni, F.; Broekhuis, A. A. Polymeric Surfactants: Synthesis, Properties, and Links to Applications. Chem. Rev. 2015, 115, 8504-8563. \",\"(5) Menger, F. M.; Mbadugha, B. N. A. Gemini Surfactants with a Disaccharide Spacer. J. Am. Chem. Soc. 2001, 123, 875-885. \",\"(6) Lee, H. J.; Lee, H. S.; Youn, T.; Byrne, B.; Chae, P. S. Impact of novel detergents on membrane protein studies. Chem 2022, 8, 980-1013. \",\"(7) Stetsenko, A.; Guskov, A. An Overview of the Top Ten Detergents Used for Membrane Protein Crystallization. Crystals 2017, 7, No. 197. \",\"(8) Rasmussen, S. G. F.; Devree, B. T.; Zou, Y.; Kruse, A. C.; Chung, K. Y.; Kobilka, T. S.; Thian, F. S.; Chae, P. S.; Pardon, E.; Calinski, D.; et al. Crystal structure of the $\\\\beta$ 2 adrenergic receptor-Gs protein complex. Nature 2011, 477, 549-557. \",\"(9) Alpes, H.; Apell, H. J.; Knoll, G.; Plattner, H.; Riek, R. Reconstitution of $\\\\mathrm{Na} + / \\\\mathrm{K} +$ ATPase into phosphatidylcholine vesicles by dialysis of nonionic alkyl maltoside detergents. Biochim. Biophys. Acta, Biomembr. 1988, 946, 379-388. \",\"(10) Wan, Y.; Shi, Y.; Zhao, D. Designed synthesis of mesoporous solids via nonionic-surfactant-templating approach. Chem. Commun. 2007, 897–926. \",\"(11) da Silva, M. A.; Dreiss, C. A. Unusual Surfactants. In Wormlike Micelles: Advances in Systems, Characterisation and Applications; The Royal Society of Chemistry, 2017; pp 63-102. \",\"(12) Hellberg, P.-E.; Bergstrom, K.; Holmberg, K. Cleavable surfactants. J. Surfactants Deterg. 2000, 3, 81-91. \",\"(13) Brown, K. A.; Chen, B.; Guardado-Alvarez, T. M.; Lin, Z.; Hwang, L.; Ayaz-Guner, S.; Jin, S.; Ge, Y. A photocleavable surfactant for top-down proteomics. Nat. Methods 2019, 16, 417-420. \",\"(14) Chang, Y.-H.; Gregorich, Z. R.; Chen, A. J.; Hwang, L.; Guner, H.; Yu, D.; Zhang, J.; Ge, Y. New Mass-Spectrometry-Compatible Degradable Surfactant for Tissue Proteomics. J. Proteome Res. 2015, 14, 1587-1599. \",\"(15) Saveliev, S. V.; Woodroofe, C. C.; Sabat, G.; Adams, C. M.; Klaubert, D.; Wood, K.; Urh, M. Mass Spectrometry Compatible Surfactant for Optimized In-Gel Protein Digestion. Anal. Chem. 2013, 85, 907-914. \",\"(16) Yu, Y. Q.; Gilar, M.; Lee, P. J.; Bouvier, E. S.; Gebler, J. C. Enzyme-friendly, mass spectrometry-compatible surfactant for insolu-. tion enzymatic digestion of proteins. Anal. Chem. 2003, 75, 6023-6028. \",\"(17) Liu, L.; Zhu, Z.; Zhou, F.; Xue, D.; Hu, T.; Luo, W.; Qiu, Y.; Wu, D.; Zhao, F.; Le, Z.; Tao, H. Catalytically Cleavable Detergent for Membrane Protein Studies. ACS Omega 2021, 6, 21087-21093. \",\"(18) Hwang, L.; Guardado-Alvarez, T. M.; Ayaz-Gunner, S.; Ge, Y.; Jin, S. A Family of Photolabile Nitroveratryl-Based Surfactants That Self-Assemble into Photodegradable Supramolecular Structures. Langmuir 2016, 32, 3963-3969. \",\"(19) Norris, J. L.; Hangauer, M. J.; Porter, N. A.; Caprioli, R. M. Nonacid cleavable detergents applied to MALDI mass spectrometry profiling of whole cells. J. Mass Spectrom. 2005, 40, 1319-1326. \",\"(20) Epstein, W. W.; Jones, D. S.; Bruenger, E.; Rilling, H. C. The synthesis of a photolabile detergent and its use in the isolation and characterization of protein. Anal. Biochem. 1982, 119, 304-312. \",\"(21) Nuyken, O.; Meindl, K.; Wokaun, A.; Mezger, T. Photolabile surfactants based on the diazosulphonate group 2. 4-(Acyloxy)-benzenediazosulphonates and 4-(acylamino)- \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,46,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[434,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,952,512,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1472 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[721,952,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,71,481,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"benzenediazosulphonates. J. Photochem. Photobiol., A 1995, 85, 291-298. \",\"(22) Jaeger, D. A.; Reddy, V. B.; Bohle, D. S. Cleavable double-chain surfactant Co(III) complexes. Tetrahedron Lett. 1999, 40, 649-652. \",\"(23) Dunkin, I. R.; Gittinger, A.; Sherrington, D. C.; Whittaker, P. Synthesis, characterization and applications of azo-containing photodestructible surfactants. J. Chem. Soc., Perkin Trans. 2 1996, 1837-1842. \",\"(24) Norris, J. L.; Porter, N. A.; Caprioli, R. M. Mass Spectrometry of Intracellular and Membrane Proteins Using Cleavable Detergents. Anal. Chem. 2003, 75, 6642-6647. \",\"(25) Kakiyama, T.; Usui, K.; Tomizaki, K.-y.; Mie, M.; Kobatake, E.; Mihara, H. A peptide release system using a photo-cleavable linker in a cell array format for cell-toxicity analysis. Polym. J. 2013, 45, 535-539. \",\"(26) Mezger, T.; Nuyken, O.; Meindl, K.; Wokaun, A. Light decomposable emulsifiers: application of alkyl-substituted aromatic azosulfonates in emulsion polymerization. Prog. Org. Coat. 1996, 29, 147-157. \",\"(27) Nuyken, O.; Voit, B. The photoactive diazosulfonate group and its role in polymer chemistry. Macromol. Chem. Phys. 1997, 198, 2337-2372. \",\"(28) Kim, M. S.; Diamond, S. L. Photocleavage of o-nitrobenzyl ether derivatives for rapid biomedical release applications. Bioorg. Med. Chem. Lett. 2006, 16, 4007-4010. \",\"(29) Urner, L. H.; Schulze, M.; Maier, Y. B.; Hoffmann, W.; Warnke, S.; Liko, I.; Folmert, K.; Manz, C.; Robinson, C. V.; Haag, R.; Pagel, K. A new azobenzene-based design strategy for detergents in membrane protein research. Chem. Sci. 2020, 11, 3538-3546. \",\"(30) Brown, K. A.; Tucholski, T.; Eken, C.; Knott, S.; Zhu, Y.; Jin, S.; Ge, Y. High-throughput Proteomics Enabled by a Photocleavable Surfactant. Angew. Chem., Int. Ed. 2020, 59, 8406-8410. \",\"(31) Knott, S. J.; Brown, K. A.; Josyer, H.; Carr, A.; Inman, D.; Jin, S.; Friedl, A.; Ponik, S. M.; Ge, Y. Photocleavable Surfactant-Enabled Extracellular Matrix Proteomics. Anal. Chem. 2020, 92, 15693–15698. \",\"(32) Buck, K. M.; Roberts, D. S.; Aballo, T. J.; Inman, D. R.; Jin, S.; Ponik, S.; Brown, K. A.; Ge, Y. One-Pot Exosome Proteomics Enabled by a Photocleavable Surfactant. Anal. Chem. 2022, 94, 7164-7168. \",\"(33) Aballo, T. J.; Roberts, D. S.; Melby, J. A.; Buck, K. M.; Brown, K. A.; Ge, Y. Ultrafast and Reproducible Proteomics from Small Amounts of Heart Tissue Enabled by Azo and timsTOF Pro. J. Proteome Res. 2021, 20, 4203-4211. \",\"(34) Brown, G. M.; Dubreuil, P.; Ichhaporia, F. M.; Desnoyers, J. E. Synthesis and properties of some $\\\\alpha$ -D-alkyl glucosides and mannosides: apparent molal volumes and solubilization of nitrobenzene in water at $25^{\\\\circ}\\\\mathrm{C}$ . Can. J. Chem. 1970, 48, 2525-2531. \",\"(35) Chae, P. S.; Rasmussen, S. G. F.; Rana, R. R.; Gotfried, K.; Chandra, R.; Goren, M. A.; Kruse, A. C.; Nurva, S.; Loland, C. J.; Pierre, Y.; et al. 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Micelle Formation and the Hydrophobic Effect. J. Phys. Chem. B 2004, 108, 6778-6781. \",\"(41) Shin, J. Y.; Abbott, N. L. Using Light to Control Dynamic Surface Tensions of Aqueous Solutions of Water Soluble Surfactants. Langmuir 1999, 15, 4404-4410. \"]","page_idx":"8","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[515,71,915,560]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"(42) Aguilar, Z. P. Types of Nanomaterials and Corresponding Methods of Synthesis. In Nanomaterials for Medical Applications; Aguilar, Z. P., Ed.; Elsevier, 2013; pp 33-82. \",\"(43) Kwan, T. O. C.; Reis, R.; Siligardi, G.; Hussain, R.; Cheruvara, H.; Moraes, I. Selection of Biophysical Methods for Characterisation of Membrane Proteins. Int. J. Mol. Sci. 2019, 20, No. 2605. \",\"(44) Hussain, H.; Du, Y.; Scull, N. J.; Mortensen, J. S.; Tarrasch, J.; Bae, H. E.; Loland, C. J.; Byrne, B.; Kobilka, B. K.; Chae, P. S. Accessible Mannitol-Based Amphiphiles (MNAs) for Membrane Protein Solubilisation and Stabilisation. Chem. - Eur. J. 2016, 22, 7068-7073. \",\"(45) Speers, A. E.; Wu, C. C. Proteomics of integral membrane proteins-theory and application. Chem. Rev. 2007, 107, 3687-3714. \",\"(46) Ohlendieck, K. Purification of Membrane Proteins. In Protein Purification Protocols; Cutler, P., Ed.; Humana Press, 2004; pp 301-308. \",\"(47) Xue, D.; Wang, J.; Song, X.; Wang, W.; Hu, T.; Ye, L.; Liu, Y.; Zhou, Q.; Zhou, F.; Jiang, Z.-X.; et al. A Chemical Strategy for Amphiphile Replacement in Membrane Protein Research. Langmuir 2019, 35, 4319-4327. \",\"(48) Rabilloud, T. Protein Solubility in Two-Dimensional Electrophoresis. In The Protein Protocols Handbook; Walker, J. M., Ed.; Humana Press, 2009; pp 73-84. \",\"(49) Seddon, A. M.; Curnow, P.; Booth, P. J. Membrane proteins, lipids and detergents: not just a soap opera. Biochim. Biophys. Acta, Biomembr. 2004, 1666, 105-117. \",\"(50) Keener, J. E.; Zhang, G.; Marty, M. T. Native Mass Spectrometry of Membrane Proteins. Anal. Chem. 2021, 93, 583-597. \",\"(51) Urner, L. H.; Liko, I.; Yen, H. Y.; Hoi, K. K.; Bolla, J. R.; Gault, J.; Almeida, F. G.; Schweder, M. P.; Shutin, D.; Ehrmann, S.; et al. Modular detergents tailor the purification and structural analysis of membrane proteins including G-protein coupled receptors. Nat. Commun. 2020, 11, No. 564. \",\"(52) Chen, E. I.; Cociorva, D.; Norris, J. L.; Yates, J. R. Optimization of Mass Spectrometry Compatible Surfactants for Shotgun Proteomics. J. Proteome Res. 2007, 6, 2529-2538. \",\"(53) Brown, K. A.; Gugger, M. K.; Yu, Z.; Moreno, D.; Jin, S.; Ge, Y. Nonionic, Cleavable Surfactant for Top-Down Proteomics. Anal. Chem. 2023, DOI: 10.1021/acs.analchem.2c03916. \"]","page_idx":"8","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,47,153,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[436,48,570,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pubs.acs.org/Langmuir ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[864,48,904,60]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[484,952,512,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1473 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[723,953,914,962]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1021/acs.langmuir.2c02820 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[780,962,914,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Langmuir 2023, 39, 1465-1473 ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[80,103,212,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[863,103,904,115]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,135,807,205]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Synthesis, Self-Assembly Properties, and Degradation Characterization of a Nonionic Photocleavable Azo-Sulfide Surfactant Family \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,208,883,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Kyle A. 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\"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article Recommendations \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[706,305,728,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0934/c697c7e697fec83d47cecba3b7bd15c1ff48d0150dc5204b6d3d83e76ad0d868.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[731,305,871,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supporting Information \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,335,680,515]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ABSTRACT: We report the synthesis and characterization of a new family of maltose-derived nonionic surfactants that contain a photocleavable azo-sulfide linker (mAzo). The self-assembly properties of these surfactants were investigated using surface tension measurements to determine the critical micelle concentration (CMC), dynamic light scattering (DLS) to reveal the hydrodynamic radius of their self-assemblies, and transmission electron microscopy (TEM) to elucidate the micelle morphology. Ultraviolet-visible (UV-visible) spectroscopy confirmed the rapid photodegradation of these surfactants, but surface tension measurements of the surfactant solutions before and after degradation showed unusual degradation products. The photodegradation process was further studied using online liquid chromatography coupled with mass spectrometry (LC-MS), which revealed that these surfactants can form another photo-stable surfactant post-degradation. Finally, traditionally challenging proteins from heart tissue were solubilized using the mAzo surfactants to demonstrate their potential in biological applications. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[691,333,914,406]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0527/c9f272da1e70c49e7cc9dac1919c19ea6ca5eb77bef2ac9c82b7129af6869239.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[690,410,914,505]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0348/c2320c06aa9666902b9ace7d195aa9725ff41a050432d1bace81aa501570bca2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,542,230,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,561,482,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Surfactants are molecules that contain both a hydrophobic and hydrophilic component. $^{1-3}$ They can alter the surface tension of the liquid in which they are present and have proven to be valuable across several industries and scientific fields ranging from vessels for chemical reactions to membrane mimics for the characterization of biomolecules. $^{1-6}$ Consequently, it is important to develop and characterize new surfactant compounds with specifically desired attributes. Surfactants have been traditionally categorized as ionic, zwitterionic, or nonionic, and these characteristics have important behavioral implications that make the surfactants suitable for different applications. For example, nonionic surfactants can preserve the native states and biological functions of proteins. $^{7-9}$ They can also act as effective templates to design and synthesize mesoporous solids, a process termed nonionic-surfactant-templating. $^{10}$ More recently, novel surfactants with unique properties, such as cleavable surfactants, multimeric surfactants (e.g., Gemini and trimeric), and surfactants with constituents of biological origin, have been of increasing interest. $^{11,12}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,825,481,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cleavable surfactants, wherein a weakened bond is engineered between the hydrophobic and hydrophilic portions of the molecule, can be especially useful when their surface tension-altering property is initially needed yet is a subsequent nuisance. Several cleavable motifs are labile under various external stimuli including light, acid, alkali, temperature, redox environment, and enzymatic conditions.[12-24] Light offers advantages over other stimuli, as it can be administered at a \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,542,915,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"specific time and location within a larger system, it is relatively inexpensive, and it is noninvasive.[25] Some of the most widely used photocleavable motifs include phenacyl, nitrobenzyl-based, azo-based, and benzyl-based.[18,26-29] For example, our lab recently demonstrated the use of an anionic azobenzene photocleavable surfactant (Azo) for protein extraction and subsequent proteomic analysis following rapid surfactant degradation.[13,30-33] However, the ionic nature of Azo surfactant prevents its biological applications where the proteins cannot be denatured. It is desirable to develop new classes of photocleavable surfactants with milder nonionic head and tail groups for a wide variety of biological applications. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,715,915,830]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Here, we have synthesized and characterized the molecular and supramolecular properties of a novel family of nonionic sugar-derived surfactants containing a photocleavable motif (Figure 1). This surfactant series, which we refer to as mAzo, consists of a hydrophilic head of maltose, $^{34,35}$ a photocleavable azo-sulfide linker, and a phenylalkyl hydrophobic tail with alkyl chains ranging between 6 and 10 carbons to explore how the relative hydrophobicity affects aspects of the compounds and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,847,693,860]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: October 14, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,861,703,873]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Revised: December 29, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,875,688,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published: January 13, 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[843,842,914,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0015/f90fd87c96fca9a90859b902f7335c6d09debc396e1272061b77407ac92b09f1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[14,293,31,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ished articles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[16,645,32,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"See https://pu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[80,37,352,72]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LANGMUIR \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,946,121,975]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[123,951,273,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACS Publications \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[304,950,462,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 American Chemical Society \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[484,957,512,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1465 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[721,948,914,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,960,914,966]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,70,915,201]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Design of a family of nonionic photocleavable surfactants (mAzo) consisting of a maltose head group, azobenzene linker, and tunable alkyl chain, and the hypothesized photodegradation pathway. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0894/e5a463aa4551072b176b7d02322caedce3afd8a93bcbc1b697ffe7675b4d8b98.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[133,266,861,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Scheme 1. Synthetic Scheme for the mAzo Surfactant Family \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0538/cd2a7746f6462dead222cc4386f28bd85e0156bb56bad06953ec06e60f162331.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[133,358,828,540]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0414/8f5193d493768871690f315dbddb1ca0ce111bd5f6fb1ddb70a43ce19afd3800.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[77,556,481,695]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"their assemblies. It is expected that, upon ultraviolet (UV) irradiation, the azo-sulfide would homolytically cleave to expel nitrogen gas, leaving behind alkylbenzene and phenolic-derived products as well as thiomaltose based on a previous work on the Azo surfactants (that contain a sulfate head group).[23,26,36] However, detailed characterization of the properties of the surfactant uncovered a secondary degradation pathway leading to the formation of a new surfactant that alters surface tension. These results provide insights into the continued development and application of photocleavable surfactants. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,710,299,725]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"EXPERIMENTAL SECTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,730,482,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reagents and Materials. All chemicals and reagents were obtained commercially and used without further purification. The $\\\\beta$ -D-maltose octaacetate, ammonium acetate $(\\\\mathrm{NH}_4\\\\mathrm{OAc})$ , thiourea, and high-performance liquid chromatography (HPLC)-grade water $(\\\\mathrm{H}_2\\\\mathrm{O})$ were purchased from Fischer Scientific. Boron trifluoride diethyl etherate $(\\\\mathrm{BF}_3\\\\cdot \\\\mathrm{Et}_2\\\\mathrm{O})$ , sodium metabisulfite $(\\\\mathrm{Na}_2\\\\mathrm{S}_2\\\\mathrm{O}_5)$ , magnesium sulfate $(\\\\mathrm{MgSO}_4)$ , sodium nitrite $(\\\\mathrm{NaNO}_2)$ , hydrochloric acid (HCl), potassium hydroxide (KOH), dichloromethane (DCM), acetonitrile (MeCN), ethyl acetate (EtOAc), anhydrous methanol (MeOH), anhydrous chloroform $(\\\\mathrm{CHCl}_3)$ , and silica were all purchased from Sigma-Aldrich. 4-n-Hexylaniline, 4-n-octylaniline, and 4-n-decylaniline were all obtained from TCI America. Protein extraction solutions were made in nanopure water, ammonium bicarbonate $(\\\\mathrm{NH}_4\\\\mathrm{HCO}_3)$ , potassium chloride (KCl), sucrose, sodium fluoride (NaF), phenylmethanesulfonyl fluoride (PMSF), L-methionine, ethylenediaminetetraacetic acid (EDTA), and $n$ -dodecyl- $\\\\beta$ -D-maltoside (DDM) were all purchased from Sigma-Aldrich. Swine \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,556,915,605]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"heart tissue was obtained from healthy Yorkshire domestic pigs and had been flash-frozen in liquid $\\\\mathbf{N}_2$ and stored at $-80^{\\\\circ}\\\\mathrm{C}$ prior to use. The Protein Assay Dye Reagent Concentrate was obtained from BioRad. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,605,914,631]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Surfactant Synthesis. The synthesis of the family of mAzo surfactants followed the multistep process outlined in Scheme 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,630,915,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1-Isothiouronium- $\\\\beta$ -D-maltose Heptaacetate Fluoride (1). Thiourea $(0.418\\\\mathrm{g},5.50\\\\mathrm{mmol},1.10\\\\mathrm{equiv})$ was added to a stirring solution of $\\\\beta$ -D-maltose octaacetate $(3.39~\\\\mathrm{g},5\\\\mathrm{mmol},1$ equiv) in dry acetonitrile $(10.0~\\\\mathrm{mL})$ . Then, $\\\\mathrm{BF}_3\\\\bullet \\\\mathrm{Et}_2\\\\mathrm{O}$ $(1.85~\\\\mathrm{mL},15.0~\\\\mathrm{mmol},3$ equiv) was added and the reaction was allowed to proceed under reflux for $20\\\\mathrm{min}$ All starting material should disappear at this time. The reaction mixture was cooled to room temperature before adding pyridine $(15.0\\\\mathrm{mmol},1.19\\\\mathrm{g},1.21\\\\mathrm{mL},3$ equiv) and concentrating in vacuo to a syrup. The syrup was dissolved in $40~\\\\mathrm{mL}$ of EtOAc and washed with HPLC-grade water $(3\\\\times 20~\\\\mathrm{mL})$ . The organic layer was then dried with anhydrous $\\\\mathrm{MgSO_4}$ and concentrated in vacuo.37 The isothiouronium salt 1 was obtained as a white amorphous solid and used without further purification. Crude yield, $98\\\\%$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,791,915,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1-Thio- $\\\\beta$ -D-maltose Heptaacetate (2). Sodium metabisulfite (7.50 mmol, $1.43\\\\mathrm{g},$ 1.50 equiv), DCM $(23~\\\\mathrm{mL})$ , and HPLC-grade water $(13~\\\\mathrm{mL})$ were added to the isothiouronium intermediate 1 $(3.51\\\\mathrm{g},$ $5.00\\\\mathrm{mmol}$ 1.00 equiv), and the reaction mixture was refluxed at $\\\\sim 60$ $^\\\\circ C$ for $3.5\\\\mathrm{h}$ . After the mixture was cooled to room temperature, the aqueous layer was decanted and extracted with DCM $(2\\\\times 20~\\\\mathrm{mL})$ The organic layers were then recombined and washed with brine $(1\\\\times$ $10~\\\\mathrm{mL})$ , dried over anhydrous $\\\\mathrm{MgSO_4}$ , and concentrated in vacuo to afford 2 as an amorphous white solid, which was used in the following steps without further purification. Yield, $84\\\\%$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,915,915,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1-Thio- $\\\\beta$ -D-maltose Potassium Salt (3). Peracetylated 1-thio- $\\\\beta$ -DMaltose 2 (1.00 g, 1.53 mmol, 1.00 equiv) was suspended in a \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,46,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[434,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[864,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,952,512,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1466 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[721,952,914,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,962,914,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[79,70,481,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"solution of anhydrous MeOH (5 mL) containing KOH (100 mg, 1.78 mmol, 1.18 equiv). The deacetylation was allowed to proceed for 30 min to afford a white precipitate before adding EtOAc (5 mL). The reaction mixture was then centrifuged, and the supernatant was discarded. The solid was washed once more with EtOAc (5 mL), isolated via centrifugation, and dried overnight in a desiccator to afford 3 as a white solid in quantitative yield. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,158,481,307]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4-n-Alkyl Diazonium Chloride Salts (4, 5, 6). 4-n-Hexylaniline (C6) (115 mg, 0.649 mmol, 1.0 equiv) was added to a solution of 11 M HCl (215 μL) and HPLC-grade water (630 μL), and the mixture was stirred at $0^{\\\\circ}\\\\mathrm{C}$ in an ice bath for 5 min before a cooled solution of $\\\\mathrm{NaNO}_2$ (63 mg, 0.914 mmol, 1.4 equiv) in HPLC-grade water (630 μL) was added dropwise over 5 min. The same procedure was scaled and repeated for 4-n-octylaniline (C8) (116 mg, 0.568 mmol, 1.0 equiv) and 4-n-decylaniline (C10) (35.2 mg, 0.151 mmol, 1.0 equiv). The reaction mixtures were stirred for 20 min at $0^{\\\\circ}\\\\mathrm{C}$ to afford clear, colorless to slightly yellow solutions of diazonium chloride salts 4-6 in assumed quantitative yields, which were used in situ in the following steps.[23] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,307,481,530]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Maltose Azo-Sulfide Surfactants [7 (mAzo 6), 8 (mAzo 8), 9 (mAzo 10)]. To the stirred solution of diazonium salt 4, ice-cold $\\\\mathrm{NH_4OAc}$ (6 M) was added dropwise until a pH of 6 was attained. This buffered solution was then added dropwise to a stirred, cooled solution of 3 (410 mg, 0.965 mmol, 1.7 equiv) in HPLC-grade water (2.0 mL), and a bright yellow product was immediately observed. The same procedure was scaled and repeated for the solutions of 5 and 6, and supplemental water was added in $200\\\\mu \\\\mathrm{L}$ aliquots for ease of stirring. After allowing the reaction to stir for a further $30\\\\mathrm{min}$ at $0^{\\\\circ}\\\\mathrm{C}$ , a volume of chloroform equivalent to the aqueous reaction mixture was added. Methanol was then added in $100\\\\mu \\\\mathrm{L}$ aliquots, and the mixture was shaken vigorously until the yellow product was observed to migrate into the organic layer. The organic layer was then removed, dried with anhydrous $\\\\mathrm{MgSO_4}$ , and the solvent was removed in vacuo without applying heat. The crude solids of 7-9 were purified by silica flash chromatography using ice-cold solvent (DCM:MeOH 80:20; $R_{\\\\mathrm{f}} = 0.3$ (C6), $R_{\\\\mathrm{f}} = 0.4$ (C8), $R_{\\\\mathrm{f}} = 0.45$ (C10)) to afford 7-9 as a bright yellow solid. Yield, 39% (C6), 40% (C8), 34% (C10). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,530,481,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Surfactant Characterization. The mAzo surfactants and the resulting degradation products were characterized using the following methods: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,567,481,630]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"${}^{1}\\\\mathsf{H}$ NMR. Spectra were recorded on a Bruker Avance-400 MHz spectrometer at room temperature and referenced using residual undetuerated solvent peaks $\\\\mathrm{(DMSO - d_6}$ $\\\\delta_{\\\\mathrm{H}} = 2.50$ ppm; $\\\\mathrm{D}_2\\\\mathrm{O}$ $\\\\delta_{\\\\mathrm{H}} = 4.79$ ppm). The ${}^{1}\\\\mathrm{H}$ NMR spectra and associated peak shifts for compounds 1-9 are displayed in Figures S1-S6. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,630,481,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Surface Tension Measurements. Critical micelle concentration (CMC) values were obtained using a Tensimeter Kruss K10T equipped with a Wilhelmy plate. A $1\\\\%$ wt solution of 7 (mAzo 6) and 8 (mAzo 8) as well as a $0.1\\\\%$ wt solution of 9 (mAzo 10) was prepared in nanopure water and kept in an ice bath. Small aliquots of each surfactant were added to $10~\\\\mathrm{mL}$ of ice-cold nanopure water under continuous stirring, and surface tension measurements were taken and plotted as a function of the logarithm of their corresponding concentration. The measurements were repeated three times for each surfactant. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,755,481,853]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dynamic Light Scattering. Dynamic light scattering (DLS) measurements were carried out using a Malvern Zetasizer Nano ZSP. Solutions were prepared for each surfactant at $30\\\\times$ their measured CMCs in degassed nanopure water. The surfactant solutions were then passed through a $0.2\\\\mu \\\\mathrm{m}$ filter and centrifuged at $21,100\\\\mathrm{g}$ for $10\\\\mathrm{min}$ at $4^{\\\\circ}\\\\mathrm{C}$ . Samples were allowed to equilibrate in the zetasizer for $120\\\\mathrm{s}$ before DLS measurements were taken. DLS experiments were repeated three times on each sample. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,853,481,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TEM Imaging. The surfactants were suspended in nanopure deionized water from Milli-Q water (MilliporeSigma) at $30\\\\times$ their measured CMCs, sonicated for 2 min, and allowed to equilibrate in the dark for 10 min. Transmission electron microscopy (TEM) samples were prepared by mixing surfactant solutions with a $4\\\\%$ wt aqueous phosphotungstic acid solution $(\\\\mathrm{pH}7.4)$ (MilliporeSigma) in a 1:1 ratio by volume, and then one drop of the surfactant solution \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,71,915,146]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"was pipetted onto a formvar-coated copper TEM grid with carbon film for negative staining. TEM imaging was conducted on an FEI Tecnai TF 30 TEM instrument operated at $300\\\\mathrm{kV}$ and equipped with a Gatan K2 direct electron detector for low-dose TEM. Images were collected with a total electron dose of $10\\\\mathrm{e} / \\\\mathring{\\\\mathrm{A}}^2$ , and all images were processed with digital micrograph software program. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,146,915,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Photodegradation Analysis by UV-Vis. All UV-visible (UV-vis) absorbance measurements were performed on a PerkinElmer Lambda 10 spectrophotometer. A $0.014\\\\%$ wt solution of each surfactant was prepared and aliquoted into $1.5~\\\\mathrm{mL}$ Lo-Bind Eppendorf centrifuge tubes. Samples were then irradiated using a $100\\\\mathrm{W}$ high-pressure mercury lamp for 0, 30, 120, or $600\\\\mathrm{s}$ . Samples were then immediately flash-frozen at $-80^{\\\\circ}\\\\mathrm{C}$ and thawed at $4^{\\\\circ}\\\\mathrm{C}$ before taking absorbance spectra. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,245,915,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LC-MS of the Degradation Products of Surfactants. Liquid chromatography-mass spectrometry (LC-MS) was performed on a Waters nanoACQUITY HPLC coupled to a maXis II ETD Q-TOF (Bruker Daltonics). Surfactant or degraded product $(2\\\\mu \\\\mathrm{g})$ was loaded onto a home-packed C2 column $(500~\\\\mu \\\\mathrm{M})$ and separated at room temperature with a flow rate of $12~\\\\mu \\\\mathrm{L / min}$ using a $35\\\\mathrm{min}$ gradient from 40 to $95\\\\%$ B with mobile phases of $0.2\\\\%$ formic acid in water (A) and $0.2\\\\%$ formic acid in ACN:IPA (1:1) (B). Compounds eluted from the column were infused and ionized using a capillary voltage of $4500\\\\mathrm{V}$ and transmitted with an endplate voltage of $500\\\\mathrm{V}$ . MS scans were collected at $1\\\\mathrm{Hz}$ from 500 to $2000m / z$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,382,915,670]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Insoluble Protein Extraction and Bradford Assay. The following protein extraction was carried out at $4^{\\\\circ}\\\\mathrm{C}$ . Swine heart tissue (230 mg) was cut into small pieces and homogenized for 1 min in 1 mL of a lysis buffer containing 1 mM EDTA, 25 mM $\\\\mathrm{NH_4HCO_3}$ , 250 mM sucrose, 500 mM KCl, 500 mM NaF, 2 mM L-methionine, and 1 mM PMSF. The homogenate was then centrifuged at 21,100 g for 10 min, and the supernatant was removed and discarded. The tissue pellet was then rehomogenized for 1 min in 1 mL of a washing buffer containing 25 mM $\\\\mathrm{NH_4HCO_3}$ , 2 mM L-methionine, and 1 mM PMSF, centrifuged for 10 min at 21,100 g, and the supernatant was removed. This washing process was repeated twice more, wherein the homogenate from the final wash was first partitioned into 21 separate 1.5 mL Eppendorf centrifuge tubes. To each tissue pellet was then added 100 μL of 25 mM $\\\\mathrm{NH_4HCO_3}$ containing no surfactant (NS, control), 1.0% wt mAzo 6, 1.0% wt mAzo 8, 1.0% wt mAzo 10, 1.0% wt DDM, 1.0% wt Azo 6, or a maximally concentrated solution of Azo 8. Each of these seven conditions was tested three times. The insoluble pellets were then resuspended, and the extraction was allowed to proceed for 1 h before centrifuging at 21,100g and collecting the supernatant. The concentration of the protein in the supernatants was determined using a Bradford Assay on a small, diluted sample aliquot and measuring the absorbance at 595 nm after a 5 min incubation period. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,670,915,792]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SDS-PAGE of Extracted Proteins. To $40~\\\\mu \\\\mathrm{L}$ of each supernatant, $160~\\\\mu \\\\mathrm{L}$ of ice-cold acetone was added, and the samples were allowed to sit overnight at $-20^{\\\\circ}C.$ After the samples were centrifuged for 10 min at $21,100g$ and the supernatant was removed, the precipitated proteins from each sample were reconstituted in $40~\\\\mu \\\\mathrm{L}$ of $1\\\\times$ Laemmli buffer, of which $5\\\\mu \\\\mathrm{L}$ was loaded into a $1\\\\mathrm{mm}$ 10 well $12.5\\\\%$ sodium dodecyl sulfate (SDS) polyacrylamide gel made in-house. Proteins were resolved by applying $70\\\\mathrm{V}$ for $20\\\\mathrm{min}$ and subsequently $120\\\\mathrm{V}$ for approximately $80\\\\mathrm{min}$ and the bands were visualized using Coomassie Brilliant Blue. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,810,752,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS AND DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,830,915,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We report the successful synthesis of a new class of photocleavable, nonionic surfactants (mAzo) derived from the maltose hydrophilic head group, azo-sulfide linker, and hydrophobic 4-n-alkyl anilines. These mAzo compounds represent novel analogues of the previously characterized alkylbenzene azosulfonates[23,26] but have a highly water-soluble maltose head group. This was chosen to mimic the properties of the commercially available nonionic surfactant DDM, which \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,47,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[436,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,952,512,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1467 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[721,952,914,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,962,914,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[205,83,413,163]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"a \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": 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\"images/0318/f724c4ebaca21766798ce2df4d7c57e05f3da32caa16b9f7d2906b4a4b5e878d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[205,170,416,251]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"b \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0946/344d30aa5dae396058b380f4363174d2f787b9a6daa194c3b6f5d971133fcd3e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[436,165,644,251]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"e \\\",\\\"h \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0507/101b0ba657a668904fee3ec61a6ac41e37387497ac730fb87bd1a69c1a070199.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[678,165,795,253]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0758/8b495d8ad4cf08a5e22f9160c3a1a25492e3151fb76dea5268e1ef529f677908.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[202,260,413,342]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"C \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0688/b838654c2720c2fadf85d6440d627264683ffd15a16461a28f7cdaa82ab8e2a3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[436,258,644,345]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"f \\\",\\\"i \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0227/e11f69b609b4743276524f13856bdcc8b0e6dfce105949a26e55e2125c8452c5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[678,258,795,345]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. Characterization of the supramolecular assemblies formed by the mAzo surfactants. (a-c) Surface tension measurements at different surfactant concentrations with linear regression fits to decline and plateau regions for mAzo 6, mAzo 8, and mAzo 10. (d-f) Triplicate trial overlay of hydrodynamic micelle diameters for mAzo 6, mAzo 8, and mAzo 10 as measured by DLS. (g-h) Representative low-dose TEM images of mAzo 6, mAzo 8, and mAzo 10 obtained by negative stain contrast showing micellar structures. The insets show the micelle size distribution histograms. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0043/8974bedb5d057d51d579bfacc7507e0acf0fe99e5babf125fba578f98f670611.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[79,418,479,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"has been widely used in biology for protein purification and crystallography. $^{7}$ We envision that additional photodegradable surfactants featuring a variety of head groups (e.g., different sugar moieties, oligoglycerols, etc.) could be developed using a similar process described here, which would have unique properties. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,500,479,788]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The surfactants were synthesized in four total steps (Scheme 1), the first three of which were used to form 1-thio- $\\\\beta$ -D-maltose (3). Commercially available peracetylated maltose was first taken to its 1-isothiouronium derivative 1 by exploiting the increased electrophilicity of the sugar's anomeric position, using thiourea as a nucleophile in an $\\\\mathrm{S_N2}$ substitution. The isothiouronium moiety was reduced to thiol 2, which was then subjected to alkaline deacetylation conditions to afford 3 as a potassium salt. Diazonium salts 4-6 were synthesized in aqueous conditions from $4 - n$ -hexylaniline (C6, mAzo 6), $4 - n$ octylaniline (C8, mAzo 8), or $4 - n$ -decyaniline (C10, mAzo 10), respectively. The final coupling step between 3 and diazonium salts 4-6 afforded amphiphiles 7 (mAzo 6), 8 (mAzo 8), and 9 (mAzo 10), respectively. At $4^{\\\\circ}\\\\mathrm{C},$ both mAzo 6 and mAzo 8 are soluble at or above $10\\\\%$ wt in nanopure water, whereas mAzo 10 is soluble at up to $2\\\\%$ wt. Successful synthesis was confirmed by NMR spectra of the individual mAzo compounds (Figures S1-S6). A family of surfactants was made using the same approach with a glucose head group; however, they suffered from poor water solubility $(< 0.5\\\\%)$ wt for all). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,790,481,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The solution stability of these new surfactants (7-9) was tested using UV absorbance for up to $24\\\\mathrm{h}$ . The mAzo surfactant solutions in water appear to be unstable when maintained at room temperature in the dark, as the UV-vis absorbance spectra show substantial degradation at $6\\\\mathrm{h}$ and almost complete degradation by $24\\\\mathrm{h}$ (Figure S7). The previously studied Azo surfactants were found to be stable in water at room temperature and higher.[13,23] When the mAzo surfactant solutions were stored at $4^{\\\\circ}\\\\mathrm{C}$ in the dark, minimal degradation was observed even after $24\\\\mathrm{h}$ . Due to the labile nature of this surfactant family, the proceeding characterization \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,418,915,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"experiments were carried out at colder temperatures (4-10 $^\\\\circ \\\\mathrm{C}$ ) instead of at room temperature. However, thermally labile molecules have been reported to be beneficial in drug delivery and in green chemistry, which both rely on biodegradability; thus, this property could be advantageous in select applications.[39] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,500,915,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The self-assembly of surfactants into structures like micelles or vesicles is a key property of these materials. Micelles are the simplest of amphiphile supramolecular assemblies, and their formation is driven by the hydrophobic effect.[40] We monitored changes in the surface tension as a function of the mAzo surfactant concentration as there is a linear dependency with respect to the logarithm of surfactant concentration until the critical micelle concentration (CMC) is reached, and little or no change is then observed (Figure 2a-c). By averaging three trials of such surface tension measurements (additional results shown in Figure S8), we determined the CMCs to be $(5.1 \\\\pm 0.5) \\\\times 10^{-6}$ , $(2.6 \\\\pm 0.1) \\\\times 10^{-5}$ , and $(2.5 \\\\pm 0.2) \\\\times 10^{-4} \\\\mathrm{~mol/L}$ for mAzo 10, mAzo 8, and mAzo 6, respectively. A decrease in CMC with the addition of two carbons on the tail follows the trend observed with the Azo surfactants.[26] For mAzo 10, a slight uncharacteristic decrease in surface tension was observed after the CMC was reached (Figure 2c), which could be caused by impurities (such as a small amount of thermally degraded surfactant, which will be discussed later). Because mAzo 10 has the lowest CMC, it is likely the most affected by any impurity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,776,915,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Next, we measured the micellar size and size distribution using dynamic light scattering (DLS). Because the measurement is made based on particle diffusion in a fluid, the micellar size measured is referred to as its hydrodynamic diameter.41 Intensity percentage as a function of the hydrodynamic micelle diameter distributions of mAzo 6 $(7\\\\pm 1\\\\mathrm{nm})$ ,mAzo $8(9\\\\pm 2$ nm), and mAzo $10(19\\\\pm 5\\\\mathrm{nm})$ can be seen as a set of three separate trials (Figure 2d-f). Typical hydrodynamic micelle diameters of surfactants are less than $50~\\\\mathrm{nm},$ and commonly used commercially available nonionic surfactants such as DDM, Triton X-100, and Tween 20 fall at the lower end of this range,43 as do the values obtained for the mAzo surfactants \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,46,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[436,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[484,952,512,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1468 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[723,952,914,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,962,914,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[200,73,392,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1010/b510356a3ee402c57add1732fdfd0780f40a3efeb2c24b25abceb7b0bca94716.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[401,72,594,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0160/6dd090cfcc16b56fbe76a273853d5fe6b2b6096823729e65aa3cd12ca88bb399.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[604,72,797,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0389/ea4076fa0793d6e950965a6ed8d17a791a51b51be865ba89bf914e84fb9f550a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[258,193,482,272]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0100/d60e46da543730a9909eb0e86e16bc12540ea6a5c15dc98292035bed2f438ce9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[507,193,728,272]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. (a-c) UV-visible absorbance spectra for mAzo 6, mAzo 8, and mAzo 10 (0.014% wt, 4 °C) after 0, 30, 120, and 600 s of photoirradiation. (d, e) Photographs of the solutions of mAzo 6, mAzo 8, and mAzo 10 before and after photoirradiation. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0999/c8252c3791e49bdd27e53cfaf031f1f2e4df8d1f3af9022449fc682ff3701490.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[77,320,481,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Figure 2d-f). As the aliphatic chain length increases among the mAzo surfactants, the hydrodynamic diameter increases as expected. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,361,481,513]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Negative stain low-dose TEM imaging was used to further corroborate the size and distribution measurements obtained from DLS, as well as to reveal micellar morphology and other properties. In general, the mAzo surfactant family showed slightly elongated spherical micelle morphologies (Figure 2g-i) with increasing average sizes moving from mAzo 6 $(5.8 \\\\pm 0.5 \\\\mathrm{~nm})$ to mAzo 8 $(7.4 \\\\pm 0.7 \\\\mathrm{~nm})$ and to mAzo 10 $(9.0 \\\\pm 1.0 \\\\mathrm{~nm})$ . This increase in TEM average size as a function of increased aliphatic chain length for the mAzo surfactants agrees with the trend of increasing hydrodynamic diameter of mAzo 6 to mAzo 10 observed above in the DLS results. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,513,479,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We next used UV-visible spectroscopy to examine the photodegradation of the mAzo surfactants. For each variant, a $\\\\lambda_{\\\\mathrm{max - abs}}$ was observed at $322~\\\\mathrm{nm}$ (Figure 3a-c), and the largest contribution to this absorbance is from the azo chromophore, which also gives these surfactants their characteristic bright yellow hue. Specifically, the electronic transition that takes place to create this absorbance maximum is $\\\\pi_{\\\\mathrm{N = N}}\\\\rightarrow \\\\pi^{*}_{\\\\mathrm{N = N}}$ and the absence of this transition can be used to monitor the photodegradation process (Figure 3a-c). This photodegradation can also be visualized when the color changes from bright yellow before degradation (Figure 3d) to slightly darker after degradation (Figure 3e). When comparing across UV-visible absorbance spectra, the degradation time appears to be correlated with the aliphatic chain length. After $120~\\\\mathrm{s}$ , mAzo 6 is completely degraded, whereas mAzo 8 or mAzo 10 takes around $600~\\\\mathrm{s}$ for complete degradation. The second absorbance maximum, corresponding to the aromatic region of the surfactants, also disappears post-photodegradation and is replaced by a smaller band at $\\\\sim 255~\\\\mathrm{nm}$ , congruent with the changes in ring electronics post-degradation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,790,481,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To further characterize the photodegradation products of the surfactants, we took surface tension measurements of the whole surfactant solutions after photodegradation. A $0.1\\\\%$ solution of each surfactant was irradiated for $10\\\\mathrm{min}$ and diluted as previously described to perform the series of surface tension measurements. Surprisingly, surface tension still decreased linearly with increasing surfactant concentration (Figure 4), instead of remaining constant around the level of water, as would be expected with the complete destruction of the surfactant. This behavior was unexpected based on the anticipated degradation products (illustrated in Scheme 1) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[563,320,864,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0208/59db4e301e14e125886172c774ff86116d5a5690db073afb98e38eda69bf30f3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[563,462,864,601]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0035/2ca4fa083c9bcdd66c853da863ffbce55b7cca74b0b068758e692a6a1f020514.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[568,612,866,740]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Whole-solution surface tension measurements as a function of surfactant concentration before (black) and after (red) photoirradiation $(10\\\\\\\\mathrm{min})$ of $0.1\\\\\\\\%$ (a) mAzo 6, (b) mAzo 8, and (c) mAzo 10. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0528/4a046ad63332c4e5b3694ff224265eeab6d77fa23250e22d10596788a340a839.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[512,817,915,873]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"because they are not likely to alter surface tension to this extent.[26] Thus, we hypothesize that a new, surfactant-like species could form from the recombination of the hydrophilic and hydrophobic fragments after the photodegradation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,873,915,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To investigate the surfactant degradation mechanism, we performed liquid chromatography (LC)-MS analysis to identify the photodegradation products, which differ from the previously established photodegradation mechanism of azobenzene-containing surfactants.[26] Before photodegradation, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,46,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[434,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[864,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n 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},\n {\n \"bbox\": \"[517,72,749,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1003/0919442aa107c9b415502f226e472ab7029f89987a34e9798767b51c42a01836.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[250,195,510,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0610/6fae3c90d6693653f80cf2affa631432fa19a7ba6d532336176515d77c684c20.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[518,177,749,240]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0177/d284a1a8376002d17257f07073173321d5475eaff0a932c492912c5381f8a5e1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[248,260,749,466]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. Representative extracted ion chromatograms and the corresponding mass peaks before (a, black) and after (b, red) photoirradiation for mAzo 6 obtained via LC-MS. ESI-MS for mAzo 6 $\\\\\\\\left(\\\\\\\\mathrm{C}_{24}\\\\\\\\mathrm{H}_{39}\\\\\\\\mathrm{N}_2\\\\\\\\mathrm{O}_{10}\\\\\\\\mathrm{S}\\\\\\\\right)$ , $[\\\\\\\\mathrm{M} + \\\\\\\\mathrm{H}]^{+}$ , calcd $m/z$ : 547.2325, exptl $m/z$ : 547.2300, error: $-4.6$ ppm. ESI-MS for maltose disulfide $\\\\\\\\left(\\\\\\\\mathrm{C}_{24}\\\\\\\\mathrm{H}_{43}\\\\\\\\mathrm{O}_{20}\\\\\\\\mathrm{S}_2\\\\\\\\right)$ , $[\\\\\\\\mathrm{M} + \\\\\\\\mathrm{H}]^{+}$ , calcd $m/z$ : 715.1789, exptl $m/z$ : 715.1751, error: $-5.3$ ppm. ESI-MS for the thioether degradation product $\\\\\\\\left(\\\\\\\\mathrm{C}_{48}\\\\\\\\mathrm{H}_{77}\\\\\\\\mathrm{O}_{20}\\\\\\\\mathrm{S}_2\\\\\\\\right)$ , $[2\\\\\\\\mathrm{M} + \\\\\\\\mathrm{H}]^{+}$ , calcd $m/z$ : 1037.4450, exptl $m/z$ : 1037.4399, error: $-4.9$ ppm. (c) Proposed surfactant degradation scheme based on LC-MS results. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0556/11e0fd9510e048b37cfc24547566d8e63f924006a143bd16207fe5abdfe39c5c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[148,552,500,697]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0255/2a5a8758a6c32de9b091e59410fafcb4060648453351f8f14e193dc01de0a244.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,562,846,835]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0653/37029213062c5886695dfb03fb41747a271b5c4cf65026aa1422fd0120b269e2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[148,686,492,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 6. Insoluble protein extraction performance of mAzo surfactants. (a) Tissue extraction workflow: (i) cell lysis and homogenization, (ii) centrifugation and removal of supernatant, (iii) extraction using a surfactant, (iv) sample analysis of soluble proteins via Bradford assay or SDS-PAGE. (b) Bradford assay results from triplicate insoluble protein extracts using either no surfactant (NS), DDM, mAzo 6, mAzo 8, mAzo 10, Azo 6, or Azo 8. (c) $12\\\\\\\\%$ SDS-PAGE of insoluble protein extracts using the same sets of surfactants. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0159/d9f2b804f6a46f3416b13e2f130c03eed00edc4963c1a3e8726b7189753d2e1d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,46,154,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[436,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[864,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,951,512,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1470 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[721,952,914,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,962,914,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,71,479,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the chromatograms for each surfactant were dominated by one large peak that corresponds to a mixture of surfactant monomer, dimer, and trimer, which are typical association patterns in the gas phase for molecules containing a sugar motif. After photodegradation, two species prevailed in each chromatogram, one of which was consistent with a disulfide compound formed from the oxidation of two thiomaltose fragments (Y) and eluted earlier in the gradient relative to the intact surfactant (X; Figure 5a). The second compound, Z, eluted close to the original surfactant peak and had a mass that corresponds to a compound consisting of a maltose head group and an alkylbenzene tail that were linked through a thioether bond. This amphiphilic product is likely to alter surface tension, which explains the observed decrease in surface tension as a function of surfactant concentration even after irradiation (Figure 4a-c). These photodegradation products were consistent across mAzo surfactants with different surfactant chain lengths (Figures S9 and S10). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,321,479,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on these results, we propose that the surfactant degrades upon irradiation by two pathways as illustrated in Figure 5c. The first is the traditional (and original anticipated) pathway wherein the surfactant undergoes homolytic cleavage to form maltose (which in turn forms a disulfide bond with another free molecule of thiomaltose yielding Y), phenol, and alkylbenzene byproducts. We note that the phenolic and benzene-derived degradation products in pathway 1 were not observed likely because of the poor ionization efficiency of these species using electrospray ionization (ESI)-MS analysis. The amphiphilic product Z from pathway 2 forms because of the recombination of thiomaltose and alkylbenzyl radicals (Figure S11). Interestingly, when surfactant solutions were allowed to degrade under nonphotolytic conditions (i.e., allowed to remain in the dark in room temperature water), this amphiphilic product still formed as evidenced by LC-MS (Figure S12), albeit to a lesser extent. The formation of this new product under nonphotolytic conditions could proceed via an alternative mechanism (Figure S13). Overall, the formation of a new surfactant (Z) explains the continued decrease in surface tension observed in Figure 4 even after photodegradation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,625,479,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, we explored the use of the mAzo surfactants for protein extraction, as surfactants are widely used throughout biology to solubilize proteins from cells and tissues.[6,44,45] To examine this property of the mAzo surfactants, heart tissue was homogenized and washed in $\\\\mathrm{NH_4HCO_3}$ extraction and washing buffers to remove water-soluble proteins and obtain an insoluble tissue pellet (Figure 6a). Depleting the soluble species allows us to better evaluate the surfactants' ability to extract challenging, insoluble proteins such as membrane proteins. The pellet was then treated with the mAzo surfactants $(1\\\\% \\\\mathrm{w / v})$ , DDM $(1\\\\% \\\\mathrm{w / v})$ , no surfactant (NS), or the Azo surfactants $(1\\\\% \\\\mathrm{w / v}$ or $0.2\\\\% \\\\mathrm{w / v}$ , based on maximum solubility in water), which have been previously shown to facilitate protein extraction (Figure 6b,c).[13] The concentration of surfactants used is in great excess of their CMC to achieve high protein solubilization.[44,46] All steps were performed at $4^{\\\\circ}\\\\mathrm{C}$ to prevent surfactant degradation as well as to reduce proteolytic activity and preserve protein integrity. Thus, the mAzo surfactants can serve as a cleavable alternative to common biological surfactants when this functionality is desirable (e.g., detergent exchange).[17,47] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,913,479,942]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Overall, all extraction conditions using various surfactants, including the mAzo surfactants, show an improved protein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,71,914,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"extraction efficacy relative to using no surfactant. The Bradford assay results in Figure 6b as well as the SDS-polyacrylamide gel electrophoresis (SDS-PAGE) gel in Figure 6c show that mAzo 8 provides the best protein solubility, while mAzo 6, mAzo 10, and DDM were slightly less effective. The results suggest a chain length of 8 provides the best hydrophilic-lipophilic balance to enable protein solubilization for the mAzo surfactants. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,182,914,430]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Not surprisingly, anionic surfactants like Azo 6 and Azo 8 appear to be more effective at solubilizing proteins compared to the nonionic surfactants,[6,13,35,45] even though they contain the same hydrophobic and photocleavable components as the mAzo surfactants. Ionic head groups destabilize lipid membranes and denature proteins by disturbing noncovalent interaction (e.g., hydrogen bonding), enabling more effective protein extraction and solubilization relative to surfactants with nonionic head groups.[48,49] Although the mAzos were less efficient than the anionic Azos at extracting membrane proteins in the current study, these surfactants presumably are superior to the original surfactants in stabilizing extracted membrane proteins.[6,8] Therefore, they could be amenable to techniques requiring nondenaturing conditions such as crystallography or native MS.[29,50,51] Moreover, cleavable surfactants are generally useful in proteomics for protein solubilization and then detergent removal before MS analysis[13,15,16,19,30-32,52,53] or in detergent exchange before biophysical characterization.[17,47] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,442,657,455]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CONCLUSIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,460,914,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We have successfully synthesized and characterized a new family of nonionic photocleavable surfactants (mAzo) derived from maltose, azo-sulfide benzenelinker, and a variable hydrophobic alkyl chain. Surface tension measurements, dynamic light scattering, and transmission electron microscopy show that these mAzo surfactants are able to form supramolecular assemblies. UV-visible spectroscopy shows the rapid photodegradation of the mAzo surfactants, and surface tension measurements of the whole post-degradation solutions suggest an unexpected degradation pathway. LC-MS studies of the photodegradation products reveal that the mAzo surfactants could undergo a recombination event after nitrogen expulsion to nonquantitatively form another photo-stable surfactant. Moreover, we have demonstrated that these surfactants are capable of solubilizing proteins in a comparable way to a commercially available nonionic surfactant analogue (DDM), which is widely used for protein purification and crystallography. Despite the complexity of their photodegradation processes, these new nonionic cleavable mAzo surfactants provide another set of tools for the applications of mild and switchable surfactants in chemical synthesis, green chemistry, drug delivery, characterization of insoluble biomolecules, and more. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,790,721,803]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ASSOCIATED CONTENT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,808,708,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supporting Information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,823,914,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.langmuir.2c02820. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[551,855,914,940]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"${}^{1}\\\\mathrm{H}$ NMR spectra of 1-isothiouronium- $\\\\beta$ -D-maltose heptaacetate fluoride; ${}^{1}\\\\mathrm{H}$ NMR spectra of 1-thio- $\\\\beta$ -D maltose heptaacetate; ${}^{1}\\\\mathrm{H}$ NMR spectra of 1-thio- $\\\\beta$ -D maltose potassium salt; ${}^{1}\\\\mathrm{H}$ NMR spectra of mAzo 6; ${}^{1}\\\\mathrm{H}$ NMR of mAzo 8; ${}^{1}\\\\mathrm{H}$ NMR spectra of mAzo 10; solution stability determination of mAzo 6, mAzo 8, and mAzo \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,47,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[436,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,952,512,961]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1471 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[721,952,914,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,962,914,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[118,73,482,225]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 at room temperature and $4^{\\\\circ}\\\\mathrm{C}$ ; surface tension measurements for replicate CMC trials for mAzo 6, mAzo 8, and mAzo 10; dynamic light scattering curves for mAzo 6, mAzo 8, and mAzo 10 after photodegradation; EICs of photodegradation products from mAzo 8 and mAzo 10; proposed photodegradation mechanism; EICs of thermal degradation products from mAzo 6, mAzo 8, and mAzo 10; proposed thermal degradation mechanism; and particle size, standard deviation, and PDI for triplicate DLS trials before photodegradation (PDF) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,240,293,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHOR INFORMATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,260,245,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Corresponding Authors \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[98,275,464,411]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Kyle A. Brown - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; orcid.org/0000-0003-1255-9146; Email: kbrown33@wisc.edu \\\",\\\"Song Jin - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; orcid.org/0000-0001-8693-7010; Email: jin@chem.wisc.edu \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[80,420,138,432]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Authors \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[98,435,482,695]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Morgan K. Gugger - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States \\\",\\\"David S. Roberts - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; orcid.org/0000-0002-0478-4987 \\\",\\\"David Moreno - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States \\\",\\\"Pil Seok Chae - Department of Bionano Engineering, Hanyang University, Ansan 15588, South Korea; orcid.org/0000-0003-1799-3304 \\\",\\\"Ying Ge - Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States; Department of Cell and Regenerative Biology and Human Proteomics Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States; $\\\\\\\\oplus$ orcid.org/0000-0001-5211-6812 \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[80,700,413,730]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Complete contact information is available at: https://pubs.acs.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,741,230,753]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author Contributions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,755,426,770]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{\\\\#}$ K.A.B. and M.K.G. contributed equally to this work. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,772,123,783]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Notes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,786,418,800]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare no competing financial interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,812,276,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,830,481,940]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This research was supported by National Institutes of Health (NIH) R01 GM117058 (to both S.J. and Y.G.). The authors acknowledge funding from the HL096971, HL109810, GM125085, and S10 OD018475 (to Y.G.). K.A.B. acknowledges the Vascular Surgery Research Training Program Grant T32 HL110853. D.S.R. acknowledges the support from the American Heart Association Predoctoral Fellowship Grant No. 832615/David S. Roberts/2021. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[517,71,640,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,91,915,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"(1) Chowdhury, S.; Shrivastava, S.; Kakati, A.; Sangwai, J. S. Comprehensive Review on the Role of Surfactants in the Chemical Enhanced Oil Recovery Process. Ind. Eng. Chem. Res. 2022, 61, 21-64. \\\",\\\"(2) De, S.; Malik, S.; Ghosh, A.; Saha, R.; Saha, B. A review on natural surfactants. RSC Adv. 2015, 5, 65757-65767. \\\",\\\"(3) Song, T.; Gao, F.; Guo, S.; Zhang, Y.; Li, S.; You, H.; Du, Y. A review of the role and mechanism of surfactants in the morphology control of metal nanoparticles. Nanoscale 2021, 13, 3895-3910. \\\",\\\"(4) Raffa, P.; Wever, D. A. Z.; Picchioni, F.; Broekhuis, A. A. Polymeric Surfactants: Synthesis, Properties, and Links to Applications. Chem. Rev. 2015, 115, 8504-8563. \\\",\\\"(5) Menger, F. M.; Mbadugha, B. N. A. Gemini Surfactants with a Disaccharide Spacer. J. Am. Chem. Soc. 2001, 123, 875-885. \\\",\\\"(6) Lee, H. J.; Lee, H. S.; Youn, T.; Byrne, B.; Chae, P. S. Impact of novel detergents on membrane protein studies. Chem 2022, 8, 980-1013. \\\",\\\"(7) Stetsenko, A.; Guskov, A. An Overview of the Top Ten Detergents Used for Membrane Protein Crystallization. Crystals 2017, 7, No. 197. \\\",\\\"(8) Rasmussen, S. G. F.; Devree, B. T.; Zou, Y.; Kruse, A. C.; Chung, K. Y.; Kobilka, T. S.; Thian, F. S.; Chae, P. S.; Pardon, E.; Calinski, D.; et al. Crystal structure of the $\\\\\\\\beta$ 2 adrenergic receptor-Gs protein complex. Nature 2011, 477, 549-557. \\\",\\\"(9) Alpes, H.; Apell, H. J.; Knoll, G.; Plattner, H.; Riek, R. Reconstitution of $\\\\\\\\mathrm{Na} + / \\\\\\\\mathrm{K} +$ ATPase into phosphatidylcholine vesicles by dialysis of nonionic alkyl maltoside detergents. Biochim. Biophys. Acta, Biomembr. 1988, 946, 379-388. \\\",\\\"(10) Wan, Y.; Shi, Y.; Zhao, D. Designed synthesis of mesoporous solids via nonionic-surfactant-templating approach. Chem. Commun. 2007, 897–926. \\\",\\\"(11) da Silva, M. A.; Dreiss, C. A. Unusual Surfactants. In Wormlike Micelles: Advances in Systems, Characterisation and Applications; The Royal Society of Chemistry, 2017; pp 63-102. \\\",\\\"(12) Hellberg, P.-E.; Bergstrom, K.; Holmberg, K. Cleavable surfactants. J. Surfactants Deterg. 2000, 3, 81-91. \\\",\\\"(13) Brown, K. A.; Chen, B.; Guardado-Alvarez, T. M.; Lin, Z.; Hwang, L.; Ayaz-Guner, S.; Jin, S.; Ge, Y. A photocleavable surfactant for top-down proteomics. Nat. Methods 2019, 16, 417-420. \\\",\\\"(14) Chang, Y.-H.; Gregorich, Z. R.; Chen, A. J.; Hwang, L.; Guner, H.; Yu, D.; Zhang, J.; Ge, Y. New Mass-Spectrometry-Compatible Degradable Surfactant for Tissue Proteomics. J. Proteome Res. 2015, 14, 1587-1599. \\\",\\\"(15) Saveliev, S. V.; Woodroofe, C. C.; Sabat, G.; Adams, C. M.; Klaubert, D.; Wood, K.; Urh, M. Mass Spectrometry Compatible Surfactant for Optimized In-Gel Protein Digestion. Anal. Chem. 2013, 85, 907-914. \\\",\\\"(16) Yu, Y. Q.; Gilar, M.; Lee, P. J.; Bouvier, E. S.; Gebler, J. C. Enzyme-friendly, mass spectrometry-compatible surfactant for insolu-. tion enzymatic digestion of proteins. Anal. Chem. 2003, 75, 6023-6028. \\\",\\\"(17) Liu, L.; Zhu, Z.; Zhou, F.; Xue, D.; Hu, T.; Luo, W.; Qiu, Y.; Wu, D.; Zhao, F.; Le, Z.; Tao, H. Catalytically Cleavable Detergent for Membrane Protein Studies. ACS Omega 2021, 6, 21087-21093. \\\",\\\"(18) Hwang, L.; Guardado-Alvarez, T. M.; Ayaz-Gunner, S.; Ge, Y.; Jin, S. A Family of Photolabile Nitroveratryl-Based Surfactants That Self-Assemble into Photodegradable Supramolecular Structures. Langmuir 2016, 32, 3963-3969. \\\",\\\"(19) Norris, J. L.; Hangauer, M. J.; Porter, N. A.; Caprioli, R. M. Nonacid cleavable detergents applied to MALDI mass spectrometry profiling of whole cells. J. Mass Spectrom. 2005, 40, 1319-1326. \\\",\\\"(20) Epstein, W. W.; Jones, D. S.; Bruenger, E.; Rilling, H. C. The synthesis of a photolabile detergent and its use in the isolation and characterization of protein. Anal. Biochem. 1982, 119, 304-312. \\\",\\\"(21) Nuyken, O.; Meindl, K.; Wokaun, A.; Mezger, T. Photolabile surfactants based on the diazosulphonate group 2. 4-(Acyloxy)-benzenediazosulphonates and 4-(acylamino)- \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[80,46,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[434,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pubs.acs.org/Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,48,904,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,952,512,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1472 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[721,952,914,962]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1021/acs.langmuir.2c02820 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[780,962,914,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir 2023, 39, 1465-1473 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,71,481,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"benzenediazosulphonates. J. Photochem. Photobiol., A 1995, 85, 291-298. \\\",\\\"(22) Jaeger, D. A.; Reddy, V. B.; Bohle, D. S. Cleavable double-chain surfactant Co(III) complexes. Tetrahedron Lett. 1999, 40, 649-652. \\\",\\\"(23) Dunkin, I. R.; Gittinger, A.; Sherrington, D. C.; Whittaker, P. Synthesis, characterization and applications of azo-containing photodestructible surfactants. J. Chem. Soc., Perkin Trans. 2 1996, 1837-1842. \\\",\\\"(24) Norris, J. L.; Porter, N. A.; Caprioli, R. M. Mass Spectrometry of Intracellular and Membrane Proteins Using Cleavable Detergents. Anal. Chem. 2003, 75, 6642-6647. \\\",\\\"(25) Kakiyama, T.; Usui, K.; Tomizaki, K.-y.; Mie, M.; Kobatake, E.; Mihara, H. A peptide release system using a photo-cleavable linker in a cell array format for cell-toxicity analysis. Polym. J. 2013, 45, 535-539. \\\",\\\"(26) Mezger, T.; Nuyken, O.; Meindl, K.; Wokaun, A. Light decomposable emulsifiers: application of alkyl-substituted aromatic azosulfonates in emulsion polymerization. Prog. Org. Coat. 1996, 29, 147-157. \\\",\\\"(27) Nuyken, O.; Voit, B. The photoactive diazosulfonate group and its role in polymer chemistry. Macromol. Chem. Phys. 1997, 198, 2337-2372. \\\",\\\"(28) Kim, M. S.; Diamond, S. L. Photocleavage of o-nitrobenzyl ether derivatives for rapid biomedical release applications. Bioorg. Med. Chem. Lett. 2006, 16, 4007-4010. \\\",\\\"(29) Urner, L. H.; Schulze, M.; Maier, Y. B.; Hoffmann, W.; Warnke, S.; Liko, I.; Folmert, K.; Manz, C.; Robinson, C. V.; Haag, R.; Pagel, K. A new azobenzene-based design strategy for detergents in membrane protein research. Chem. Sci. 2020, 11, 3538-3546. \\\",\\\"(30) Brown, K. A.; Tucholski, T.; Eken, C.; Knott, S.; Zhu, Y.; Jin, S.; Ge, Y. High-throughput Proteomics Enabled by a Photocleavable Surfactant. Angew. Chem., Int. Ed. 2020, 59, 8406-8410. \\\",\\\"(31) Knott, S. J.; Brown, K. A.; Josyer, H.; Carr, A.; Inman, D.; Jin, S.; Friedl, A.; Ponik, S. M.; Ge, Y. Photocleavable Surfactant-Enabled Extracellular Matrix Proteomics. Anal. Chem. 2020, 92, 15693–15698. \\\",\\\"(32) Buck, K. M.; Roberts, D. S.; Aballo, T. J.; Inman, D. R.; Jin, S.; Ponik, S.; Brown, K. A.; Ge, Y. One-Pot Exosome Proteomics Enabled by a Photocleavable Surfactant. Anal. Chem. 2022, 94, 7164-7168. \\\",\\\"(33) Aballo, T. J.; Roberts, D. S.; Melby, J. A.; Buck, K. M.; Brown, K. A.; Ge, Y. Ultrafast and Reproducible Proteomics from Small Amounts of Heart Tissue Enabled by Azo and timsTOF Pro. J. Proteome Res. 2021, 20, 4203-4211. \\\",\\\"(34) Brown, G. M.; Dubreuil, P.; Ichhaporia, F. M.; Desnoyers, J. E. Synthesis and properties of some $\\\\\\\\alpha$ -D-alkyl glucosides and mannosides: apparent molal volumes and solubilization of nitrobenzene in water at $25^{\\\\\\\\circ}\\\\\\\\mathrm{C}$ . Can. J. Chem. 1970, 48, 2525-2531. \\\",\\\"(35) Chae, P. S.; Rasmussen, S. G. F.; Rana, R. R.; Gotfried, K.; Chandra, R.; Goren, M. A.; Kruse, A. C.; Nurva, S.; Loland, C. J.; Pierre, Y.; et al. Maltose-neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nat. Methods 2010, 7, 1003-1008. \\\",\\\"(36) Bradley, M.; Vincent, B.; Warren, N.; Eastoe, J.; Vesperinas, A. Photoresponsive Surfactants in Microgel Dispersions. Langmuir 2006, 22, 101-105. \\\",\\\"(37) Ibatullin, F. M.; Shabalin, K. A.; Janis, J. V.; Shavva, A. G. Reaction of 1,2-trans-glycosyl acetates with thiourea: a new entry to 1-thiosugars. Tetrahedron Lett. 2003, 44, 7961-7964. \\\",\\\"(38) Doyle, L. M.; O'Sullivan, S.; Di Salvo, C.; McKinney, M.; McArdle, P.; Murphy, P. V. Stereoselective Epimerizations of Glycosyl Thiols. Org. Lett. 2017, 19, 5802-5805. \\\",\\\"(39) McElhanon, J. R.; Zifer, T.; Kline, S. R.; Wheeler, D. R.; Loy, D. A.; Jamison, G. M.; Long, T. M.; Rahimian, K.; Simmons, B. A. Thermally Cleavable Surfactants Based on Furan-Maleimide Diels-Alder Adducts. Langmuir 2005, 21, 3259-3266. \\\",\\\"(40) Maibaum, L.; Dinner, A. R.; Chandler, D. Micelle Formation and the Hydrophobic Effect. J. Phys. Chem. B 2004, 108, 6778-6781. \\\",\\\"(41) Shin, J. Y.; Abbott, N. L. Using Light to Control Dynamic Surface Tensions of Aqueous Solutions of Water Soluble Surfactants. Langmuir 1999, 15, 4404-4410. \\\"]\",\n \"page_idx\": \"8\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[515,71,915,560]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"(42) Aguilar, Z. P. Types of Nanomaterials and Corresponding Methods of Synthesis. In Nanomaterials for Medical Applications; Aguilar, Z. P., Ed.; Elsevier, 2013; pp 33-82. \\\",\\\"(43) Kwan, T. O. C.; Reis, R.; Siligardi, G.; Hussain, R.; Cheruvara, H.; Moraes, I. Selection of Biophysical Methods for Characterisation of Membrane Proteins. Int. J. Mol. Sci. 2019, 20, No. 2605. \\\",\\\"(44) Hussain, H.; Du, Y.; Scull, N. J.; Mortensen, J. S.; Tarrasch, J.; Bae, H. E.; Loland, C. J.; Byrne, B.; Kobilka, B. K.; Chae, P. S. Accessible Mannitol-Based Amphiphiles (MNAs) for Membrane Protein Solubilisation and Stabilisation. Chem. - Eur. J. 2016, 22, 7068-7073. \\\",\\\"(45) Speers, A. E.; Wu, C. C. Proteomics of integral membrane proteins-theory and application. Chem. Rev. 2007, 107, 3687-3714. \\\",\\\"(46) Ohlendieck, K. Purification of Membrane Proteins. In Protein Purification Protocols; Cutler, P., Ed.; Humana Press, 2004; pp 301-308. \\\",\\\"(47) Xue, D.; Wang, J.; Song, X.; Wang, W.; Hu, T.; Ye, L.; Liu, Y.; Zhou, Q.; Zhou, F.; Jiang, Z.-X.; et al. A Chemical Strategy for Amphiphile Replacement in Membrane Protein Research. Langmuir 2019, 35, 4319-4327. \\\",\\\"(48) Rabilloud, T. Protein Solubility in Two-Dimensional Electrophoresis. In The Protein Protocols Handbook; Walker, J. M., Ed.; Humana Press, 2009; pp 73-84. \\\",\\\"(49) Seddon, A. M.; Curnow, P.; Booth, P. J. Membrane proteins, lipids and detergents: not just a soap opera. Biochim. Biophys. Acta, Biomembr. 2004, 1666, 105-117. \\\",\\\"(50) Keener, J. E.; Zhang, G.; Marty, M. T. Native Mass Spectrometry of Membrane Proteins. Anal. Chem. 2021, 93, 583-597. \\\",\\\"(51) Urner, L. H.; Liko, I.; Yen, H. Y.; Hoi, K. K.; Bolla, J. R.; Gault, J.; Almeida, F. G.; Schweder, M. P.; Shutin, D.; Ehrmann, S.; et al. Modular detergents tailor the purification and structural analysis of membrane proteins including G-protein coupled receptors. Nat. Commun. 2020, 11, No. 564. \\\",\\\"(52) Chen, E. I.; Cociorva, D.; Norris, J. L.; Yates, J. R. Optimization of Mass Spectrometry Compatible Surfactants for Shotgun Proteomics. J. Proteome Res. 2007, 6, 2529-2538. \\\",\\\"(53) Brown, K. A.; Gugger, M. K.; Yu, Z.; Moreno, D.; Jin, S.; Ge, Y. Nonionic, Cleavable Surfactant for Top-Down Proteomics. Anal. Chem. 2023, DOI: 10.1021/acs.analchem.2c03916. \\\"]\",\n \"page_idx\": \"8\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[80,47,153,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Langmuir \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[436,48,570,60]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": 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}\n]","isConversational":false},"doi":{"kind":"string","value":"10.1021/acs.langmuir.2c02820"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Life Sciences"},"sha256":{"kind":"string","value":"65c14b6d0876bfe7ae545f861c690df824ad433d5a273e8595637b50a827a391"},"title":{"kind":"string","value":"Synthesis, Self-Assembly Properties, and Degradation Characterization of a Nonionic Photocleavable Azo-Sulfide Surfactant Family"}}},{"rowIdx":166,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Zhihang Wang|Zhenhua Wu|Zhiyu Hu|Jessica Orrego-Hernández|Erzhen Mu|Zhao-Yang Zhang|Martyn Jevric|Yang Liu|Xuecheng Fu|Fengdan Wang|Tao Li|Kasper Moth-Poulsen"},"content_list":{"kind":"list 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Wang et al. demonstrate a molecular thermal power generation system that stores solar energy and converts it to electric power on demand. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,264,870,317]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Zhihang Wang, Zhenhua Wu, Zhiyu Hu, ..., Fengdan Wang, Tao Li, Kasper Moth-Poulsen ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,326,855,377]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"zhiyuhu@sjtu.edu.cn (Z.H.) \nlitao1983@sjtu.edu.cn (T.L.) \nkasper.moth-poulsen@chalmers.se \n(K.M.-P.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[666,388,737,402]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Highlights ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[664,402,865,448]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Solar energy storage and conversion to electrical power generation is demonstrated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,464,883,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Continuous power output can be generated from the combined device ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,525,877,570]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Photophysical properties of two photoswitches are fully characterized ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,586,867,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A microelectromechanical ultrathin thermoelectric chip is designed and fabricated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,873,875,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Wang et al., Cell Reports Physical Science 3, 100789 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[664,898,867,924]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"March 16, 2022 © 2022 The Author(s). https://doi.org/10.1016/j.xcrp.2022.100789 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","text_format":null,"text_level":null,"type":"header"},{"bbox":"[797,63,903,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[797,84,903,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[873,955,903,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chuck for updates ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[89,127,171,145]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[91,145,500,204]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chip-scale solar thermal electrical power generation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[88,216,807,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Zhihang Wang, $^{1}$ Zhenhua Wu, $^{2}$ Zhiyu Hu, $^{2,*}$ Jessica Orrego-Hernández, $^{1}$ Erzhen Mu, $^{3}$ Zhao-Yang Zhang, $^{4}$ Martyn Jevric, $^{1}$ Yang Liu, $^{2}$ Xuecheng Fu, $^{5}$ Fengdan Wang, $^{5}$ Tao Li, $^{4,*}$ and Kasper Moth-Poulsen $^{1,6,7,8,*}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,310,181,324]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUMMARY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,328,627,604]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There is an urgent need for alternative compact technologies that can derive and store energy from the sun, especially the large amount of solar heat that is not effectively used for power generation. Here, we report a combination of solution- and neat-film-based molecular solar thermal (MOST) systems, where solar energy can be stored as chemical energy and released as heat, with microfabricated thermoelectric generators to produce electricity when solar radiation is not available. The photophysical properties of two MOST couples are characterized both in liquid with a catalytic cycling setup and in a phase-interconvertible neat film. Their suitable photophysical properties let us combine them individually with a microelectromechanical ultrathin thermoelectric chip to use the stored solar energy for electrical power generation. The generator can produce, as a proof of concept, a power output of up to $0.1\\mathrm{nW}$ (power output per unit volume up to $1.3\\mathrm{Wm}^{-3}$ ). Our results demonstrate that such a molecular thermal power generation system has a high potential to store and transfer solar power into electricity and is thus potentially independent of geographical restrictions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,627,220,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,647,627,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From the Industrial Revolution to 2018, the global average temperature increased by $1^{\\circ}\\mathrm{C}$ as a result of human activities and may hit $1.5^{\\circ}\\mathrm{C}$ as early as 2030, as warned by the United Nations Intergovernmental Panel on Climate Change (IPCC).<sup>1</sup> People have been actively looking for a technology that can slow down or reduce the rise in global temperature. As the global population increases, total worldwide energy use from all sectors is expected to reach 21 TWy by 2040, corresponding to an increase of $130\\%$ over 2019 levels.<sup>2</sup> Electricity is an essential commodity in modern society, and around 3 TW is currently used. To complicate matters, about $85\\%$ of this power is derived from fossil fuels.<sup>3</sup> Therefore, searching for new decarbonized energy sources to reduce greenhouse gas emissions is imminent. Nuclear energy is a low-carbon energy source, but its installations are complex, and their thermal pollution can potentially be serious. As the most common renewable energy at present, hydropower is geographically limited, while wind energy fluctuates with season or time.<sup>4</sup> It is noteworthy that solar energy is the most abundant energy resource on Earth, and maximizing the use of solar power can potentially meet the intensive demand for power while reducing detrimental effects to the environment.<sup>5</sup> For instance, an estimated $2.3 \\times 10^{4}$ TWy of solar power reaches Earth each year, which equates to only $7\\mathrm{~h}$ of sunlight needed to meet current annual global energy requirements.<sup>6,7</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,602,905,636]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Department of Chemistry and Chemical Engineering, Chalmers University of Technology, 41296 Gothenburg, Sweden ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,639,903,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{2}$ National Key Laboratory of Science and Technology on Micro-Nano Fabrication, Shanghai Jiao Tong University, Shanghai 200240, China ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,687,892,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{3}$ School of Materials Science and Engineering, Henan Polytechnic University, Jiaozuo 454003, Henan, China ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,723,901,769]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{4}$ Shanghai Key Laboratory of Electrical Insulation and Thermal Aging, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,772,897,806]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{5}$ Center for Advanced Electronic, Materials and Devices (AEMD) of Shanghai Jiao Tong University, Shanghai 200240, China ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,809,901,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{6}$ Institute of Materials Science of Barcelona, ICMAB-CSIC, 08193 Bellaterra, Barcelona, Spain ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,835,897,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{7}$ Catalan Institution for Research and Advanced Studies ICREA, Pg. Lluis Companys 23, Barcelona, Spain ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,872,725,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lead contact ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,887,888,918]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"*Correspondence: zhiyuhu@sjtu.edu.cn (Z.H.), litao1983@sjtu.edu.cn (T.L.), kasper.moth-poulsen@chalmers.se (K.M.-P.) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[647,924,872,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1016/j.xcrp.2022.100789 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,46,317,86]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,62,906,97]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,953,122,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[456,964,868,975]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 © 2022 The Author(s). ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[343,975,868,985]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[893,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[89,127,626,387]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Photovoltaic (PV) cells can directly convert solar energy into electrical power with a maximum efficiency of around $30\\%$ , and most of the solar energy is not only lost as heat but also contributes to deteriorating the performance. $^{8-11}$ In addition, solar intensity naturally varies with time and geographical location and these variations currently limit the utilization of PV. Obviously, PV cells do not produce power during the night. Solar thermal power plants with phase-change molten salts can generate power for several hours after sunset; however, these plants require very large solar concentrators and consequently can be installed only in remote areas. $^{12,13}$ Previously, solar actuators based on hydrogen-bonded azopolymers for electricity generation have been investigated; however, the device cannot store solar energy for later on-demand power generation. $^{14}$ Hence, in addition to the above mainstream technologies, there is an urgent need for new alternative compact technologies that can derive and store energy from the sun, especially the large amount of solar heat that is not effectively used for future power generation. In this paper, we demonstrate a compact, chip-based device that allows for direct storage of solar energy as chemical energy that is released in the form of heat on demand and then converted into electrical energy in a controlled way. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,402,627,602]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To explore ways to store solar energy, we are investigating a class of materials that can capture sunlight via reversible photochemical reactions and later release this stored energy on demand. These materials operate in a closed cycle, and they use photochromic chemical compounds to form the basis of molecular solar thermal (MOST) energy storage systems. $^{15-18}$ Upon exposure to sunlight, a suitable MOST material (in the parent state) can photoisomerize to a high-energy metastable photoisomer that can be stored for extended periods of time. Depending on the photochrome used, the back-conversion reaction releasing heat energy can be triggered through different processes, including thermal, $^{19,20}$ catalytic, $^{21,22}$ electrocatalytic, $^{23,24}$ and photoinduced conversion. $^{25-27}$ It has been previously estimated that, for an ideal liquid MOST device, up to $21\\%$ of the solar energy can be stored as chemical energy for later heat production. $^{28}$ Such heat produced can be delivered locally and on demand, unlike other thermal storage technologies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,616,627,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"While MOST systems can be used in closed-cycle devices for efficient storage and release of heat, additional engineering is necessary to generate electrical power. Thermoelectric generators (TEGs) are able to directly convert thermal energy into electrical power via the Seebeck effect. TEGs have been widely used in various applications due to their attractive features such as silent operation, minimal maintenance, and long lifetime. And they have been considered as promising alternatives to meet the urgent demand for energy around the world.[29,30] Traditional solar thermal-to-electric power generation systems use heat engines to convert heat into electricity in two steps (heat to mechanical movements and then mechanical energy to electrical power generation).[31,32] However, a large amount of heat can be lost during the conversion process. To solve this issue, bulk TEGs have been combined with phase-change materials for power generation to convert heat to electricity directly.[31,33] Recently, low-dimensional material-based microelectromechanical system (MEMS) technology has enabled the production of ultrathin and highly sensitive TEG devices that can integrate large arrays of thermoelectric (TE) modules.[34] From our previous results, we explored a reliable and efficient hybrid method for ultrathin MEMS-TEG fabrication, and achieved up to 46,000 TE modules on a 3-in silicon wafer.[35,36] Such a MEMS-TEG equipped with an 800-nm-thin TE film has shown a steady electrical output, which was sensitive to small temperature differences and could effectively utilize low-grade thermal energy.[37] The temperatures accessible by the energy release reaction of the MOST are, at the current stage of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[93,62,122,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[126,63,230,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[124,85,230,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[724,53,815,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[725,67,903,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[828,86,903,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,965,102,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,962,421,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[166,130,554,239]","code_body":null,"code_caption":null,"image_caption":"[\"Scheme 1. Schematic illustration of the MOST to power generation concept \"]","image_footnote":"[]","img_path":"images/0676/910baed1f553f4ac9febcc933b476a54cc4ca9ab62244bb2f0ae1aef8506dc5e.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,295,626,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"development, less than $100^{\\circ}\\mathrm{C}$ , which is not high enough to be utilized for electrical power generation by traditional means. Therefore, it is necessary to match the MOST systems with high-efficiency and sensitive TE devices to effectively utilize this relatively low-grade thermal energy. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,370,627,601]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Here, we design a compact, chip-based device that combines two different MOST systems operating either in the liquid or in the solid state with a novel designed MEMS-TEG to demonstrate the storage of solar energy to the release of heat energy and the cascading energy flow to the harvester that is finally used to generate power (see Scheme 1). Two molecular photoswitches with suitable properties—a norbornadiene derivative (NBD) investigated as a solution and a phase-interconvertible arylazopyrazole derivative (AZO) measured as a neat film—are selected for their potential to produce heat energy for electrical generation. The ultrathin MEMS-TEG with 572 TE modules is designed and fabricated, in which the TE films are only $1\\mu \\mathrm{m}$ thick. We characterize and couple each of these photoswitches individually with the MEMS-TEG chip (effective thermoelectricity area $10\\times 6\\mathrm{mm}$ ), demonstrating that chemical energy stored in MOST systems (in Sweden) can successfully generate electrical power (in China) through the process of solar energy storage, heat release, and TE conversion, thus affirming that solar energy can generate electrical power independent of time and geographical restrictions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,615,305,629]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS AND DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,632,313,645]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Solar energy storage properties ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,647,627,938]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MOST systems can function in both liquid and film forms, which can be tailored toward different applications.[21,38-45] In liquid form, MOST systems can transport stored energy, meaning that energy can be stored and released in two different locations, whereas in film form, MOST systems can be used in smart windows and other device integrations.[43,46] In this study, we selected and tested two systems: an NBD in liquid form (in toluene solution, which can provide a low specific-heat capacity of ca. $1.6\\mathrm{Jg}^{-1}\\cdot \\circ \\mathrm{C}^{-1}$ ) and a neat AZO in thin films with suitable energy capture and storage functionality. The molecular structures of both photoswitch couples are shown in Figure 1A. The photoconversion of NBD proceeds via a $[2 + 2\\pi ]$ cycloaddition reaction to its corresponding photoisomer quadricyclane derivative (QC). Thus, the energy storage density $\\Delta H_{\\mathrm{storage}}$ was experimentally determined to be $93\\mathrm{kJ mol}^{-1}(0.37\\mathrm{MJkg}^{-1})$ . Meanwhile, QC has a thermal back conversion half-life of 1 month at room temperature, demonstrating the possibility for long-term storage in toluene. Spectroscopically, we previously showed that norbornadiene with a push-pull system has a spectral red-shifting effect on the absorption.[21] Hence, this NBD with dimethoxy donor units exhibits an absorption feature around $340~\\mathrm{nm}$ with a maximum absorptivity of $\\varepsilon_{\\mathrm{max@340nm}} = 1.4\\times$ $10^{4}\\mathrm{M}^{-1}\\mathrm{cm}^{-1}$ . In contrast, the absorption profile of QC is virtually negligible above $300~\\mathrm{nm}$ , leaving a transparent optical window of around $85~\\mathrm{nm}$ between both forms due to the selected push-pull substituents (see Figure 1B). This significant spectral ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,53,272,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,62,906,98]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[574,962,870,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[893,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[191,130,506,200]","code_body":null,"code_caption":null,"image_caption":"[\"A \"]","image_footnote":"[]","img_path":"images/0295/245731ed9beb1c24c2d8a088fea23ce3b935e022454cb5d85043bfae9f7a7d87.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[101,223,360,292]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0693/37db155377a3b4085661e138d23898671fa06efbf217304aa2341dc1f5b70024.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[370,214,629,292]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0356/e4ddf2d2270d04dbf67ada0ad26dbd077fe6cb2702c86f4b45bc8a2bca4e7b1d.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[116,308,355,455]","code_body":null,"code_caption":null,"image_caption":"[\"B \",\"C \"]","image_footnote":"[]","img_path":"images/0118/49e2401b2514c469e4bd6c662e68e25e50a38c536f0f44f2d110e67d3e801249.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[380,308,622,456]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Structures and absorption spectra of the two MOST candidates used in this work \"]","image_footnote":"[\"(A) Molecular structures of NBD-QC couple (top) and trans/cis-AZO photoswitch couple (bottom). A thermal $(\\\\Delta)$ or catalytic (cat.) route can facilitate the back conversion of QC $\\\\rightarrow$ NBD. The back conversion of cis- $\\\\rightarrow$ trans-AZO can be achieved by a thermal or light-induced activation. (B) Absorption profile of NBD before and after irradiation with 340-nm light (in toluene). (C) Absorption profile of AZO photoswitch before and after irradiation with 365-nm light (in acetonitrile). \"]","img_path":"images/0685/ed53ce697fa6a4645ad145e52ea3d09358c23818a35e5fd253b6eb99004c5af1.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,571,626,631]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"difference enables near-quantitative photoconversion, even in concentrated solutions. In addition, the photoisomerization quantum yield was $68\\%$ in toluene. Considering the above-mentioned MOST properties, solar energy storage efficiency of the system could exceed $0.70\\%^{38}$ (see Note S1 for details). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,647,627,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Neat-film thermal storage devices have several attractive features, such as simple device integration and no need for mechanical pumping. Further, systems that combine energy input from solar irradiation with absorption of ambient heat have recently emerged. $^{46-55}$ Such systems couple a phase-change event to the photoconversion process found in MOST systems. One example is the AZO explored here (see Figure 1A). To take advantage of the exothermic process not only from the photoisomerization reaction but also from an additional phase-change process (liquid $\\rightarrow$ crystal), we investigated the AZO photoswitch in its neat form. The energy stored in cis-AZO was easily released by triggering heat release following irradiation with a 532-nm light source (this wavelength is considered cis-AZO's onset of absorption). As shown in Figure 1C, the absorption maximum of the trans isomer was $344\\mathrm{nm}$ with an absorptivity of $\\varepsilon_{\\max@340\\mathrm{nm}} = 2.9\\times 10^{4}\\mathrm{M}^{-1}\\mathrm{cm}^{-1}$ . The trans-AZO has a quantum yield of only $41\\%$ , but this is considered high for other azobenzene-based photoswitches. The photoisomerization energy density $\\Delta H_{\\mathrm{isom}}$ was $52\\mathrm{kJ mol}^{-1}$ ( $0.17\\mathrm{MJ kg}^{-1}$ ). In addition to heat release from the chemical reaction, the crystal-to-liquid transition ( $\\Delta H_{\\mathrm{phase\\_change}}$ ) can provide an additional $50\\mathrm{kJ mol}^{-1}$ ( $0.16\\mathrm{MJ kg}^{-1}$ ) of thermal energy because of its long alkenyl chain. As a result, the solar energy storage efficiency of the AZO couple was estimated to be $1.2\\%$ , which is much higher than that of other azobenzene photoswitches. $^{40}$ Moreover, cis-AZO is remarkably stable at room ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[93,62,122,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[126,63,232,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[124,84,230,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[724,53,815,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[725,67,903,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[828,86,903,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,964,102,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,962,423,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[147,129,488,249]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0362/0963d5d6a06fca553f38506a2117c93ffac2352ecfd6695eeedb79fa773c8636.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[149,249,473,367]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0936/cb606570b2a76bff573ad04ab4d7f997d41615e16d845d5051e6c3c2118b27e9.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[504,129,843,361]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. Conversion performance, cycling performance, and experimental setup of NBD in the device \"]","image_footnote":"[\"(A) Conversion percentage (in blue) and calculated energy storage efficiency (in red) of 0.1 M NBD in toluene as a function of residence time in the device. \",\"(B) Normalized absorbance before irradiation with $340\\\\mathrm{nm}$ LED light and after catalytic reactor. Blue dots show the normalized absorbance at $340\\\\mathrm{nm}$ , red dots show the normalized absorbance after irradiation. \",\"(C) Cycling test setup for NBD. Boxes 1 and 2 represent the flow UV-vis spectrometer before and after a catalytic reaction center. Box 3 refers to the microfluidic chip. The conversion process has proceeded with irradiation from a $340~\\\\mathrm{nm}$ LED lamp. \"]","img_path":"images/0982/f520db9903e4cdd1e956aee83301e742f5dff5b810649ffc0fe039f8f8b498f8.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,479,626,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"temperature, with a thermal half-life of 3 months at $25^{\\circ}\\mathrm{C}$ . Thus, using this photoswitch from a neat film would allow two different sources of stored energy to be used: thermal ambient energy and light.[46,47] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,540,626,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Photoconversion in the device under various exposure times and complete interconversion through multiple cycles are important tests for photoswitch viability in a MOST system. These experimental factors have previously been reported for $\\mathsf{AZO}^{46}$ but not for NBD. Therefore, additional experiments were necessary to determine the compatibility of the NBD photoswitch. A custom-made $400\\mathrm{-mm}^2$ microfluidic reactor was used for this photoconversion experiment (see Note S2 and Figure S1 for details). A solution of 0.1 M NBD ( $25\\mathrm{gL}^{-1}$ ) in toluene- $\\mathsf{d}_8$ was pumped through the microfluidic reactor with residence times from 34 to 343 s. The degree of photoconversion was monitored immediately afterward by ${}^{1}\\mathsf{H}$ NMR spectroscopy. For an ideal MOST system, where the absorption of the photoisomer (QC) does not compete with the absorption of the parent (NBD), the energy storage efficiency, $\\eta_{MOST}$ , should remain approximately unchanged prior to full conversion.[40,45,56] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,723,626,799]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Here, we observed a decrease in solar energy storage efficiency from $\\approx 0.5\\%$ at short residence times to $0.25\\%$ at full conversion. While not ideal, it is normal for efficiency to lower progressively during the conversion process. In this context, this system is better than our previous attempts at flow conversion (see Figure 2A and Note S3 for details).<sup>21</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,815,627,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Typically, for cyclability testing, solution-based photoswitches are irradiated at elevated temperatures.[21,45] However, this method seemed impractical as QC has a long half-life ( $t_{1/2} \\approx 29$ days) in toluene. To address this, an alternate protocol was employed, which hastened the time frame for each successive cycle. Cobalt(II) phthalocyanine is physisorbed on activated carbon (CoPc@C) and can rapidly facilitate the back reaction of a very similar quadricyclane structure.[21] This new setup involved converting and back converting an NBD solution (0.5 mM in toluene) continuously through a microfluidic photoreactor and a catalytic reactor in a closed ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,53,272,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,86,169,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,62,905,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[797,85,905,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[574,962,870,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[893,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[94,129,350,287]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0464/a3abf9df5f81e324006e63c6b1b6bc218257e16c0569cd45f32961035b71b7cd.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[358,129,624,287]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Macroscopic heat-release performance of QC and cis-AZO under infrared camera \"]","image_footnote":"[\"(A) Recorded temperature increment of QC heat release over time; inset shows the thermal image from the heat-releasing copper device. The area indicated by the dashed line represents the device position. \",\"(B) Recorded temperature increment of the cis-AZO system over time; inset shows the thermal image from the heat-releasing cis-AZO sample. The dashed line represents the position of the compound (maximum temperature gradient of $17^{\\\\circ}\\\\mathrm{C}$ after the heat generated from the laser is subtracted). \"]","img_path":"images/0363/7297ca0b7db2cd7e67758bd453dcc95acb31047ee3e1e551ab636a086007269e.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,419,626,465]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"cycle. Happily, no obvious drop in performance was observed after 54 charge and discharge cycles on the NBD couple (see Figures 2B and 2C and Note S4 for details). This setup drastically reduced the total experimental time to only $61\\mathrm{h}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,480,370,493]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Stored energy release for NBD and AZO ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,494,626,616]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Once solar energy is stored as QC and cis-AZO, one should be able to release the chemical energy from these metastable compounds as heat. However, we performed simulations to determine how much energy could be extracted from these charged materials. To achieve this, a simulation of possible temperature increases based on molecular parameters was performed. In the case of QC, the maximum temperature increase depended on the concentration of initial NBD in toluene. Based on the highest possible concentration of $0.78\\mathrm{M}$ in toluene, the maximum estimated temperature difference under adiabatic conditions was $40^{\\circ}\\mathrm{C}$ (see Note S5 and Figure S2 for details). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,632,627,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To test the experiment in practice, we designed a fixed-bed catalytic heat-release device consisting of a copper tube flanked on two sides with copper plates to maximize heat transfer to the MEMS-TEG device (see Note S6 and Figure S3 for details). By taking advantage of the mobile nature of the QC solution, a heterogeneous CoPc@C catalyst $^{21}$ was loaded inside the copper tube, and a thermally conductive pad was used to provide a homogeneous thermal distribution from the tube to all areas of the device. A saturated NBD solution was initially photoconverted to QC and then pumped through the reactor at a flow speed of $5 \\, \\text{mL} \\, \\text{h}^{-1}$ . This speed leads to complete back conversion from QC to NBD and a maximum surface temperature of $37^{\\circ}\\text{C}$ ( $\\approx 13^{\\circ}\\text{C}$ maximum temperature gradient, see Figure 3A and Video S1 for details). A thermal camera recorded liquid-QC macroscopic heat release, determined by the camera focusing on the top of the device. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,831,627,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Concerning the trans/cis-AZO photoswitch couple, the charged cis isomer releases $0.17\\mathrm{MJkg}^{-1}$ , equating to a simulated thermal difference of $84^{\\circ}\\mathrm{C}$ . From here, an additional $0.16\\mathrm{MJkg}^{-1}$ can be extracted at the crystallization point of the trans-AZO (melting point $83^{\\circ}\\mathrm{C}$ ) from the phase-change event. Thus, cis-AZO theoretically shows a larger potential thermal gradient than the QC solution. In this case, the experimental measurement of the heat release involved the placement of a droplet of liquid cis-AZO ( $\\approx 8\\mathrm{mg}$ ) under ambient conditions onto a glass substrate ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[93,62,122,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[126,63,230,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[124,85,230,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[724,53,815,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[725,67,903,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[828,86,903,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,965,102,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,962,421,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[91,129,229,227]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0694/bc1db50eb0529d800c7193e45861e2a2e0f750395ee36eef3180293918e0ecfc.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[230,130,413,225]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0846/7091d06e9c3e9b93745b0ecdc7f03bad9773e5239f4f0171bda35a431a3000d9.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[401,130,624,225]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0808/ec6b15741e33eaa2244cbde83042f976e31a203d1138937a13fab46c31ff79bc.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[91,231,629,396]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Thermal performance of MEMS-TEG used in this work \"]","image_footnote":"[\"(A) Optical microscope photo of MEMS-TEG with 572 TE modules. \",\"(B) Three-dimensional laser scanning confocal microscope images of the fabricated thermoelectric pairs. \",\"(C) Top view of the fabricated thermoelectric pairs by laser scanning confocal microscopy. Scale bar shows the relative height of the device. \",\"(D) Power generation of MEMS-TEG when hot water of different temperature flows through the copper tube at the hot end of the TEG. \"]","img_path":"images/0844/7cc38602c82d3d6dee31e5dcf2837ba60aab2564ad484c376988bd3cef9aef7d.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,511,626,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$(1 \\times 0.7 \\mathrm{~cm})$ . A $532 \\mathrm{~nm}$ laser was used to irradiate the sample and trigger the heat release in conjunction with a thermal camera. This triggered a full back conversion, affording a maximum surface temperature of $52^{\\circ} \\mathrm{C}$ , corresponding to a $17^{\\circ} \\mathrm{C}$ maximum temperature difference after accounting for heat from the laser. The large difference in temperature gradient between theoretical and experimental values is likely due to the strong heat dissipation from the thin film under ambient conditions (see Figure 3B and Video S2 for details). The thermal camera recorded the cis-AZO film macroscopic heat release. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,649,626,694]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"These results showed that both solution-based NBD and neat AZO photoswitches can successfully generate heat. Next, we wanted to use this thermal energy by converting it to electrical power using the MEMS-TEG device. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,709,493,722]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Single-layered microelectromechanical thermoelectric chip ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,723,627,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Theoretically, the figures of merit $(ZT_{ave})$ of low-dimensional TE materials are higher than those of bulk TE materials and can potentially yield a higher TE conversion efficiency.[57] Thin-film-based TE devices are also sensitive to small temperature differences.[35] Such technology can be used to monitor local thermal variations at micro-nano scales, such as bioactivity in yeast cultures.[58] On the other hand, if the number of integrated TE modules is high enough, the output electrical power can be significantly increased.[59] To effectively convert the heat released from MOST systems to electrical power, a large array integrated MEMS-TEG based on $\\mathrm{Bi}_{2}\\mathrm{Te}_{3}$ (n type) and $\\mathrm{Sb}_{2}\\mathrm{Te}_{3}$ (p type) TE modules was fabricated. The unit structure is designed in a $\\Pi$ shape, with a resistance of $72.8\\Omega$ and a single p/n surface area of $200\\times 200\\mu m$ . The fabrication process and structure diagram of the MEMS-TEG device are shown in Note S7, Figures S4-S9, and Table S1. In total, 572 TE modules were connected in series, where the height of each TE column was increased to $\\sim 1\\mu m$ with the aim of improving the TE performance at low temperature gradients, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,53,272,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,86,169,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,62,906,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[797,85,903,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[574,962,870,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[893,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[161,129,551,244]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0327/f609b59dd038d4a3d59ae3d3b913c2d4aec104752433f3c96b3fc1d3b499add6.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[159,253,365,377]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0882/491cd7dbf8be70a608cfd36c6d22bf7c44d267b9d9063f3be50f28b60a0554c7.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[370,253,554,379]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0508/6231efa326b5c4d06eea76444218c2d153f322c26b88629dde1d1e78a4ad048e.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[161,378,367,492]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0273/1f8c34f4b71b65bb77311326ec97e8a7afce15ddd35703c5070ab0d40473d87c.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[370,379,556,493]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. MOST to power generation performance \"]","image_footnote":"[\"(A) Schematic concept of MOST to power generation. \",\"(B) NBD couple-based solar energy storage for power-generation experimental setup. \",\"(C) Heat release monitoring by thermocouple and voltage generated from MEMS-TEG chip over time. The inset is a photo of the device. Scale bar, 1 cm. \",\"(D) Schematic experimental setup of AZO film-based solar energy for power generation. \",\"(E) Net voltage generated from MEMS-TEG chip over time. The inset is a photo of the device. Scale bar, 1 cm. \"]","img_path":"images/0466/5b04dea95874a3b42a0a8fce3d6b2c5617beaeb12e71ac25ddb5f38192e8da09.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,618,627,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"as shown in Figure 4. $^{37}$ Most importantly, the thickness of the whole working part from the chip did not exceed $2\\mu \\mathrm{m}$ . This ultrathin structure (thickness of top contact layer of only $\\sim 300$ nm and a mass of only a few picograms) responded effectively to small variations in temperature. The structure and properties of the TE materials constituting the MEMS-TEG and the power generation performance of the device are shown in Table S1 and Figures S5-S8. Since the heat released by QC in the copper tube does not cover all the tubes uniformly, as shown in Figure 3, a reference experiment was conducted to investigate the power generation of the MEMS-TEG by passing hot water into the copper tube at a flow speed of $73~\\mathrm{mL}~\\mathrm{h}^{-1}$ in advance (see Figure S9). When the temperature of the inlet hot water was $36.5^{\\circ}\\mathrm{C}$ and $54.5^{\\circ}\\mathrm{C}$ , the corresponding voltages generated by the MEMS-TEG were $0.4\\mathrm{mV}$ (maximum power output of density $6\\mathrm{Wm}^{-3}$ ) and $3\\mathrm{mV}$ (maximum power output of density $349\\mathrm{Wm}^{-3}$ ), respectively. This shows that the higher the average temperature in the MOST reaction chamber, the greater the power output density can be reached. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,846,355,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Power generation from NBD and AZO ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,861,626,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the physical properties of NBD and AZO couples, two heat-to-power generation device concepts were put forth (see Figure 5A). For the NBD system, a saturated solution of QC in toluene was prepared in Gothenburg, Sweden, using a photochemical flow reactor (see Note S8 and Figure S10 for details) and shipped to Shanghai, China. For this experiment, $5\\mathrm{mg}$ of CoPc@C was loaded inside the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[93,62,122,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[126,63,232,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[124,84,230,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[724,53,815,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[725,67,903,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[828,86,903,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[91,964,102,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,962,421,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[89,129,627,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"catalytic reactor (inside the central copper tube), where a thermally conductive pad was used to fill the gap between copper plates in the device (see Figure 5B). The reactor was placed above the MEMS-TEG chip, and the whole setup was then placed on top of an aluminum brick heat sink, which ensured a stable ambient temperature and served as the cold side of the device. Importantly, the hot side of the system was covered with thermally insulated plastic foam to ensure that the heat generated was reflected instead of being lost to the environment. As a result, with less than $1\\mathrm{mL}$ of a $0.78\\mathrm{M}$ solution and a flow speed of $5\\mathrm{mL}\\mathrm{h}^{-1}$ , a measured bias voltage of up to $0.18\\mathrm{mV}$ was recorded. According to the MEMS-TEG chip characterization, this voltage can generate a maximum power output of $\\approx 0.1$ nW (power output density of $1.3\\mathrm{Wm}^{-3}$ , see Figure 5C). With the same flow speed, a continuous operating test with slightly lower concentration of $0.62\\mathrm{M}$ in toluene was also performed. This successfully generated, for the first time, a total electric energy of up to $0.44\\mathrm{W}\\mathrm{h}\\cdot \\mathrm{m}^{-3}$ over $24\\mathrm{min}$ (see Note S9 and Figure S11). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,356,627,586]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the case of AZO, a smaller amount of material was used; 7 mg of cis-AZO, generated from a 365 nm LED light source, was loaded onto the thermally conductive pad. A polyethylene terephthalate (PET) film was gently pressed on top of the material to allow it to fully cover the surface of the MEMS-TEG chip evenly. Laser irradiation at 532 nm triggered the back conversion (see Figure 5D), leading to a bias output voltage of up to $0.13\\mathrm{mV}$ . This corresponds to a maximum power output of 0.06 nW (power output density of $0.7\\mathrm{Wm}^{-3}$ ) (see Note S10 and Figures S12-S15 for details). Interestingly, various peaks were observed when the voltage approached the maximum. This was likely due to the complex release of heat, which involved both photoisomerization and phase transitions (see Figure 5E). We observed that less power is generated from cis-AZO than from QC, although the former reached a higher surface temperature, but the temperature distribution in the latter tube is more even. Not surprisingly, this is because the amount of heat released from these two systems is markedly different: 1 mL of 0.78 M QC could produce 72.5 J, while 7 mg of cis-AZO could produce only 2.3 J of energy. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,601,627,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Here, we noticed that the maximum temperatures reached by the NBD couple and the AZO couple are $37^{\\circ}\\mathrm{C}$ and $52^{\\circ}\\mathrm{C}$ , respectively, while the corresponding voltages generated by MEMS-TEG are 0.18 and $0.13\\mathrm{mV}$ , respectively. However, compared with the hot water with similar temperature, the maximum power output density generated by the NBD couple and the AZO couple is greatly reduced. It is worth noting that the hot water flowing continuously and rapidly in the copper reactor has a better thermal contact surface with the pipe wall than the discharging QC solution and cis-AZO film. Consequently, the hot water flowing at a temperature of $36.5^{\\circ}\\mathrm{C}$ makes the power density generated by MEMS-TEG nearly 5 times that of the QC solution with similar temperature $(37^{\\circ}\\mathrm{C})$ . This demonstrates that, with the MOST materials at hand, better thermal management and TE materials may increase the power output of the next generation of devices. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,800,627,938]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To the best of our knowledge, these results show the first proof of principle that solution-based MOST and PCM-MOST systems can generate electric power. Future work should focus on red shifting the absorption band (capturing more sunlight) and increasing the temperature gradient produced by the back reaction (improving energy density). The next generation of combined devices should include a better thermal management system to avoid heat dissipation from the MOST system to the surrounding environment, thereby increasing the amount of heat energy converted to electrical power output. Based on the TE film preparation method,[60] the TE efficiency can be simulated to be over $8\\%$ at room temperature $(ZT_{ave} = 2.4)$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,53,272,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,62,906,98]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[574,962,870,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[893,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[89,127,626,264]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and around $29\\%$ between 0 and $100\\mathrm{K}$ ( $ZT_{ave} = 1.0$ ) with a temperature difference of $100^{\\circ}\\mathrm{C}$ (see Note S11 and Figure S16 for details), assuming that MOST systems can achieve this absolute temperature of $100^{\\circ}\\mathrm{C}$ , which is close to what has recently been demonstrated.[21] Producing a highly soluble photoswitch of ca. $1.5\\mathrm{M}$ , accompanied by a heat release of $100\\mathrm{kJ mol}^{-1}$ with a $5\\mathrm{mL h}^{-1}$ flow speed, would allow the system to produce a power output of $16.7\\mathrm{mW}$ ( $0.2\\mathrm{GW m}^{-3}$ ) at room temperature and $60.4\\mathrm{mW}$ ( $0.7\\mathrm{GW m}^{-3}$ ) at temperatures of $0 - 100\\mathrm{K}$ . This would be enough to power a low-power-supplied Internet of Things device on Earth or in the outer space environment.[61] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,281,627,554]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this work, we have shown two molecular photoswitches in different physical forms (liquid-based NBD and neat AZO film) for coupling MOST systems with electrical power generation via MEMS-TEG devices. The liquid-based NBD exhibits a solar energy storage efficiency of $\\approx 0.5\\%$ in $0.5\\mathrm{mM}$ toluene, which is more efficient than photosynthesis $(0.1\\% -0.3\\%)$ .62 NBD was also, for the first time, tested through 54 charge and discharge cycles in a continuously operating energy storage and catalyzed release cycle, and showed no sign of degradation. Alternatively, the PCM-MOST hybrid neat AZO film captures and releases energy in photochemical solid-liquid transitions, which allows the MOST system to harness energy both from sunlight and from the ambient environment, meaning that upgraded heat can be produced on demand. Comparing the two candidates, both of them can store solar energy in the visible range for over a month at room temperature. To improve the macroscopic heat-release capability, future investigation of increasing the solubility of liquid-based NBD is necessary. For neat AZO, with addition phase-change properties, the overall energy storage capacity has been greatly improved. However, due to the light-induced back-conversion property of AZO, for future real-world-conditions device design, it is necessary to add a band-pass filter that is able to filter out the photons that initiate back conversion of AZO. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,571,627,754]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To demonstrate generation of power from the MOST system, an ultrathin-film-based, highly sensitive MEMS-TEG device was used to capture the heat released from either scenario. For the first time, electricity was produced in this setup, with power output up to $0.1\\mathrm{nW}$ (power output per unit volume up to $1.3\\mathrm{Wm}^{-3}$ ). Furthermore, this device continuously generated electricity, for the first time, for over 25 min. We note that this is a very compact and local solar energy storage-power generation system that operates through a mechanism entirely different from traditional PV-battery storage combinations. Furthermore, these systems can be charged and discharged across different geographic locations (Sweden to China in this work) over a few months, showing that solar energy can be stored for power generation on demand. Although the efficiency of these systems needs to be improved, we envision that they can be used in local power generation applications in the future. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,769,328,783]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"EXPERIMENTAL PROCEDURES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,787,235,801]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Resource availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[91,801,181,814]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lead contact ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,815,624,846]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Further information and requests for resources and procedures should be directed to the lead contact, Prof. Kasper Moth-Poulsen (kasper.moth-poulsen@chalmers.se). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,861,227,875]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Materials availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,875,626,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"NBD and AZO were synthesized by following the existing procedure in the literature. $^{38,46}$ All QC samples were prepared by irradiating an NBD solution with a $340\\mathrm{nm}$ LED light source from Thorlabs. The conversion percentage was checked by either a $^1\\mathrm{H}$ NMR 400 MHz instrument or a Cary 60 UV-vis spectrophotometer. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[93,62,122,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[126,63,232,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[124,85,230,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[724,53,815,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[725,67,903,85]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Physical Science ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[828,86,903,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[93,964,109,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,962,423,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[89,127,627,267]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CoPc@C catalyst was produced by following the existing procedure. $^3$ The cis-AZO state was prepared using a $365~\\mathrm{nm}$ LED light source. For photoinduced back conversion, a $532~\\mathrm{nm}$ laser ( $110~\\mathrm{mW~cm}^{-2}$ , the beam diameter of $1.3~\\mathrm{cm}$ ) was used to prepare the trans-AZO state by irradiating the cis-AZO sample. All solution-based spectroscopic measurements were performed in a cuvette with path length of $1~\\mathrm{cm}$ on a Cary 100 UV-vis spectrophotometer, scanning the wavelength from 750 to $290~\\mathrm{nm}$ . Absorption spectra for the outdoor test were recorded by two microflow cells and a portable spectrometer, which was purchased from Avantes. Teflon plastic tubing used was from Cole-Parmer Instrument Company. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,280,260,294]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data and code availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,294,626,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All of the data supporting the findings are presented within the article and supplemental information. All other data are available from the lead contact upon reasonable request. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,360,340,375]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUPPLEMENTAL INFORMATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,379,626,409]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplemental information can be found online at https://doi.org/10.1016/j.xcrp.2022.100789. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,430,270,443]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,448,627,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was supported by the K. & A. Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council Formas, the Swedish Energy Agency, the European Research Council (ERC) under grant agreement CoG, PHOTHERM - 101002131, the Catalan Institute of Advanced Studies (ICREA), and the European Union's Horizon 2020 Framework Programme under grant agreement no. 951801. The MEMS-TEG chip manufacture and experimentation were supported by the National Natural Science Foundation of China (grant 51776126). The authors would like to thank the Center for Advanced Electronic Materials and Devices (AEMD) and Instrumental Analysis Center of Shanghai Jiao Tong University (SJTU) and the startup fund of Shanghai Jiao Tong University. We thank Dr. Sarah Lerch and Prof. Ben Greatrex for reading and commenting on the manuscript. We acknowledge Neuroncollective.com and Daniel Spacek for the graphical abstract. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,650,299,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHOR CONTRIBUTIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[89,670,627,808]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Z. Wang performed all the material and MEMS-TEG chip characterizations, conversion tests, cycling tests, heat-release experiments, and power-generation demonstrations. Z. Wu carried out the MEMS-TEG chip fabrication, characterization, and TE efficiency simulation. E.M. and Z.Y.Z. performed the heat-release experiments and power-generation experiments. Y.L., X.F., and F.W. performed MEMS-TEG chip fabrication. J.O.H. performed the sample preparation with an automated flow system. M.J. and Z.Y.Z. synthesized the used compounds. Z. Wang, Z.H., T.L., and K.M.P. designed the experiments. All authors contributed to writing the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,827,323,841]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DECLARATION OF INTERESTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[91,846,380,861]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare no competing interests. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,875,290,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: November 15, 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[91,892,262,905]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Revised: January 26, 2022 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[91,907,275,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted: February 7, 2022 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[91,921,259,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published: March 2, 2022 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[89,53,272,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,62,906,98]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[574,962,870,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[888,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[91,127,196,141]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[94,150,353,930]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. 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Engl. 18, 652-662. https://doi.org/10.1002/anie.197906521. \"]","page_idx":"13","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[91,53,270,103]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science Article ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[765,63,905,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CellPress OPEN ACCESS ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[574,962,868,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell Reports Physical Science 3, 100789, March 16, 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[888,964,903,974]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[89,127,189,150]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,154,815,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Chip-scale solar thermal electrical power generation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,273,599,644]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0322/145aaa6dd11046ad69c64313d1ad8a4e3d25f4f38b03279af23f466b181543e8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,675,617,736]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Molecular solar thermal energy storage is a technology based on photoswitchable materials, which allow sunlight to be stored and released as chemical energy on demand. 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\"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Zhihang Wang, $^{1}$ Zhenhua Wu, $^{2}$ Zhiyu Hu, $^{2,*}$ Jessica Orrego-Hernández, $^{1}$ Erzhen Mu, $^{3}$ Zhao-Yang Zhang, $^{4}$ Martyn Jevric, $^{1}$ Yang Liu, $^{2}$ Xuecheng Fu, $^{5}$ Fengdan Wang, $^{5}$ Tao Li, $^{4,*}$ and Kasper Moth-Poulsen $^{1,6,7,8,*}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,310,181,324]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUMMARY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,328,627,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There is an urgent need for alternative compact technologies that can derive and store energy from the sun, especially the large amount of solar heat that is not effectively used for power generation. Here, we report a combination of solution- and neat-film-based molecular solar thermal (MOST) systems, where solar energy can be stored as chemical energy and released as heat, with microfabricated thermoelectric generators to produce electricity when solar radiation is not available. The photophysical properties of two MOST couples are characterized both in liquid with a catalytic cycling setup and in a phase-interconvertible neat film. Their suitable photophysical properties let us combine them individually with a microelectromechanical ultrathin thermoelectric chip to use the stored solar energy for electrical power generation. The generator can produce, as a proof of concept, a power output of up to $0.1\\\\mathrm{nW}$ (power output per unit volume up to $1.3\\\\mathrm{Wm}^{-3}$ ). Our results demonstrate that such a molecular thermal power generation system has a high potential to store and transfer solar power into electricity and is thus potentially independent of geographical restrictions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,627,220,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,647,627,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From the Industrial Revolution to 2018, the global average temperature increased by $1^{\\\\circ}\\\\mathrm{C}$ as a result of human activities and may hit $1.5^{\\\\circ}\\\\mathrm{C}$ as early as 2030, as warned by the United Nations Intergovernmental Panel on Climate Change (IPCC).<sup>1</sup> People have been actively looking for a technology that can slow down or reduce the rise in global temperature. As the global population increases, total worldwide energy use from all sectors is expected to reach 21 TWy by 2040, corresponding to an increase of $130\\\\%$ over 2019 levels.<sup>2</sup> Electricity is an essential commodity in modern society, and around 3 TW is currently used. To complicate matters, about $85\\\\%$ of this power is derived from fossil fuels.<sup>3</sup> Therefore, searching for new decarbonized energy sources to reduce greenhouse gas emissions is imminent. Nuclear energy is a low-carbon energy source, but its installations are complex, and their thermal pollution can potentially be serious. As the most common renewable energy at present, hydropower is geographically limited, while wind energy fluctuates with season or time.<sup>4</sup> It is noteworthy that solar energy is the most abundant energy resource on Earth, and maximizing the use of solar power can potentially meet the intensive demand for power while reducing detrimental effects to the environment.<sup>5</sup> For instance, an estimated $2.3 \\\\times 10^{4}$ TWy of solar power reaches Earth each year, which equates to only $7\\\\mathrm{~h}$ of sunlight needed to meet current annual global energy requirements.<sup>6,7</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,602,905,636]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Department of Chemistry and Chemical Engineering, Chalmers University of Technology, 41296 Gothenburg, Sweden \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,639,903,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{2}$ National Key Laboratory of Science and Technology on Micro-Nano Fabrication, Shanghai Jiao Tong University, Shanghai 200240, China \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,687,892,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{3}$ School of Materials Science and Engineering, Henan Polytechnic University, Jiaozuo 454003, Henan, China \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,723,901,769]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{4}$ Shanghai Key Laboratory of Electrical Insulation and Thermal Aging, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,772,897,806]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{5}$ Center for Advanced Electronic, Materials and Devices (AEMD) of Shanghai Jiao Tong University, Shanghai 200240, China \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,809,901,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{6}$ Institute of Materials Science of Barcelona, ICMAB-CSIC, 08193 Bellaterra, Barcelona, Spain \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,835,897,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{7}$ Catalan Institution for Research and Advanced Studies ICREA, Pg. Lluis Companys 23, Barcelona, Spain \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,872,725,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lead contact \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,887,888,918]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"*Correspondence: zhiyuhu@sjtu.edu.cn (Z.H.), litao1983@sjtu.edu.cn (T.L.), kasper.moth-poulsen@chalmers.se (K.M.-P.) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[647,924,872,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1016/j.xcrp.2022.100789 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,46,317,86]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,62,906,97]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[91,953,122,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[456,964,868,975]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 © 2022 The Author(s). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[343,975,868,985]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[893,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[89,127,626,387]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Photovoltaic (PV) cells can directly convert solar energy into electrical power with a maximum efficiency of around $30\\\\%$ , and most of the solar energy is not only lost as heat but also contributes to deteriorating the performance. $^{8-11}$ In addition, solar intensity naturally varies with time and geographical location and these variations currently limit the utilization of PV. Obviously, PV cells do not produce power during the night. Solar thermal power plants with phase-change molten salts can generate power for several hours after sunset; however, these plants require very large solar concentrators and consequently can be installed only in remote areas. $^{12,13}$ Previously, solar actuators based on hydrogen-bonded azopolymers for electricity generation have been investigated; however, the device cannot store solar energy for later on-demand power generation. $^{14}$ Hence, in addition to the above mainstream technologies, there is an urgent need for new alternative compact technologies that can derive and store energy from the sun, especially the large amount of solar heat that is not effectively used for future power generation. In this paper, we demonstrate a compact, chip-based device that allows for direct storage of solar energy as chemical energy that is released in the form of heat on demand and then converted into electrical energy in a controlled way. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,402,627,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To explore ways to store solar energy, we are investigating a class of materials that can capture sunlight via reversible photochemical reactions and later release this stored energy on demand. These materials operate in a closed cycle, and they use photochromic chemical compounds to form the basis of molecular solar thermal (MOST) energy storage systems. $^{15-18}$ Upon exposure to sunlight, a suitable MOST material (in the parent state) can photoisomerize to a high-energy metastable photoisomer that can be stored for extended periods of time. Depending on the photochrome used, the back-conversion reaction releasing heat energy can be triggered through different processes, including thermal, $^{19,20}$ catalytic, $^{21,22}$ electrocatalytic, $^{23,24}$ and photoinduced conversion. $^{25-27}$ It has been previously estimated that, for an ideal liquid MOST device, up to $21\\\\%$ of the solar energy can be stored as chemical energy for later heat production. $^{28}$ Such heat produced can be delivered locally and on demand, unlike other thermal storage technologies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,616,627,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"While MOST systems can be used in closed-cycle devices for efficient storage and release of heat, additional engineering is necessary to generate electrical power. Thermoelectric generators (TEGs) are able to directly convert thermal energy into electrical power via the Seebeck effect. TEGs have been widely used in various applications due to their attractive features such as silent operation, minimal maintenance, and long lifetime. And they have been considered as promising alternatives to meet the urgent demand for energy around the world.[29,30] Traditional solar thermal-to-electric power generation systems use heat engines to convert heat into electricity in two steps (heat to mechanical movements and then mechanical energy to electrical power generation).[31,32] However, a large amount of heat can be lost during the conversion process. To solve this issue, bulk TEGs have been combined with phase-change materials for power generation to convert heat to electricity directly.[31,33] Recently, low-dimensional material-based microelectromechanical system (MEMS) technology has enabled the production of ultrathin and highly sensitive TEG devices that can integrate large arrays of thermoelectric (TE) modules.[34] From our previous results, we explored a reliable and efficient hybrid method for ultrathin MEMS-TEG fabrication, and achieved up to 46,000 TE modules on a 3-in silicon wafer.[35,36] Such a MEMS-TEG equipped with an 800-nm-thin TE film has shown a steady electrical output, which was sensitive to small temperature differences and could effectively utilize low-grade thermal energy.[37] The temperatures accessible by the energy release reaction of the MOST are, at the current stage of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[93,62,122,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[126,63,230,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[124,85,230,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[724,53,815,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[725,67,903,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[828,86,903,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[91,965,102,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,962,421,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[166,130,554,239]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Scheme 1. Schematic illustration of the MOST to power generation concept \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0676/910baed1f553f4ac9febcc933b476a54cc4ca9ab62244bb2f0ae1aef8506dc5e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,295,626,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"development, less than $100^{\\\\circ}\\\\mathrm{C}$ , which is not high enough to be utilized for electrical power generation by traditional means. Therefore, it is necessary to match the MOST systems with high-efficiency and sensitive TE devices to effectively utilize this relatively low-grade thermal energy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,370,627,601]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Here, we design a compact, chip-based device that combines two different MOST systems operating either in the liquid or in the solid state with a novel designed MEMS-TEG to demonstrate the storage of solar energy to the release of heat energy and the cascading energy flow to the harvester that is finally used to generate power (see Scheme 1). Two molecular photoswitches with suitable properties—a norbornadiene derivative (NBD) investigated as a solution and a phase-interconvertible arylazopyrazole derivative (AZO) measured as a neat film—are selected for their potential to produce heat energy for electrical generation. The ultrathin MEMS-TEG with 572 TE modules is designed and fabricated, in which the TE films are only $1\\\\mu \\\\mathrm{m}$ thick. We characterize and couple each of these photoswitches individually with the MEMS-TEG chip (effective thermoelectricity area $10\\\\times 6\\\\mathrm{mm}$ ), demonstrating that chemical energy stored in MOST systems (in Sweden) can successfully generate electrical power (in China) through the process of solar energy storage, heat release, and TE conversion, thus affirming that solar energy can generate electrical power independent of time and geographical restrictions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,615,305,629]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS AND DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,632,313,645]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Solar energy storage properties \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,647,627,938]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MOST systems can function in both liquid and film forms, which can be tailored toward different applications.[21,38-45] In liquid form, MOST systems can transport stored energy, meaning that energy can be stored and released in two different locations, whereas in film form, MOST systems can be used in smart windows and other device integrations.[43,46] In this study, we selected and tested two systems: an NBD in liquid form (in toluene solution, which can provide a low specific-heat capacity of ca. $1.6\\\\mathrm{Jg}^{-1}\\\\cdot \\\\circ \\\\mathrm{C}^{-1}$ ) and a neat AZO in thin films with suitable energy capture and storage functionality. The molecular structures of both photoswitch couples are shown in Figure 1A. The photoconversion of NBD proceeds via a $[2 + 2\\\\pi ]$ cycloaddition reaction to its corresponding photoisomer quadricyclane derivative (QC). Thus, the energy storage density $\\\\Delta H_{\\\\mathrm{storage}}$ was experimentally determined to be $93\\\\mathrm{kJ mol}^{-1}(0.37\\\\mathrm{MJkg}^{-1})$ . Meanwhile, QC has a thermal back conversion half-life of 1 month at room temperature, demonstrating the possibility for long-term storage in toluene. Spectroscopically, we previously showed that norbornadiene with a push-pull system has a spectral red-shifting effect on the absorption.[21] Hence, this NBD with dimethoxy donor units exhibits an absorption feature around $340~\\\\mathrm{nm}$ with a maximum absorptivity of $\\\\varepsilon_{\\\\mathrm{max@340nm}} = 1.4\\\\times$ $10^{4}\\\\mathrm{M}^{-1}\\\\mathrm{cm}^{-1}$ . In contrast, the absorption profile of QC is virtually negligible above $300~\\\\mathrm{nm}$ , leaving a transparent optical window of around $85~\\\\mathrm{nm}$ between both forms due to the selected push-pull substituents (see Figure 1B). This significant spectral \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,53,272,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,62,906,98]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[574,962,870,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[893,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[191,130,506,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"A \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0295/245731ed9beb1c24c2d8a088fea23ce3b935e022454cb5d85043bfae9f7a7d87.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[101,223,360,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0693/37db155377a3b4085661e138d23898671fa06efbf217304aa2341dc1f5b70024.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[370,214,629,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0356/e4ddf2d2270d04dbf67ada0ad26dbd077fe6cb2702c86f4b45bc8a2bca4e7b1d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[116,308,355,455]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"B \\\",\\\"C \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0118/49e2401b2514c469e4bd6c662e68e25e50a38c536f0f44f2d110e67d3e801249.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[380,308,622,456]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Structures and absorption spectra of the two MOST candidates used in this work \\\"]\",\n \"image_footnote\": \"[\\\"(A) Molecular structures of NBD-QC couple (top) and trans/cis-AZO photoswitch couple (bottom). A thermal $(\\\\\\\\Delta)$ or catalytic (cat.) route can facilitate the back conversion of QC $\\\\\\\\rightarrow$ NBD. The back conversion of cis- $\\\\\\\\rightarrow$ trans-AZO can be achieved by a thermal or light-induced activation. (B) Absorption profile of NBD before and after irradiation with 340-nm light (in toluene). (C) Absorption profile of AZO photoswitch before and after irradiation with 365-nm light (in acetonitrile). \\\"]\",\n \"img_path\": \"images/0685/ed53ce697fa6a4645ad145e52ea3d09358c23818a35e5fd253b6eb99004c5af1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,571,626,631]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"difference enables near-quantitative photoconversion, even in concentrated solutions. In addition, the photoisomerization quantum yield was $68\\\\%$ in toluene. Considering the above-mentioned MOST properties, solar energy storage efficiency of the system could exceed $0.70\\\\%^{38}$ (see Note S1 for details). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,647,627,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Neat-film thermal storage devices have several attractive features, such as simple device integration and no need for mechanical pumping. Further, systems that combine energy input from solar irradiation with absorption of ambient heat have recently emerged. $^{46-55}$ Such systems couple a phase-change event to the photoconversion process found in MOST systems. One example is the AZO explored here (see Figure 1A). To take advantage of the exothermic process not only from the photoisomerization reaction but also from an additional phase-change process (liquid $\\\\rightarrow$ crystal), we investigated the AZO photoswitch in its neat form. The energy stored in cis-AZO was easily released by triggering heat release following irradiation with a 532-nm light source (this wavelength is considered cis-AZO's onset of absorption). As shown in Figure 1C, the absorption maximum of the trans isomer was $344\\\\mathrm{nm}$ with an absorptivity of $\\\\varepsilon_{\\\\max@340\\\\mathrm{nm}} = 2.9\\\\times 10^{4}\\\\mathrm{M}^{-1}\\\\mathrm{cm}^{-1}$ . The trans-AZO has a quantum yield of only $41\\\\%$ , but this is considered high for other azobenzene-based photoswitches. The photoisomerization energy density $\\\\Delta H_{\\\\mathrm{isom}}$ was $52\\\\mathrm{kJ mol}^{-1}$ ( $0.17\\\\mathrm{MJ kg}^{-1}$ ). In addition to heat release from the chemical reaction, the crystal-to-liquid transition ( $\\\\Delta H_{\\\\mathrm{phase\\\\_change}}$ ) can provide an additional $50\\\\mathrm{kJ mol}^{-1}$ ( $0.16\\\\mathrm{MJ kg}^{-1}$ ) of thermal energy because of its long alkenyl chain. As a result, the solar energy storage efficiency of the AZO couple was estimated to be $1.2\\\\%$ , which is much higher than that of other azobenzene photoswitches. $^{40}$ Moreover, cis-AZO is remarkably stable at room \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[93,62,122,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[126,63,232,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[124,84,230,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[724,53,815,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[725,67,903,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[828,86,903,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[91,964,102,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,962,423,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[147,129,488,249]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0362/0963d5d6a06fca553f38506a2117c93ffac2352ecfd6695eeedb79fa773c8636.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[149,249,473,367]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0936/cb606570b2a76bff573ad04ab4d7f997d41615e16d845d5051e6c3c2118b27e9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[504,129,843,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. Conversion performance, cycling performance, and experimental setup of NBD in the device \\\"]\",\n \"image_footnote\": \"[\\\"(A) Conversion percentage (in blue) and calculated energy storage efficiency (in red) of 0.1 M NBD in toluene as a function of residence time in the device. \\\",\\\"(B) Normalized absorbance before irradiation with $340\\\\\\\\mathrm{nm}$ LED light and after catalytic reactor. Blue dots show the normalized absorbance at $340\\\\\\\\mathrm{nm}$ , red dots show the normalized absorbance after irradiation. \\\",\\\"(C) Cycling test setup for NBD. Boxes 1 and 2 represent the flow UV-vis spectrometer before and after a catalytic reaction center. Box 3 refers to the microfluidic chip. The conversion process has proceeded with irradiation from a $340~\\\\\\\\mathrm{nm}$ LED lamp. \\\"]\",\n \"img_path\": \"images/0982/f520db9903e4cdd1e956aee83301e742f5dff5b810649ffc0fe039f8f8b498f8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,479,626,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"temperature, with a thermal half-life of 3 months at $25^{\\\\circ}\\\\mathrm{C}$ . Thus, using this photoswitch from a neat film would allow two different sources of stored energy to be used: thermal ambient energy and light.[46,47] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,540,626,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Photoconversion in the device under various exposure times and complete interconversion through multiple cycles are important tests for photoswitch viability in a MOST system. These experimental factors have previously been reported for $\\\\mathsf{AZO}^{46}$ but not for NBD. Therefore, additional experiments were necessary to determine the compatibility of the NBD photoswitch. A custom-made $400\\\\mathrm{-mm}^2$ microfluidic reactor was used for this photoconversion experiment (see Note S2 and Figure S1 for details). A solution of 0.1 M NBD ( $25\\\\mathrm{gL}^{-1}$ ) in toluene- $\\\\mathsf{d}_8$ was pumped through the microfluidic reactor with residence times from 34 to 343 s. The degree of photoconversion was monitored immediately afterward by ${}^{1}\\\\mathsf{H}$ NMR spectroscopy. For an ideal MOST system, where the absorption of the photoisomer (QC) does not compete with the absorption of the parent (NBD), the energy storage efficiency, $\\\\eta_{MOST}$ , should remain approximately unchanged prior to full conversion.[40,45,56] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,723,626,799]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Here, we observed a decrease in solar energy storage efficiency from $\\\\approx 0.5\\\\%$ at short residence times to $0.25\\\\%$ at full conversion. While not ideal, it is normal for efficiency to lower progressively during the conversion process. In this context, this system is better than our previous attempts at flow conversion (see Figure 2A and Note S3 for details).<sup>21</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,815,627,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Typically, for cyclability testing, solution-based photoswitches are irradiated at elevated temperatures.[21,45] However, this method seemed impractical as QC has a long half-life ( $t_{1/2} \\\\approx 29$ days) in toluene. To address this, an alternate protocol was employed, which hastened the time frame for each successive cycle. Cobalt(II) phthalocyanine is physisorbed on activated carbon (CoPc@C) and can rapidly facilitate the back reaction of a very similar quadricyclane structure.[21] This new setup involved converting and back converting an NBD solution (0.5 mM in toluene) continuously through a microfluidic photoreactor and a catalytic reactor in a closed \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,53,272,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[91,86,169,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,62,905,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[797,85,905,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[574,962,870,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[893,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[94,129,350,287]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0464/a3abf9df5f81e324006e63c6b1b6bc218257e16c0569cd45f32961035b71b7cd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[358,129,624,287]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Macroscopic heat-release performance of QC and cis-AZO under infrared camera \\\"]\",\n \"image_footnote\": \"[\\\"(A) Recorded temperature increment of QC heat release over time; inset shows the thermal image from the heat-releasing copper device. The area indicated by the dashed line represents the device position. \\\",\\\"(B) Recorded temperature increment of the cis-AZO system over time; inset shows the thermal image from the heat-releasing cis-AZO sample. The dashed line represents the position of the compound (maximum temperature gradient of $17^{\\\\\\\\circ}\\\\\\\\mathrm{C}$ after the heat generated from the laser is subtracted). \\\"]\",\n \"img_path\": \"images/0363/7297ca0b7db2cd7e67758bd453dcc95acb31047ee3e1e551ab636a086007269e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,419,626,465]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"cycle. Happily, no obvious drop in performance was observed after 54 charge and discharge cycles on the NBD couple (see Figures 2B and 2C and Note S4 for details). This setup drastically reduced the total experimental time to only $61\\\\mathrm{h}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,480,370,493]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Stored energy release for NBD and AZO \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,494,626,616]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Once solar energy is stored as QC and cis-AZO, one should be able to release the chemical energy from these metastable compounds as heat. However, we performed simulations to determine how much energy could be extracted from these charged materials. To achieve this, a simulation of possible temperature increases based on molecular parameters was performed. In the case of QC, the maximum temperature increase depended on the concentration of initial NBD in toluene. Based on the highest possible concentration of $0.78\\\\mathrm{M}$ in toluene, the maximum estimated temperature difference under adiabatic conditions was $40^{\\\\circ}\\\\mathrm{C}$ (see Note S5 and Figure S2 for details). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,632,627,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To test the experiment in practice, we designed a fixed-bed catalytic heat-release device consisting of a copper tube flanked on two sides with copper plates to maximize heat transfer to the MEMS-TEG device (see Note S6 and Figure S3 for details). By taking advantage of the mobile nature of the QC solution, a heterogeneous CoPc@C catalyst $^{21}$ was loaded inside the copper tube, and a thermally conductive pad was used to provide a homogeneous thermal distribution from the tube to all areas of the device. A saturated NBD solution was initially photoconverted to QC and then pumped through the reactor at a flow speed of $5 \\\\, \\\\text{mL} \\\\, \\\\text{h}^{-1}$ . This speed leads to complete back conversion from QC to NBD and a maximum surface temperature of $37^{\\\\circ}\\\\text{C}$ ( $\\\\approx 13^{\\\\circ}\\\\text{C}$ maximum temperature gradient, see Figure 3A and Video S1 for details). A thermal camera recorded liquid-QC macroscopic heat release, determined by the camera focusing on the top of the device. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,831,627,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Concerning the trans/cis-AZO photoswitch couple, the charged cis isomer releases $0.17\\\\mathrm{MJkg}^{-1}$ , equating to a simulated thermal difference of $84^{\\\\circ}\\\\mathrm{C}$ . From here, an additional $0.16\\\\mathrm{MJkg}^{-1}$ can be extracted at the crystallization point of the trans-AZO (melting point $83^{\\\\circ}\\\\mathrm{C}$ ) from the phase-change event. Thus, cis-AZO theoretically shows a larger potential thermal gradient than the QC solution. In this case, the experimental measurement of the heat release involved the placement of a droplet of liquid cis-AZO ( $\\\\approx 8\\\\mathrm{mg}$ ) under ambient conditions onto a glass substrate \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[93,62,122,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[126,63,230,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n 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\"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,962,421,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[91,129,229,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0694/bc1db50eb0529d800c7193e45861e2a2e0f750395ee36eef3180293918e0ecfc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[230,130,413,225]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0846/7091d06e9c3e9b93745b0ecdc7f03bad9773e5239f4f0171bda35a431a3000d9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[401,130,624,225]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0808/ec6b15741e33eaa2244cbde83042f976e31a203d1138937a13fab46c31ff79bc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[91,231,629,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Thermal performance of MEMS-TEG used in this work \\\"]\",\n \"image_footnote\": \"[\\\"(A) Optical microscope photo of MEMS-TEG with 572 TE modules. \\\",\\\"(B) Three-dimensional laser scanning confocal microscope images of the fabricated thermoelectric pairs. \\\",\\\"(C) Top view of the fabricated thermoelectric pairs by laser scanning confocal microscopy. Scale bar shows the relative height of the device. \\\",\\\"(D) Power generation of MEMS-TEG when hot water of different temperature flows through the copper tube at the hot end of the TEG. \\\"]\",\n \"img_path\": \"images/0844/7cc38602c82d3d6dee31e5dcf2837ba60aab2564ad484c376988bd3cef9aef7d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,511,626,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$(1 \\\\times 0.7 \\\\mathrm{~cm})$ . A $532 \\\\mathrm{~nm}$ laser was used to irradiate the sample and trigger the heat release in conjunction with a thermal camera. This triggered a full back conversion, affording a maximum surface temperature of $52^{\\\\circ} \\\\mathrm{C}$ , corresponding to a $17^{\\\\circ} \\\\mathrm{C}$ maximum temperature difference after accounting for heat from the laser. The large difference in temperature gradient between theoretical and experimental values is likely due to the strong heat dissipation from the thin film under ambient conditions (see Figure 3B and Video S2 for details). The thermal camera recorded the cis-AZO film macroscopic heat release. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,649,626,694]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"These results showed that both solution-based NBD and neat AZO photoswitches can successfully generate heat. Next, we wanted to use this thermal energy by converting it to electrical power using the MEMS-TEG device. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,709,493,722]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Single-layered microelectromechanical thermoelectric chip \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,723,627,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Theoretically, the figures of merit $(ZT_{ave})$ of low-dimensional TE materials are higher than those of bulk TE materials and can potentially yield a higher TE conversion efficiency.[57] Thin-film-based TE devices are also sensitive to small temperature differences.[35] Such technology can be used to monitor local thermal variations at micro-nano scales, such as bioactivity in yeast cultures.[58] On the other hand, if the number of integrated TE modules is high enough, the output electrical power can be significantly increased.[59] To effectively convert the heat released from MOST systems to electrical power, a large array integrated MEMS-TEG based on $\\\\mathrm{Bi}_{2}\\\\mathrm{Te}_{3}$ (n type) and $\\\\mathrm{Sb}_{2}\\\\mathrm{Te}_{3}$ (p type) TE modules was fabricated. The unit structure is designed in a $\\\\Pi$ shape, with a resistance of $72.8\\\\Omega$ and a single p/n surface area of $200\\\\times 200\\\\mu m$ . The fabrication process and structure diagram of the MEMS-TEG device are shown in Note S7, Figures S4-S9, and Table S1. In total, 572 TE modules were connected in series, where the height of each TE column was increased to $\\\\sim 1\\\\mu m$ with the aim of improving the TE performance at low temperature gradients, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,53,272,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[91,86,169,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,62,906,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[797,85,903,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[574,962,870,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[893,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[161,129,551,244]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0327/f609b59dd038d4a3d59ae3d3b913c2d4aec104752433f3c96b3fc1d3b499add6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[159,253,365,377]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0882/491cd7dbf8be70a608cfd36c6d22bf7c44d267b9d9063f3be50f28b60a0554c7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[370,253,554,379]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0508/6231efa326b5c4d06eea76444218c2d153f322c26b88629dde1d1e78a4ad048e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[161,378,367,492]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0273/1f8c34f4b71b65bb77311326ec97e8a7afce15ddd35703c5070ab0d40473d87c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[370,379,556,493]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. MOST to power generation performance \\\"]\",\n \"image_footnote\": \"[\\\"(A) Schematic concept of MOST to power generation. \\\",\\\"(B) NBD couple-based solar energy storage for power-generation experimental setup. \\\",\\\"(C) Heat release monitoring by thermocouple and voltage generated from MEMS-TEG chip over time. The inset is a photo of the device. Scale bar, 1 cm. \\\",\\\"(D) Schematic experimental setup of AZO film-based solar energy for power generation. \\\",\\\"(E) Net voltage generated from MEMS-TEG chip over time. The inset is a photo of the device. Scale bar, 1 cm. \\\"]\",\n \"img_path\": \"images/0466/5b04dea95874a3b42a0a8fce3d6b2c5617beaeb12e71ac25ddb5f38192e8da09.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,618,627,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"as shown in Figure 4. $^{37}$ Most importantly, the thickness of the whole working part from the chip did not exceed $2\\\\mu \\\\mathrm{m}$ . This ultrathin structure (thickness of top contact layer of only $\\\\sim 300$ nm and a mass of only a few picograms) responded effectively to small variations in temperature. The structure and properties of the TE materials constituting the MEMS-TEG and the power generation performance of the device are shown in Table S1 and Figures S5-S8. Since the heat released by QC in the copper tube does not cover all the tubes uniformly, as shown in Figure 3, a reference experiment was conducted to investigate the power generation of the MEMS-TEG by passing hot water into the copper tube at a flow speed of $73~\\\\mathrm{mL}~\\\\mathrm{h}^{-1}$ in advance (see Figure S9). When the temperature of the inlet hot water was $36.5^{\\\\circ}\\\\mathrm{C}$ and $54.5^{\\\\circ}\\\\mathrm{C}$ , the corresponding voltages generated by the MEMS-TEG were $0.4\\\\mathrm{mV}$ (maximum power output of density $6\\\\mathrm{Wm}^{-3}$ ) and $3\\\\mathrm{mV}$ (maximum power output of density $349\\\\mathrm{Wm}^{-3}$ ), respectively. This shows that the higher the average temperature in the MOST reaction chamber, the greater the power output density can be reached. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,846,355,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Power generation from NBD and AZO \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,861,626,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the physical properties of NBD and AZO couples, two heat-to-power generation device concepts were put forth (see Figure 5A). For the NBD system, a saturated solution of QC in toluene was prepared in Gothenburg, Sweden, using a photochemical flow reactor (see Note S8 and Figure S10 for details) and shipped to Shanghai, China. For this experiment, $5\\\\mathrm{mg}$ of CoPc@C was loaded inside the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[93,62,122,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[126,63,232,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[124,84,230,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[724,53,815,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[725,67,903,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[828,86,903,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[91,964,102,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,962,421,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[89,129,627,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"catalytic reactor (inside the central copper tube), where a thermally conductive pad was used to fill the gap between copper plates in the device (see Figure 5B). The reactor was placed above the MEMS-TEG chip, and the whole setup was then placed on top of an aluminum brick heat sink, which ensured a stable ambient temperature and served as the cold side of the device. Importantly, the hot side of the system was covered with thermally insulated plastic foam to ensure that the heat generated was reflected instead of being lost to the environment. As a result, with less than $1\\\\mathrm{mL}$ of a $0.78\\\\mathrm{M}$ solution and a flow speed of $5\\\\mathrm{mL}\\\\mathrm{h}^{-1}$ , a measured bias voltage of up to $0.18\\\\mathrm{mV}$ was recorded. According to the MEMS-TEG chip characterization, this voltage can generate a maximum power output of $\\\\approx 0.1$ nW (power output density of $1.3\\\\mathrm{Wm}^{-3}$ , see Figure 5C). With the same flow speed, a continuous operating test with slightly lower concentration of $0.62\\\\mathrm{M}$ in toluene was also performed. This successfully generated, for the first time, a total electric energy of up to $0.44\\\\mathrm{W}\\\\mathrm{h}\\\\cdot \\\\mathrm{m}^{-3}$ over $24\\\\mathrm{min}$ (see Note S9 and Figure S11). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,356,627,586]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the case of AZO, a smaller amount of material was used; 7 mg of cis-AZO, generated from a 365 nm LED light source, was loaded onto the thermally conductive pad. A polyethylene terephthalate (PET) film was gently pressed on top of the material to allow it to fully cover the surface of the MEMS-TEG chip evenly. Laser irradiation at 532 nm triggered the back conversion (see Figure 5D), leading to a bias output voltage of up to $0.13\\\\mathrm{mV}$ . This corresponds to a maximum power output of 0.06 nW (power output density of $0.7\\\\mathrm{Wm}^{-3}$ ) (see Note S10 and Figures S12-S15 for details). Interestingly, various peaks were observed when the voltage approached the maximum. This was likely due to the complex release of heat, which involved both photoisomerization and phase transitions (see Figure 5E). We observed that less power is generated from cis-AZO than from QC, although the former reached a higher surface temperature, but the temperature distribution in the latter tube is more even. Not surprisingly, this is because the amount of heat released from these two systems is markedly different: 1 mL of 0.78 M QC could produce 72.5 J, while 7 mg of cis-AZO could produce only 2.3 J of energy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,601,627,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Here, we noticed that the maximum temperatures reached by the NBD couple and the AZO couple are $37^{\\\\circ}\\\\mathrm{C}$ and $52^{\\\\circ}\\\\mathrm{C}$ , respectively, while the corresponding voltages generated by MEMS-TEG are 0.18 and $0.13\\\\mathrm{mV}$ , respectively. However, compared with the hot water with similar temperature, the maximum power output density generated by the NBD couple and the AZO couple is greatly reduced. It is worth noting that the hot water flowing continuously and rapidly in the copper reactor has a better thermal contact surface with the pipe wall than the discharging QC solution and cis-AZO film. Consequently, the hot water flowing at a temperature of $36.5^{\\\\circ}\\\\mathrm{C}$ makes the power density generated by MEMS-TEG nearly 5 times that of the QC solution with similar temperature $(37^{\\\\circ}\\\\mathrm{C})$ . This demonstrates that, with the MOST materials at hand, better thermal management and TE materials may increase the power output of the next generation of devices. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,800,627,938]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To the best of our knowledge, these results show the first proof of principle that solution-based MOST and PCM-MOST systems can generate electric power. Future work should focus on red shifting the absorption band (capturing more sunlight) and increasing the temperature gradient produced by the back reaction (improving energy density). The next generation of combined devices should include a better thermal management system to avoid heat dissipation from the MOST system to the surrounding environment, thereby increasing the amount of heat energy converted to electrical power output. Based on the TE film preparation method,[60] the TE efficiency can be simulated to be over $8\\\\%$ at room temperature $(ZT_{ave} = 2.4)$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,53,272,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,62,906,98]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[574,962,870,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[893,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[89,127,626,264]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and around $29\\\\%$ between 0 and $100\\\\mathrm{K}$ ( $ZT_{ave} = 1.0$ ) with a temperature difference of $100^{\\\\circ}\\\\mathrm{C}$ (see Note S11 and Figure S16 for details), assuming that MOST systems can achieve this absolute temperature of $100^{\\\\circ}\\\\mathrm{C}$ , which is close to what has recently been demonstrated.[21] Producing a highly soluble photoswitch of ca. $1.5\\\\mathrm{M}$ , accompanied by a heat release of $100\\\\mathrm{kJ mol}^{-1}$ with a $5\\\\mathrm{mL h}^{-1}$ flow speed, would allow the system to produce a power output of $16.7\\\\mathrm{mW}$ ( $0.2\\\\mathrm{GW m}^{-3}$ ) at room temperature and $60.4\\\\mathrm{mW}$ ( $0.7\\\\mathrm{GW m}^{-3}$ ) at temperatures of $0 - 100\\\\mathrm{K}$ . This would be enough to power a low-power-supplied Internet of Things device on Earth or in the outer space environment.[61] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,281,627,554]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this work, we have shown two molecular photoswitches in different physical forms (liquid-based NBD and neat AZO film) for coupling MOST systems with electrical power generation via MEMS-TEG devices. The liquid-based NBD exhibits a solar energy storage efficiency of $\\\\approx 0.5\\\\%$ in $0.5\\\\mathrm{mM}$ toluene, which is more efficient than photosynthesis $(0.1\\\\% -0.3\\\\%)$ .62 NBD was also, for the first time, tested through 54 charge and discharge cycles in a continuously operating energy storage and catalyzed release cycle, and showed no sign of degradation. Alternatively, the PCM-MOST hybrid neat AZO film captures and releases energy in photochemical solid-liquid transitions, which allows the MOST system to harness energy both from sunlight and from the ambient environment, meaning that upgraded heat can be produced on demand. Comparing the two candidates, both of them can store solar energy in the visible range for over a month at room temperature. To improve the macroscopic heat-release capability, future investigation of increasing the solubility of liquid-based NBD is necessary. For neat AZO, with addition phase-change properties, the overall energy storage capacity has been greatly improved. However, due to the light-induced back-conversion property of AZO, for future real-world-conditions device design, it is necessary to add a band-pass filter that is able to filter out the photons that initiate back conversion of AZO. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,571,627,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To demonstrate generation of power from the MOST system, an ultrathin-film-based, highly sensitive MEMS-TEG device was used to capture the heat released from either scenario. For the first time, electricity was produced in this setup, with power output up to $0.1\\\\mathrm{nW}$ (power output per unit volume up to $1.3\\\\mathrm{Wm}^{-3}$ ). Furthermore, this device continuously generated electricity, for the first time, for over 25 min. We note that this is a very compact and local solar energy storage-power generation system that operates through a mechanism entirely different from traditional PV-battery storage combinations. Furthermore, these systems can be charged and discharged across different geographic locations (Sweden to China in this work) over a few months, showing that solar energy can be stored for power generation on demand. Although the efficiency of these systems needs to be improved, we envision that they can be used in local power generation applications in the future. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,769,328,783]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"EXPERIMENTAL PROCEDURES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,787,235,801]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Resource availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,801,181,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lead contact \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,815,624,846]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Further information and requests for resources and procedures should be directed to the lead contact, Prof. Kasper Moth-Poulsen (kasper.moth-poulsen@chalmers.se). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,861,227,875]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Materials availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,875,626,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NBD and AZO were synthesized by following the existing procedure in the literature. $^{38,46}$ All QC samples were prepared by irradiating an NBD solution with a $340\\\\mathrm{nm}$ LED light source from Thorlabs. The conversion percentage was checked by either a $^1\\\\mathrm{H}$ NMR 400 MHz instrument or a Cary 60 UV-vis spectrophotometer. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[93,62,122,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[126,63,232,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[124,85,230,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[724,53,815,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[725,67,903,85]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Physical Science \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[828,86,903,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[93,964,109,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,962,423,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[89,127,627,267]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CoPc@C catalyst was produced by following the existing procedure. $^3$ The cis-AZO state was prepared using a $365~\\\\mathrm{nm}$ LED light source. For photoinduced back conversion, a $532~\\\\mathrm{nm}$ laser ( $110~\\\\mathrm{mW~cm}^{-2}$ , the beam diameter of $1.3~\\\\mathrm{cm}$ ) was used to prepare the trans-AZO state by irradiating the cis-AZO sample. All solution-based spectroscopic measurements were performed in a cuvette with path length of $1~\\\\mathrm{cm}$ on a Cary 100 UV-vis spectrophotometer, scanning the wavelength from 750 to $290~\\\\mathrm{nm}$ . Absorption spectra for the outdoor test were recorded by two microflow cells and a portable spectrometer, which was purchased from Avantes. Teflon plastic tubing used was from Cole-Parmer Instrument Company. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,280,260,294]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data and code availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,294,626,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All of the data supporting the findings are presented within the article and supplemental information. All other data are available from the lead contact upon reasonable request. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,360,340,375]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUPPLEMENTAL INFORMATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,379,626,409]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplemental information can be found online at https://doi.org/10.1016/j.xcrp.2022.100789. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,430,270,443]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,448,627,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was supported by the K. & A. Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council Formas, the Swedish Energy Agency, the European Research Council (ERC) under grant agreement CoG, PHOTHERM - 101002131, the Catalan Institute of Advanced Studies (ICREA), and the European Union's Horizon 2020 Framework Programme under grant agreement no. 951801. The MEMS-TEG chip manufacture and experimentation were supported by the National Natural Science Foundation of China (grant 51776126). The authors would like to thank the Center for Advanced Electronic Materials and Devices (AEMD) and Instrumental Analysis Center of Shanghai Jiao Tong University (SJTU) and the startup fund of Shanghai Jiao Tong University. We thank Dr. Sarah Lerch and Prof. Ben Greatrex for reading and commenting on the manuscript. We acknowledge Neuroncollective.com and Daniel Spacek for the graphical abstract. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,650,299,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHOR CONTRIBUTIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,670,627,808]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Z. Wang performed all the material and MEMS-TEG chip characterizations, conversion tests, cycling tests, heat-release experiments, and power-generation demonstrations. Z. Wu carried out the MEMS-TEG chip fabrication, characterization, and TE efficiency simulation. E.M. and Z.Y.Z. performed the heat-release experiments and power-generation experiments. Y.L., X.F., and F.W. performed MEMS-TEG chip fabrication. J.O.H. performed the sample preparation with an automated flow system. M.J. and Z.Y.Z. synthesized the used compounds. Z. Wang, Z.H., T.L., and K.M.P. designed the experiments. All authors contributed to writing the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,827,323,841]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DECLARATION OF INTERESTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,846,380,861]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare no competing interests. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,875,290,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: November 15, 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,892,262,905]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Revised: January 26, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,907,275,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted: February 7, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,921,259,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published: March 2, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[89,53,272,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,62,906,98]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[574,962,870,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[888,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[91,127,196,141]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,150,353,930]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Engl. 18, 652-662. https://doi.org/10.1002/anie.197906521. \\\"]\",\n \"page_idx\": \"13\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[91,53,270,103]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[765,63,905,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CellPress OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[574,962,868,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell Reports Physical Science 3, 100789, March 16, 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[888,964,903,974]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1016/j.xcrp.2022.100789"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Chemistry/Materials Science and Engineering"},"sha256":{"kind":"string","value":"156a6ca3157ff8be46337b4d70376116c1a12d9b190be73b8180defdfa7a3100"},"title":{"kind":"string","value":"Chip-scale solar thermal electrical power generation"}}},{"rowIdx":167,"cells":{"abstract":{"kind":"string","value":"\n \nA key open question in the study of layered superconducting nickelate films is the role that hydrogen incorporation into the lattice plays in the appearance of the superconducting state. Due to the challenges of stabilizing highly crystalline square planar nickelate films, films are prepared by the deposition of a more stable parent compound which is then transformed into the target phase via a topotactic reaction with a strongly reducing agent such as CaH$_2$. Recent studies, both experimental and theoretical, have introduced the possibility that the incorporation of hydrogen from the reducing agent into the nickelate lattice may be critical for the superconductivity. In this work, we use secondary ion mass spectrometry to examine superconducting La$_{1-x}$X$_x$NiO$_2$ / SrTiO$_3$ (X = Ca and Sr) and Nd$_6$Ni$_5$O$_{12}$ / NdGaO$_3$ films, along with non-superconducting NdNiO$_2$ / SrTiO$_3$ and (Nd,Sr)NiO$_2$ / SrTiO$_3$. We find no evidence for extensive hydrogen incorporation across a broad range of samples, including both superconducting and non-superconducting films. Theoretical calculations indicate that hydrogen incorporation is broadly energetically unfavorable in these systems, supporting our conclusion that hydrogen incorporation is not generally required to achieve a superconducting state in layered square-planar nickelates.\n "},"author":{"kind":"string","value":"Qi Song|Mythili Surendran|Alexander J. Grutter|A. Ariando|Harrison LaBollita|Julia A. Mundy|Lin Er Chow|Yu-Tsun Shao|Yang Zhang|Jayakanth Ravichandran|Lena F. Kourkoutis|Shin Muramoto|Purnima P. Balakrishnan|P. Quarterman|Dan Ferenc Segedin|Berit H. Goodge|Srimanta Middey|Ranjan K. Patel|Antia S. Botana|Grace A. Pan|Ismail El Baggari|Koushik Jagadish"},"content_list":{"kind":"list like","value":[{"bbox":"[138,87,854,122]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Hydrogen is not necessary for superconductivity in topotactically reduced nickelates ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[186,137,805,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Purnima P. Balakrishnan, $^{1, *}$ Dan Ferenc Segedin, $^{2}$ Lin Er Chow, $^{3}$ P. Quarterman, $^{1}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[186,154,810,167]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Shin Muramoto, $^{4}$ Mythili Surendran, $^{5,6}$ Ranjan K. Patel, $^{7}$ Harrison LaBollita, $^{8}$ Grace ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[171,169,823,185]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. Pan, $^{2}$ Qi Song, $^{2}$ Yang Zhang, $^{9}$ Ismail El Baggari, $^{9}$ Koushik Jagadish, $^{5}$ Yu-Tsun Shao, $^{5}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,185,808,200]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Berit H. Goodge, $^{10,11}$ Lena F. Kourkoutis, $^{10,11}$ Srimanta Midley, $^{7}$ Antia S. Botana, $^{8}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[160,200,834,215]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Jayakanth Ravichandran, $^{5,6,12}$ A. Ariando, $^{3}$ Julia A. Mundy, $^{2,\\dagger}$ and Alexander J. Grutter $^{1,\\ddagger}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[116,219,880,234]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"<sup>1</sup>NIST Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[245,234,750,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{2}$ Department of Physics, Harvard University, Cambridge, MA 02138, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[140,247,854,260]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{3}$ Department of Physics, Faculty of Science, National University of Singapore, Singapore 117551, Singapore ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[116,260,880,273]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{4}$ Material Measurement Laboratory, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[336,300,658,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Core Center for Excellence in Nano Imaging, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[279,313,718,325]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"University of Southern California, Los Angeles, CA 90089, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,325,764,339]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{7}$ Department of Physics, Indian Institute of Science, Bengaluru, 560012, India ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[243,339,754,352]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{8}$ Department of Physics, Arizona State University, Tempe, AZ 85287, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[207,352,787,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"<sup>9</sup>The Rowland Institute at Harvard, Harvard University, Cambridge, MA 02138, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[343,366,653,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{10}$ School of Applied and Engineering Physics, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[330,380,666,392]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cornell University, Ithaca, New York 14853, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[222,392,774,405]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{11}$ Kavli Institute at Cornell for Nanoscale Science, Ithaca, New York 14853, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,405,725,417]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{12}$ Ming Hsieh Department of Electrical and Computer Engineering, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[279,419,718,431]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"University of Southern California, Los Angeles, CA 90089, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[419,431,576,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Dated: March 5, 2024) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[166,452,826,638]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A key open question in the study of layered superconducting nickelate films is the role that hydrogen incorporation into the lattice plays in the appearance of the superconducting state. Due to the challenges of stabilizing highly crystalline square planar nickelate films, films are prepared by the deposition of a more stable parent compound which is then transformed into the target phase via a topotactic reaction with a strongly reducing agent such as $\\mathrm{CaH_2}$ . Recent studies, both experimental and theoretical, have introduced the possibility that the incorporation of hydrogen from the reducing agent into the nickelate lattice may be critical for the superconductivity. In this work, we use secondary ion mass spectrometry to examine superconducting $\\mathrm{La}_{1 - x}X_x\\mathrm{NiO}_2 / \\mathrm{SrTiO}_3$ ( $X = \\mathrm{Ca}$ and $\\mathrm{Sr}$ ) and $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12} / \\mathrm{NdGaO}_3$ films, along with non-superconducting $\\mathrm{NdNiO}_2 / \\mathrm{SrTiO}_3$ and $(\\mathrm{Nd},\\mathrm{Sr})\\mathrm{NiO}_2 / \\mathrm{SrTiO}_3$ . We find no evidence for extensive hydrogen incorporation across a broad range of samples, including both superconducting and non-superconducting films. Theoretical calculations indicate that hydrogen incorporation is broadly energetically unfavorable in these systems, supporting our conclusion that hydrogen incorporation is not generally required to achieve a superconducting state in layered square-planarNickelates. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,662,486,838]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Superconductivity in nickelates has been pursued ever since the discovery of the cuprates [1-5], but it was not until 2019 that it was demonstrated in thin films of the infinite-layer compound $\\mathrm{NdNiO_2}$ via hole doping with Sr [6]. This discovery introduced a novel family of layered nickelate superconductors that has now been extended to include the Pr- and La- analogs of the infinite-layer compound as well as the five-layer material $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ [7-10]. While superconducting nickelates exhibit many interesting phenomena [11-14], they also represent a unique materials synthesis challenge [15-19]. In gen ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,662,883,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"eral, layered square-planar nickelates cannot be synthesized directly, instead requiring a two-step fabrication method wherein an oxygen-rich precursor material is grown by traditional thin film deposition methods and then topotactically reduced, as illustrated in Fig. 1a,b. Typically, reduction is performed via a thermal anneal employing a chemical reducing agent and oxygen sink, such as $\\mathrm{H}_{2}$ , $\\mathrm{NaH}$ , or $\\mathrm{CaH}_{2}$ [6, 20-22]. One of the most pressing open questions is the degree to which the reduction process incorporates hydrogen into the nickelate film, and whether hydrogen is important in stabilizing superconductivity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,854,883,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A notable recent study by X. Ding et al. reported that hydrogen is critical for the emergence of superconductivity, requiring a stoichiometry around $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_2\\mathrm{H}_{0.25}$ [23]. However, in this study, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[22,210,60,775]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"arXiv:2403.01796v1 [cond-mat.supr-con] 4 Mar 2024 ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[114,872,321,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"* purnima.balakrishnan@nist.gov ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[117,885,276,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"† mundy@fas.harvard.edu ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[117,896,292,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\ddagger$ alexander.grutter@nist.gov ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[124,95,442,214]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0964/c824fb3f073bcef1e1dc56534c5d93b889a71028dabe64342ac7ff23899ad59b.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[464,95,826,277]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0270/5e3882ca9d7c7e02ad6675fb54a8042620266f68621a1313b75e71450bf3db12.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,215,444,474]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0463/45792427230e0cb9453e5a4bf751139f1504fa57730ba2e429b32c573b37cac0.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[464,287,870,470]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 1. Schematic crystal structures for precursor phase and reduced a. $n = \\\\infty$ and b. $n = 5$ layered square-planar nickelate compounds. c. Schematic of the ToF-SIMS measurement technique. d. SIMS spectra measured separately for positive and negative ions are analyzed by identifying peaks by mass to charge ratio $(m / z)$ and extracting integrated area. \"]","image_footnote":"[]","img_path":"images/0361/4ffd8dfefbec53b205e1ab3ba332dbebfb65aea1651d133e8fbe0c87a030a2ef.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,580,485,727]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the precursor films are hydrogen-rich, while hydrogen and oxygen stoichiometry are highly correlated through reduction. Furthermore, recent results using alternative reduction processes with no hydrogen source have cast doubt on the role of incorporated hydrogen on the electronic state [9, 21]. Theoretical investigations yield widely varying results, with conclusions ranging from hydrogen incorporation promoting [24], having no effect [25], or suppressing superconductivity altogether [26]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,737,486,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Given the differing conclusions in the literature, a comprehensive examination of the role of hydrogen incorporation in superconducting nickelates is urgently needed. To understand more broadly applicable trends rather than the specifics of one sample type or fabrication protocol, we used time-of-flight secondary ion mass spectrometry (ToF-SIMS) to study the relationship between hydrogen incorporation and superconductivity in a broad range of nickelate films grown and reduced by three different research groups. The films used in this study were grown via either molecular beam epitaxy (MBE) or ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,580,883,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"pulsed laser deposition (PLD), in a variety of geometries, and reduced with $\\mathrm{CaH_2}$ at different conditions. As the energetics of incorporating hydrogen may vary greatly depending on stoichiometry and structure [26], we compared multiple nickellate systems, including superconducting examples of $\\mathrm{La}_{1 - x}\\mathrm{Ca}_x\\mathrm{NiO}_2$ , $\\mathrm{La}_{1 - x}\\mathrm{Sr}_x\\mathrm{NiO}_2$ , and $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ . We also examined non-superconducting $\\mathrm{NdNiO_2}$ and $\\mathrm{Nd}_{1 - x}\\mathrm{Sr}_x\\mathrm{NiO}_2$ . We find no evidence that a large concentration of incorporated hydrogen is necessary to observe superconductivity. Instead, a wide range of films, superconducting and non-superconducting, exhibit $\\mathrm{H}^-$ intensities which are similar to the substrate background. Theoretical calculations support this picture, revealing that hydrogen incorporation is energetically unfavorable across all materials studied in this work. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,838,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As illustrated in Fig. 1c, ToF-SIMS is a destructive technique in which an ion beam sputters through the film, and ejected molecular ions are analyzed using a mass spectrometer to provide a depth-and element-resolved picture of the ejected species, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[109,90,486,207]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and thereby chemical composition. ToF-SIMS allows the isolation and identification of elemental $\\mathrm{H}^{\\pm}$ , and $\\mathrm{O}^{\\pm}$ as well as larger ejected molecules such as $\\mathrm{OH}^{\\pm}$ , $\\mathrm{O}_2^{\\pm}$ , and $\\mathrm{TiO}_2^{\\pm}$ , as shown in Fig. 1d. The change in molecular species intensity over time as the sample is sputtered results in a nanometer-resolved understanding of the chemical composition with depth. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,207,486,426]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However, the measured intensity depends significantly on the sputtering conditions, chemical environment, film composition, density, electronic state, and prevalence of structural defects. Absolute scaling of stoichiometry and depth therefore requires calibration standards with known stoichiometry and similar chemical environment to the films of interest. Since the defect levels and chemistry in superconducting nickelates evolves extensively during the reduction process, such standards are nearly impossible to obtain, and we instead adopt the convention of Ding et al., in which the hydrogen level observed in the $\\mathrm{SrTiO_3}$ or $\\mathrm{NdGaO_3}$ substrate is considered to be the \"background\" level representing minimal hydrogen [23]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,457,480,472]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. SUPERCONDUCTING $\\mathrm{La}_{1 - x}(\\mathrm{Sr},\\mathrm{Ca})_x\\mathrm{NiO}_2$ ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[109,491,486,895]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We first present results from two doped superconducting infinite-layer systems: $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ grown by pulsed laser deposition on $\\mathrm{SrTiO_3}$ substrates, as described in section VA1. The quality of representative samples has been previously demonstrated through x-ray diffraction (XRD), cross-sectional scanning transmission electron microscopy (STEM), and electron energy loss spectroscopy (EELS) analysis [27, 28]. To ensure depth-wise uniformity, the film thickness was limited to below $6\\mathrm{nm}$ . Fig. 2a shows the superconducting transitions for these samples, which have a residual resistivity ratio $\\approx 4.1$ , comparable to the highest reported values so far [18, 29]. After reduction, an amorphous $\\mathrm{SrTiO_3}$ cap is deposited to act as an oxidation barrier, with varying thickness due to the challenges associated with the room-temperature growth. Film and cap thicknesses were verified using x-ray reflectometry (XRR), shown in Fig. 2b, which reveals that the initial perovskite phase is uniform with the expected scattering length densities. After reduction, the sharp interfaces slight roughen, likely linked to the energetic deposition of the caps. While we focus on superconducting films, we also measured the as-grown perovskite and over-reduced (non-superconducting) films from the same growth, the details of which can be found in the supplemental information section VIE. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[129,896,483,911]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To understand the sensitivity of this experiment ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,90,883,454]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"to hydrogen, we first compare the overall hydrogen content of as-grown $\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and superconducting $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ samples in Fig. 2c. Here, we show the $\\mathrm{H^{-}}$ peak for both samples integrated across all sputtering times. The as-grown sample contains negligible hydrogen within either the film or substrate, indicating an extremely clean growth and handling process. The superconducting sample, in contrast, exhibits a clearly-resolved $\\mathrm{H^{-}}$ peak much larger than the measurement background. The additional hydrogen introduced into the reduced superconducting sample is easily detectable. We next compare the integrated peak intensity, indicated by the shaded region, over sputter time (depth). For this same pair of samples, Fig. 2d shows the $\\mathrm{H^{-}}$ intensity in just the $\\mathrm{SrTiO_3}$ substrate. Interestingly, while the substrate intensity of the as-grown sample is less than 40 counts per frame, the $\\mathrm{SrTiO_3}$ substrate associated with the superconducting $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ is an excellent match for the samples in Ding et al. [23], with approximately 200 counts per frame of $\\mathrm{H^{-}}$ . Thus we may be confident that the observed hydrogen levels in the substrates are above the instrumental detection limit and closely match previous observations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,457,883,734]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Having firmly established that the hydrogen levels reported previously in superconducting films are readily detectable with the instrument used in this study, we show SIMS data from superconducting $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ in Fig. 2e,f. Here the $\\mathrm{NiO_2}$ and $\\mathrm{TiO_2}$ intensities are normalized to their maximum values while the $\\mathrm{H^{-}}$ and $\\mathrm{OH^{-}}$ intensities are normalized to the steady-state value within the substrate, while alternative normalizations and raw counts are shown in the supplemental information section VIE. The film and substrate positions are indicated by the peak and dip in $\\mathrm{NiO_2^{-}}$ and $\\mathrm{TiO_2^{-}}$ intensities, respectively. The trends in $\\mathrm{H^{-}}$ and $\\mathrm{OH^{-}}$ intensities quite clearly disagree with prior reports: the superconducting $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ films do not exhibit the large 1 to 3 order of magnitude increases in $\\mathrm{H^{-}}$ or $\\mathrm{OH^{-}}$ signal which would be expected for extensive, multiplepercent hydrogen incorporation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,737,885,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Instead, apart from the quickly decaying signal associated with surface adsorbates, the $\\mathrm{H^{-}}$ and $\\mathrm{OH^{-}}$ signals within the $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ film are invariant within a factor of two of the signal within the substrate. Interestingly, the $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ sample, with a thicker amorphous $\\mathrm{SrTiO_3}$ cap (29 nm), exhibits higher $\\mathrm{H^{-}}$ intensity within the cap than within the nickelate film, concentrated near the interface. In the $\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ sample with a thinner $\\mathrm{SrTiO_3}$ cap (approximately 6 nm), $\\mathrm{H^{-}}$ is much lower in the nickelate film than either the $\\mathrm{SrTiO_3}$ substrate or the other superconducting film. We speculate ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,85,344,253]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0538/c91c178402c1b8171bc367f7cc211a8b475d8a1832c195a227a78d9f7e7166e4.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[346,85,826,253]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0444/584200cd1de3428e238f350a902ab06c584ec01bc4c6d3409ebca920d884814d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,263,442,431]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0435/9a3f38f729bde42ca2a7b06c5dad4f996e56ac2d5532fc1335be406fbab34ad5.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[467,263,823,431]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0685/a1a109f4617a02e7e3fd512f83e53398dd789925e716ceef97ec598b30cec511.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,441,452,609]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0741/dea0056a1fff5784442c174dda7d5921f9a98e81f0623d4497f90dd511d59851.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[465,441,883,609]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 2. a. Resistivity vs. temperature for the superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ samples, showing a clear transition and large RRR. b. XRR depth profiles of the as-grown and superconducting films, specifically the real component of the scattering length density (SLD). c. Intensity vs. mass to charge ratio near the $\\\\mathrm{H^{-}}$ peak for an as-grown $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ film, integrated over the entire measurement time. d. Raw intensity (counts) of the $\\\\mathrm{H^{-}}$ peak in the substrate region for the same as-grown $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ . e. SIMS depth profile of superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ . f. SIMS depth profile of superconducting $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ . \"]","image_footnote":"[]","img_path":"images/0325/f7d057b73cfb434c28a0a1236f316afcf72d238e5c273de9540782c0c34b7afa.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,743,486,830]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"that the $\\mathrm{SrTiO_3}$ cap may play a role in hydrogen capture or transport [30]. Most importantly, the coexistence of different low hydrogen concentrations with superconductivity definitively demonstrates that hydrogen doping is not required for superconductivity in the infinite-layer nickelates. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[540,744,849,758]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"II. SUPERCONDUCTING $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,780,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To test whether our findings are applicable more broadly within the square-planar nickelate family, beyond the infinite-layer structure, we examine the $n = 5$ member: superconducting $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ . This film consists of $23~\\mathrm{nm}$ $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ synthesized on $\\mathrm{NdGaO_3}$ (110) (see section V A 2 for details), with 10 nm titanium followed by $100~\\mathrm{nm}$ platinum patterned on the film surface as electrodes. Fig. 3a shows the zero-field superconducting transition of this sample ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,60,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[143,95,405,220]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0717/b9dd955c59fa310ac169877cd22f5869008f4a6cf5fac5afd09e20f2328c60a3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[143,232,401,367]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0098/507b37d77329d098c3e61a6a67a19e6228488749850f10543fc687f73bad7d9f.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[143,386,472,551]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 3. a. Temperature-dependent resistivity of reduced $\\\\mathrm{Nd_6Ni_5O_{12}}$ / $\\\\mathrm{NdGaO_3}$ showing a clear superconducting transition. Reproduced from Ref. [10]. b. STEM image of the reduced, superconducting $\\\\mathrm{Nd_6Ni_5O_{12}}$ film and $\\\\mathrm{NdGaO_3}$ substrate. c. SIMS depth profiles of superconducting $\\\\mathrm{Nd_6Ni_5O_{12}}$ . \"]","image_footnote":"[]","img_path":"images/0826/8bbcf3fd41d5a284bd69c5612e93570d7e2163da9fc7fe04e80b6d05444fda0e.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[111,691,486,763]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"from reference [10], with a residual resistivity ratio of 3.8. Further characterization of this sample can be found in Ref. [10]. Fig. 3(b) shows a representative STEM image of this sample, revealing the $n = 5$ square-planar structure. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[111,766,486,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 3c plots the SIMS depth profile of this superconducting sample. $\\mathrm{NiO}_2^-$ and $\\mathrm{GaO}_2^-$ peaks are normalized to their maximum values, and clearly identify the electrode, film, and substrate regions. As before, we obtain information regarding the hydrogen concentration by examining the relative intensity of the $\\mathrm{H}^-$ and $\\mathrm{OH}^-$ peaks in the film and substrate. An advantage of the relatively thick electrode is the removal of surface contaminant effects from the measurement. Both the $\\mathrm{H}^-$ and $\\mathrm{OH}^-$ intensities are low ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,90,882,220]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in the platinum and titanium, increase slowly in the $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ film, and further increase deeper into the $\\mathrm{NdGaO_3}$ substrate. Similar to the superconducting $\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ sample, we find that the hydrogen content appears to be highest in the substrate, although again the nickelate film and substrate intensities are very similar. Once again there is no evidence of an order of magnitude increase in hydrogen intensity in the film. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[527,253,864,268]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"III. NON-SUPERCONDUCTING FILMS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,287,882,474]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With little evidence of extensive hydrogen incorporation in high-quality superconducting samples, the question remains whether some structures or processes are more susceptible to hydrogen. We speculate that films with increased defect densities, whether due to growth conditions or from long or overly aggressive reduction treatments, may incorporate additional hydrogen as a defect compensation mechanism. These films do not exhibit superconductivity, but do provide a mechanism for understanding the extent to which hydrogen can be incorporated during reduction and whether it might inhibit the fabrication of superconducting films. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,476,883,635]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We first consider $17\\mathrm{nm}$ $\\mathrm{NdNiO_3}$ / $\\mathrm{SrTiO_3}$ (001) films grown by MBE and subjected to an incomplete reduction, at a lower temperature but for longer times compared to the optimized treatment for achieving high-quality $\\mathrm{NdNiO_2}$ . XRD scans shown in Fig. 4a indicate reduction towards the infinite-layer $\\mathrm{NdNiO_2}$ phase, but with a modest decrease in crystallinity. Electron microscopy measurements on an equivalent sister sample, shown in Fig. 4b, reveals the presence of defects and phase boundaries, as expected. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,636,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The film was cut in half before reduction, and both as-grown and reduced samples were measured using ToF-SIMS, yielding the intensity depth profiles in Figures 4c,d. As before, the NiO, $\\mathrm{NiO}_2$ , and $\\mathrm{TiO}_2$ peaks are normalized to their maximum value while the $\\mathrm{H}^{-}$ and $\\mathrm{OH}^{-}$ are normalized to the steady-state values in the substrate. The $\\mathrm{H}^{-}$ and $\\mathrm{OH}^{-}$ signals are slightly higher in the $\\mathrm{SrTiO_3}$ substrate than in the as-grown $\\mathrm{NdNiO_3}$ film. Upon reduction, $\\mathrm{H}^{-}$ and $\\mathrm{OH}^{-}$ increase at the surface of the films, and the lineshape of this increase only partially matches that of various peaks including $\\mathrm{C}_2^-$ and $\\mathrm{Ca^{+}}$ (see supplemental section VIC), indicating that they do not solely originate from surface adsorbates introduced during the reduction process. Near the substrate interface, which has previously been shown to be the highest-quality region of the film [17, 27], the $\\mathrm{H}^{-}$ intensity remains lower than in the $\\mathrm{SrTiO_3}$ substrate. Thus, while some insignificant hydrogen ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[133,106,553,299]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0738/52edf8fe3b5bd31b1b681e948d9446c1a73adc43bd142e60a58d83cc05e5d86a.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[571,104,843,304]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0826/1bb6b9708fb55b721a660d591ca480c1a2698cd6fd4c80c7f1a942fd39fd5982.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[133,316,459,539]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0523/df46246666b85149f21dde3f1bd47e4b2101e4f52ccd586e93049e1a30470909.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[460,316,844,539]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 4. a. XRD of as-grown and $\\\\mathrm{NdNiO_3}$ and reduced $\\\\mathrm{NdNiO_2}$ films showing partial reduction to the infinite-layer phase. b. STEM of an equivalent sister $\\\\mathrm{NdNiO_2}$ sample revealing extended defects concentrated near the surface. c. SIMS depth profile of the as-grown film $\\\\mathrm{NdNiO_3}$ film. d. SIMS depth profile of the $\\\\mathrm{NdNiO_2}$ film, reduced for an extended time of $6\\\\mathrm{h}$ at $290^{\\\\circ}\\\\mathrm{C}$ . SIMS shows increased hydrogen concentration at the surface even without full oxygen removal. \"]","image_footnote":"[]","img_path":"images/0602/abef16c0866a93c579a85cd4b0a5ebaa232b3b6ce77badd4f25b54fafccab9c8.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,647,485,691]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"content may be introduced during the reduction process, it seems to be limited near the surface of these uncapped films. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,694,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We next present our findings on non-superconducting infinite-layer films $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_2$ / $\\mathrm{SrTiO_3}$ films, which are appropriately doped to result in superconductivity, but which were reduced aggressively at high temperatures $(600^{\\circ}\\mathrm{C}$ compared to $\\sim 300^{\\circ}\\mathrm{C})$ ; this reduction is enough to significantly hydrogen-dope a similar perovskite material, $\\mathrm{BaZrO_3}$ [31]. Furthermore, a common practice is to cap perovskite nickelate films with $\\mathrm{SrTiO_3}$ prior to reduction to provide balanced strain for structural stability of the film throughout its entire thickness [6, 17]. We therefore compare samples with and without an $\\mathrm{SrTiO_3}$ capping layer grown in situ on the $10~\\mathrm{nm}$ $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_3$ before reduction. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,647,883,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"XRD measurements, shown in Figure 5a, reveal that the crystalline quality of both capped and uncapped films prior to reduction is lower, with broader, lower intensity film peaks. Importantly, while the (002) $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_3$ peak is sharp, the expected perovskite (001) film peak is suppressed; further higher-resolution measurements, shown in the Supplemental Fig. S11, resolve the presence of an unidentified potential RP phase. As before, the topotactic reduction process reduces the $c$ -axis lattice parameter, but the peak intensity drops dramatically. Transmission electron micrographs of these samples, such as that shown in Fig. 5b, reveal the segregation of the film into multiple crystalline phases and amorphous-like regions. Thus, the aggressive reduction of these films is non-uniform and disordered rather than controlled, resulting in increased mosaicity and a loss of crystalline qual ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,143,472,321]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0423/18cc79aa5696c44cb6c1961ffcae4d67754119aa927e59856b286f6e03857759.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[480,143,803,309]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0221/f8bcd156921e7c1a5eccacabadfec1b3e6a4eaec065495826fbfefd567e62f65.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[133,330,467,570]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0912/22aa8123c886fef7bfda9ac285b72a58b58bd936bddf60075bfc0cc924d622de.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[478,327,870,571]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 5. a. XRD on $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ films grown by PLD, with and without a $10\\\\mathrm{nm}$ $\\\\mathrm{SrTiO_3}$ cap, showing a weak film (001) peak both before and after reduction, indicating a low-crystallinity as-grown film. Reduction further lowers crystallinity. b. Atomic-resolution cross-sectional HAADF-STEM micrograph from the reduced $\\\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ film showing amorphous (marked as 1) and crystalline regions (marked as 2 and 3). The low-crystalline quality of the film after reduction is clearly visible and agrees with the XRD data. c. SIMS depth profile of the as-grown $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ film indicates a separate surface layer. d. SIMS depth profile of the reduced $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ film with a $\\\\mathrm{SrTiO_3}$ cap, showing non-negligible but small hydrogen incorporation at the $\\\\mathrm{SrTiO_3}$ cap / $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ interface. \"]","image_footnote":"[]","img_path":"images/0044/051d90b5c99542a6ce73a53377a468d888958fcc39d2f4e91b6a7e60f0c27974.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,729,485,787]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ity. This is corroborated by electronic transport, as discussed further in the supplemental information, which indicates that capped and uncapped films exhibit sharply different resistivities. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,795,485,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As shown in Fig. 5c, which plots SIMS measurements from the as-grown, uncapped $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NO}_3$ film, the initial transient region shows much higher yields of all ions which may indicate differences in crystallinity near the surface, potentially from the emergence of a polycrystalline scale layer in uncapped samples over time [18]. In the bulk region, the $\\mathrm{H}^{-}$ and $\\mathrm{OH}^{-}$ intensities are similar to the sub ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,731,558,742]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"strate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,752,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Despite the significant difference in crystalline quality and reduction conditions, the effects of reduction are startlingly similar to our other observations. Figure 5d shows the integrated peak intensities in the reduced $\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ bilayer. Once again, $\\mathrm{H^{-}}$ and $\\mathrm{OH^{-}}$ intensities are elevated at the film/cap interface - though over a broader spatial extent - with almost a $50\\%$ increase over the baseline in the substrate. Thus, while the $\\mathrm{SrTiO_3}$ cap appears to trap hydrogen, this enhancement is again far below the orders of magnitude which would ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[111,90,485,133]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"be expected for significant hydrogen incorporation, remaining within a factor of two of the substrate values. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[138,167,459,181]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IV. THEORETICAL CALCULATIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[111,200,485,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To further understand the lack of hydrogen incorporation in the nickelates analyzed above via SIMS (both superconducting and non-superconducting), density-functional theory (DFT)-based calculations were performed to explore the energetics of topotactic hydrogen in infinite-layer $R\\mathrm{NiO}_2$ ( $R =$ rare-earth, both doped and undoped) as well as in the quintuple-layer nickelate $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ . To investigate whether it is energetically favorable to intercalate hydrogen, we compute the hydrogen binding energy $(E_b)$ for the topotactic process as: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[120,375,485,391]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nE _ {b} = \\left\\{E \\left[ R \\mathrm {N i O} _ {2} \\right] + n \\times \\mu [ H ] - E \\left[ R \\mathrm {N i O} _ {2} \\mathrm {H} \\right] \\right\\} / n, \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[111,402,485,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $E[R\\mathrm{NiO}_2]$ and $E[R\\mathrm{NiO}_2\\mathrm{H}]$ are the total energies for the infinite-layer $R\\mathrm{NiO}_2$ and hydride-oxide $R\\mathrm{NiO}_2\\mathrm{H}$ compounds, $\\mu[H] = E[\\mathrm{H}_2]/2$ is the chemical potential of H, and $n$ are the number of H atoms in the (super)cell. Analogous expressions are used for $R_{0.75}(\\mathrm{Sr},\\mathrm{Ca})_{0.25}\\mathrm{NiO}_2$ and $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ . A positive (negative) $E_b$ indicates that the topotatic hydrogen intercalation is favorable (unfavorable). The calculated binding energies are summarized in Fig. 6. We find that the incorporation of H into $R\\mathrm{NiO}_2$ , $R_{0.75}(\\mathrm{Sr},\\mathrm{Ca})_{0.25}\\mathrm{NiO}_2$ , $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ is systematically unfavorable, in agreement with experiments. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[111,579,485,911]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In summary, we searched for hydrogen across a wide range of superconducting and nonsuperconducting nickelate films, with different cation and dopant chemistry, structures, growth methods, reduction conditions, and crystalline quality. Not only did we find no significant concentrations of hydrogen in superconducting films, we were also unable to use excessive reduction temperature or time to force significant amounts of hydrogen into these structures. These results are consistent with first-principles calculations which show that hydrogen incorporation is energetically unfavorable in both infinite-layer and layered square-planar compounds. At most, we observed increased concentrations by a factor of two from the trace amounts already present within the substrates. Furthermore, hydrogen, as hydride or hydroxide ions $\\mathrm{(H^{-}}$ and $\\mathrm{OH}^{-}$ ), was more likely to be found in $\\mathrm{SrTiO_3}$ caps or in the substrates than in the nickelate films themselves. This propensity for hydrogen to appear in higher concentrations in $\\mathrm{SrTiO_3}$ capping layers and $\\mathrm{SrTiO_3 / }$ nickelate interfaces is interesting in the context of recent work showing the important role such ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,90,700,239]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0007/479b1969db105765e61fdb112bc961a54d88fec154a9769819145e18448b89ab.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[511,244,684,353]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0027/70cf5d27249364229e0176968f7c2175fe4364d55211ca71685a6cbde1ad691f.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[511,358,759,489]","code_body":null,"code_caption":null,"image_caption":"[\"d \"]","image_footnote":"[]","img_path":"images/0267/318ec71358f331d140b8679cce11b1b346cd334e25ce7d262eddf38e4826b1d2.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[754,107,880,460]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 6. Topotatic-H energetics for superconducting nickelates. Crystal structures indicating the positions of topotatic-H used for (a) $(\\\\mathrm{La,Nd})\\\\mathrm{NiO}_2$ (b) $(\\\\mathrm{La,Nd})_{0.75}(\\\\mathrm{Sr},\\\\mathrm{Ca})_{0.25}\\\\mathrm{NiO}_2$ and (c) $\\\\mathrm{Nd_6Ni_5O_{12}}$ (d) Binding energies for superconducting layered nickalates, where a positive (negative) binding energy indicates favoring (disfavoring) H-intercalation. \"]","image_footnote":"[]","img_path":"images/0502/83ecebc02783511836632826e3a98833ce4468afbc16172ec8542d016f7b4619.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[506,650,882,679]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"capping layers can play in facilitating the reduction process [18]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,680,883,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It should be noted that our measurements generally reveal as-grown samples which are almost completely devoid of hydrogen prior to reduction. $\\mathrm{CaH_2}$ does appear to introduce hydrogen into the system, as evidenced by changes in both film and substrate levels in as-grown $\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and reduced $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ films, for example. However, topotactic reduction appears unable to introduce hydrogen into these nickelates at the levels near $25\\%$ previously cited as critical doping for superconductivity [23]. At such high levels of incorporated hydrogen, Ding et al. observed $\\mathrm{H^{-}}$ intensities approximately $40\\times$ to $60\\times$ the substrate concentration, and approaching a factor of $200\\times$ to $600\\times$ near the film surface. We find no evidence of such large relative $\\mathrm{H^{-}}$ intensities in the films studied in this work. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[109,90,486,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Therefore, although superconductivity is highly sensitive to reduction optimization, this is likely due to the crystalline quality and oxygen stoichiometry, and not hydrogen stoichiometry. Of course, this study does not demonstrate that superconductivity requires the absence of incorporated hydrogen. The results of Ding et al. clearly demonstrate that it is possible to realize the superconducting state in samples which contain significant hydrogen concentrations. This work instead indicates that many films appear resistant to hydrogen infiltration, and most importantly, superconductivity may be readily realized without it. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[160,313,437,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"V. EXPERIMENTAL METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[125,345,473,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. Sample Synthesis: Thin Film Deposition and Reduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[197,391,403,405]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. $L a_{1 - x}(C a,S r)_{x}N i O_{2}$ Films ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[109,424,486,583]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thin films, $\\sim 6\\mathrm{nm}$ thick, of the infinite-layer nickelates $\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ were grown on $\\mathrm{SrTiO_3}$ (001) substrates using pulsed laser deposition (PLD) and $\\mathrm{CaH_2}$ topotactic reduction under conditions as previously reported [27, 28]. Notably, reduction was performed using $0.1\\mathrm{g}$ of $\\mathrm{CaH_2}$ powder at $340^{\\circ}\\mathrm{C}$ to $360^{\\circ}\\mathrm{C}$ for $1\\mathrm{h}$ (2 h for overreduced samples). After reduction, samples were capped ex-situ, at room temperature, with amorphous $\\mathrm{SrTiO_3}$ to protect the surface from reoxidation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[181,618,418,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. $Nd_{6}Ni_{5}O_{12}$ and $NdNiO_{2}$ Films ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[109,650,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We use ozone-assisted molecular beam epitaxy (MBE) to synthesize the precursor $\\mathrm{NdNiO_3}$ / $\\mathrm{SrTiO_3}$ (001) and $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{16} / \\mathrm{NdGaO}_3$ (110) films in Fig. 4 and Fig. 3, respectively. To calibrate the nickel and neodymium elemental fluxes, we synthesize NiO on MgO (001) and $\\mathrm{Nd}_2\\mathrm{O}_3$ on yttria-stabilized zirconia (YSZ (111)), then measure the film thickness via x-ray reflectivity. Next, we synthesize $\\mathrm{NdNiO_3}$ / $\\mathrm{LaAlO_3}$ (001) and use the $c$ -axis lattice constant and film thickness to refine the Nd / Ni ratio and monolayer dose, respectively. Using the optimized neodymium and nickel shutter times from the synthesis of $\\mathrm{NdNiO_3}$ / $\\mathrm{LaAlO_3}$ , we synthesize the Ruddlesden-Popper nickelates via monolayer shuttering. Both $\\mathrm{NdNiO_3}$ and Ruddlesden-Popper nickelates are synthesized at a substrate temperature of $500^{\\circ}\\mathrm{C}$ to $600^{\\circ}\\mathrm{C}$ with $\\sim 1.0\\times 10^{-6}$ Torr distilled ozone (Heeg Vacuum Engineering). The MBE ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,88,700,186]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0299/b51e5ad03b283651bf44a0f89aa4c165bfb36a12ef3c7b1a0c50f6a9e8b69c65.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[705,88,897,186]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 7. RHEED image of the $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ (NSNO) films (a) with out and (b) with $\\\\mathrm{SrTiO_3}$ (STO) capping layer after cooling the samples to room temperature. \"]","image_footnote":"[]","img_path":"images/0231/75049f42e26ac6f1e63c9e29d7cfaf52ad6c76ef0c5da0af38d06699a40eef2b.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[506,268,880,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"synthesis conditions and calibration scheme are described in Refs. [10, 32]; similar techniques were also used in Refs. [33, 34]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,313,883,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The perovskite and Ruddlesden-Popper films are reduced to the square-planar phase via $\\mathrm{CaH_2}$ topotactic reduction. The following methods are similar to those used elsewhere [10, 35, 36]. First, the as-grown films are cut into identical pieces, and the pieces to be reduced are tightly wrapped in aluminum foil (All- Foils) to avoid direct contact between the film and $\\mathrm{CaH_2}$ . Each film is then placed in a borosilicate tube (Chemglass Life Sciences) with $\\sim 0.1\\mathrm{g}$ of $\\mathrm{CaH_2}$ pieces ( $>92\\%$ , Alfa Aesar). The borosilicate tube is pumped down to $< 0.5\\mathrm{mTorr}$ , sealed, and then heated for several hours at $\\sim 290^{\\circ}\\mathrm{C}$ in a convection oven (Heratherm, Thermo Fisher Scientific) with a $10^{\\circ}\\mathrm{Cmin}^{-1}$ heating rate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[609,546,785,559]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. $N d_{0.8} S r_{0.2} N i O_{3}$ Films ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,577,883,881]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polycrystalline targets of $\\mathrm{NdNiO_3}$ and $\\mathrm{Nd_{0.8}Sr_{0.2}NiO_3}$ were prepared by the liquid-mix technique [37, 38]. $10\\mathrm{nm}$ thick $\\mathrm{Nd_{0.8}Sr_{0.2}NiO_3}$ films were grown on (001) $\\mathrm{SrTiO_3}$ substrates using a Neocera PLD system equipped with an in-situ RHEED (Staub Instruments, Germany). The depositions were conducted using a KrF excimer laser operating at $2\\mathrm{Hz}$ with a fluence of $1.5\\mathrm{Jcm}^{-2}$ . During the deposition, a dynamic oxygen pressure of $150\\mathrm{mTorr}$ was maintained, and the substrate temperature was $735^{\\circ}\\mathrm{C}$ . The optional $10\\mathrm{nm}$ thick $\\mathrm{SrTiO_3}$ capping layer was grown at the same condition as the film. After the deposition, all samples were in-situ annealed at the deposition temperature in an oxygen atmosphere of $500\\mathrm{Torr}$ for $30\\mathrm{min}$ and subsequently cooled to room temperature at a rate of $15^{\\circ}\\mathrm{Cmin}^{-1}$ . The streaky RHEED pattern of specular (0 0) and off-specular (0 1), (0 -1) spots, recorded after cooling the samples to room temperature confirm the excellent surface morphology of the films (Figure 7). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,882,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The as-grown films were sealed in evacuated $(\\sim 1\\mathrm{mTorr})$ quartz ampoules with $0.1\\mathrm{g}$ $\\mathrm{CaH_2}$ pow ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[870,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[111,90,486,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"der (90-95%, Thermo Scientific Chemicals). The ampoules were then baked in a muffle furnace at $600^{\\circ}\\mathrm{C}$ for up to $10\\mathrm{h}$ . The temperature ramp rate was fixed at $10^{\\circ}\\mathrm{C}\\mathrm{min}^{-1}$ . Once the ampoules were opened, the reduced films were immediately rinsed in $n$ -butanol and isopropanol in an ultrasonic bath for $3\\mathrm{min}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[214,224,385,239]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. X-ray Diffraction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[111,257,486,330]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"X-ray diffraction (XRD) measurements were performed at room temperature before and after reduction by each group on commercially available x-ray diffractometers using $\\mathrm{CuK}\\alpha_{1}$ ( $\\lambda = 1.5406\\AA$ ) radiation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[200,363,398,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. X-ray Reflectometry ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[111,396,486,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"X-ray reflectometry (XRR) measurements were performed at ambient conditions in a horizontal configuration using a Rigaku SmartLab diffractometer. The incident beam was collimated using the parallel beam slit and an incident slit of $30\\mu \\mathrm{m}$ height to improve $Q$ -resolution. The Cu $\\mathrm{K}\\alpha_{1}$ wavelength $(\\lambda = 1.5406\\AA)$ was isolated by using a Ge- $(220)\\times 2$ monochromator. The scattered beam was further collimated by a $0.2\\mathrm{mm}$ receiving slit. The data were reduced using the reductus web-service [39] and fit to a slab model using Ref1D [40]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[143,588,454,617]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"D. Time-of-Flight Secondary Ion Mass Spectroscopy ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[111,633,486,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Time-of-flight SIMS was performed using an IONTOF IV (Münster, Germany) equipped with a $20\\mathrm{keV}\\mathrm{Ar}_{2600\\pm 1000}^{+}$ cluster source for sputtering, a $30\\mathrm{keV}\\mathrm{Bi}_3^+$ liquid metal ion source for analysis, and a time-of-flight mass analyzer. Depth profiling was performed in non-interlaced mode with 1 scan of analysis with a resolution of $(128\\times 128)$ pixels, 10 scans of sputtering, and at least $0.5\\mathrm{s}$ of charge compensation per cycle, where both the analysis and sputter rasters were kept inside a $(500\\times 500)\\mu \\mathrm{m}$ area. The corresponding ion doses were $1.9\\times 10^{9}$ ions/cm $^2$ (0.12 pA) for $\\mathrm{Bi}_3^+$ , and between $2.1\\times 10^{14}$ ions/cm $^2$ to $2.6\\times 10^{14}$ ions/cm $^2$ (5.1 nA to 6.4 nA) per cycle for the cluster source due to day-to-day fluctuations in the beam current. On especially insulating samples or substrates, a small drop of silver paint was used to electrically contact the sample surface to the sample holder for further charge compensation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,90,883,193]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For reliable detection of $\\mathrm{H}^-$ ions, contributions from residual gases were minimized by keeping the chamber pressure below $5\\times 10^{-7}\\mathrm{Pa}$ . Both negative and positive ions were analyzed at separate spots, and the signal rastered over multiple spots was averaged after normalizing for the highest intensity ion unique to the substrate $(\\mathrm{TiO}_2^-$ or $\\mathrm{GaO}_2^-)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,193,883,325]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Spectra were analyzed using SurfaceLab to perform mass calibrations, identify peaks with the appropriate compounds, and extract the total integrated peak intensity as a function of sputter time. As many molecular compounds can have similar mass, peak assignments were made carefully, considering factors such as mass offset, isotopic distribution, and similarity in profile shape to other known oxide and hydroxide species. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[599,356,794,371]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E. Electron Microscopy ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,388,883,491]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{Nd}_{6}\\mathrm{Ni}_{5}\\mathrm{O}_{12}$ cross-sectional STEM specimens were prepared by the standard focussed ion beam (FIB) lift-out process on a Thermo Fisher Scientific Helios G4 UX or FEI Helios 660 FIB. HAADF-STEM was performed on a probe-corrected Thermo Fisher Scientific Spectra 300 X-CFEG operating at $300\\mathrm{kV}$ with a 30 mrad convergence semi-angle. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,491,883,665]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The reduced $\\mathrm{NiNdO_2}$ cross-sectional scanning transmission electron microscope (STEM) specimens were prepared using focused ion beam (FIB) liftout and thinning. Samples were first thinned down using an accelerating voltage of $30\\mathrm{kV}$ with a decreasing current from $100\\mathrm{pA}$ to $40\\mathrm{pA}$ , and then with a fine polishing process using an accelerating voltage of $5\\mathrm{kV}$ and a current of $41\\mathrm{pA}$ . STEM-HAADF images were acquired using Thermo Fisher Scientific Titan Themis Z G3 operated at $200\\mathrm{kV}$ . The convergence angle was $18.9\\mathrm{mrad}$ and the collection angles ranged from $68\\mathrm{mrad}$ to $280\\mathrm{mrad}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,665,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The reduced $\\mathrm{SrTiO_3}$ -capped $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_3$ cross-sectional STEM specimens were prepared using a Thermo Fisher Scientific Helios G4 UXe PFIB Dual Beam system, using a standard lift-out procedure. The film surface was protected by depositing protective C and W layers to prevent damage to the film surface during ion beam milling. The foil was first thinned down to $\\sim 200\\mathrm{nm}$ using the $30\\mathrm{kV}$ ion-beam, and then with a final polishing process using a $5\\mathrm{kV}$ ion-beam. The high-resolution STEM-HAADF imaging was carried out using a Thermo Fisher Scientific Spectra 200 operated at $200\\mathrm{kV}$ , with a probe semi-convergence angle of $25\\mathrm{mrad}$ and current of $\\sim 20\\mathrm{pA}$ , and the collection angles ranged from $54\\mathrm{mrad}$ to $200\\mathrm{mrad}$ . The energy dispersive X-ray spectroscopy (EDS) chemical mapping was performed using the same instrument ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[864,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,90,486,122]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"utilizing the Bruker Dual-X X-ray detectors, using an electron beam current of $\\sim 100\\mathrm{pA}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[187,150,410,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"F. Computational methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,183,485,588]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Density-functional theory (DFT)-based calculations were performed to theoretically explore the energetics of topotactic hydrogen in the infinite-layer nickelate $R\\mathrm{NiO}_2$ ( $R = \\mathrm{La}$ , Nd, both doped and undoped) as well as in the quintuple-layer nickelate $\\mathrm{Nd}_{6}\\mathrm{Ni}_{5}\\mathrm{O}_{12}$ . For $R\\mathrm{NiO}_2\\mathrm{H}_{\\delta}$ , $R_{0.75}(\\mathrm{Sr},\\mathrm{Ca})_{0.25}\\mathrm{NiO}_2\\mathrm{H}_{\\delta}$ , and $\\mathrm{Nd}_{6}\\mathrm{Ni}_{5}\\mathrm{O}_{12}\\mathrm{H}_{\\delta}$ ( $\\delta = 0,1$ ) structural relaxations were performed using the VASP code [41-43] with the Perdew-Burke-Ernzerhof version of the generalized gradient approximation (GGA-PBE) [44]. For the infinite-layer materials ( $R\\mathrm{NiO}_2$ and $R_{0.75}(\\mathrm{Sr},\\mathrm{Ca})_{0.25}\\mathrm{NiO}_2$ ) up to a $2\\times 2\\times 2$ supercell was used to accommodate the appropriate H content and/or ( $\\mathrm{Sr},\\mathrm{Ca}$ ) doping level. GGA-PBE was chosen as it provides lattice constants in close agreement with experimental data, as shown in Supplementary Note H. A Γ-centered $13\\times 13\\times 15$ ( $9\\times 9\\times 11$ ) $k$ -mesh was used for the $1\\times 1\\times 1$ unit cells ( $2\\times 2\\times 2$ supercells) with a $0.05\\mathrm{eV}$ Gaussian smearing. For $\\mathrm{Nd}_{6}\\mathrm{Ni}_{5}\\mathrm{O}_{12}$ , a Γ-centered $9\\times 9\\times 9$ $k$ -mesh with a $0.05\\mathrm{eV}$ Gaussian smearing was used. The size of the plane-wave basis sets was set with a kinetic energy cut-off of $520\\mathrm{eV}$ . For $R = \\mathrm{Nd}$ , we have used a pseudopotential where the $\\mathrm{Nd}(4f)$ electrons are frozen in the core. To compute the chemical potential of hydrogen ( $\\mu [\\mathrm{H}]$ ), we optimized an $\\mathrm{H}_2$ dimer in $15^3\\mathring{\\mathrm{A}}^3$ box with energy cutoff set to $325\\mathrm{eV}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[179,618,419,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHOR CONTRIBUTIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[111,650,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PPB, S. Muramoto, and AJG performed and analyzed ToF-SIMS measurements. PPB, AJG, and PQ performed XRR and analyzed and interpreted all reflectometry data. LEC deposited and reduced $\\mathrm{La_{0.8}Sr_{0.2}NiO_3 / La_{0.8}Sr_{0.2}NiO_2}$ and $\\mathrm{La_{0.78}Ca_{0.22}NiO_3 / La_{0.78}Ca_{0.22}NiO_2}$ films, and performed electronic characterization. $\\mathrm{NdNiO_3}$ and $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ films were fabricated deposited by GAP, DFS, and QS, while GAP and DFS performed reduction and electronic characterization. TEM of $\\mathrm{Nd}_6\\mathrm{Ni}_5\\mathrm{O}_{12}$ and $\\mathrm{NdNiO_2}$ films were performed by BHG and YTS, respectively. $\\mathrm{Nd_{0.8}Sr_{0.2}NiO_3}$ films were deposited and initially characterized by RKP and S. Middey, reduced by MS, and imaged via TEM by KJ and YTS. HL and ASB performed theoretical calculations for all film compositions. The study was designed by AJG, PPB, PQ, DFS, JAM, AA, and JR. The paper was written by PPB and AJG ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,90,714,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"with input from all authors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[596,135,795,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,167,882,224]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We thank Kyuho Lee for insightful discussions. We also thank Kerry Sieben for x-ray assistance. We thank Hanjong Paik for supporting the growth of the $n = 5$ superconducting sample. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,224,883,340]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Certain commercial equipment, instruments, software, or materials are identified in this paper in order to specify the experimental procedure adequately. Such identifications are not intended to imply recommendation or endorsement by NIST, nor it is intended to imply that the materials or equipment identified are necessarily the best available for the purpose. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,340,883,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Research was performed in part at the NIST Center for Nanoscale Science and Technology. Electron microscopy was performed at the Cornell Center for Materials Research (CCMR) Shared Facilities, which are supported by the NSF MRSEC Program (No. DMR-1719875). B.H.G. and L.F.K acknowledge support from PARADIM and the Packard Foundation. S. Midney acknowledges MHRD, Government of India for financial support under the STARS research funding scheme (grant number: STARS/APR2019/PS/156/FS). PPB and PQ received funding from the NRC RAP. JAM, ASB, and HL acknowledge support from NSF grant no. DMR2323971. JR and MS acknowledge support from an ARO MURI program with award no. W911NF-21-1-0327, and the National Science Foundation of the United States under grant number DMR-2122071. Materials growth and electron microscopy were supported in part by the Platform for the Accelerated Realization, Analysis, and Discovery of Interface Materials (PARADIM) under NSF Cooperative Agreement no. DMR-2039380. KJ and YTS acknowledge support from USC Viterbi startup funding and the USC Research and Innovation Instrumentation Award. Electron microscopy data were acquired at the Core Center of Excellence in Nano Imaging at USC. LEC and AA acknowledge support from the Ministry of Education (MOE), Singapore, under its Tier-2 Academic Research Fund (AcRF), Grants No. MOET2EP50121-0018 and MOE-T2EP50123-0013. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[532,818,859,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"VI. SUPPLEMENTAL INFORMATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[609,849,782,864]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. Sample Summary ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,882,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table VIA lists details of all samples referenced in this paper, along with their fabrication details and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[862,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,90,354,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which figures they correspond to. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[138,138,460,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. Hydrogen Quantification using SIMS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[109,171,485,460]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although ToF-SIMS is very sensitive to mass and depth, extracting quantitative information (e.g., chemical stoichiometries) can be challenging due to so-called matrix effects where the chemical and electronic environment of the material (matrix) affects the ionization of the sputtered species. First, the choice of the sputtering beam can change the matrix. For example, the use of a $\\mathrm{Cs^{+}}$ sputter beam results in Cs implantation into the film, lowering the work function and dramatically increasing the yield of negative ions [45]. Because different ions can interact differently with the implanted Cs, the ion yield ratios can vary drastically. To minimize potential chemical interactions with the sample, we chose to use an $\\mathrm{Ar^{+}}$ noble gas cluster source for sputtering, which is also volatile and escapes to vacuum after bombardment. The type of analysis beam $(\\mathrm{Bi}_{3}^{+},\\mathrm{O}_{2}^{+},\\mathrm{Ga}^{+}$ etc.) also has an effect on ionization, and this needs to be specified when comparing quantitative results. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,462,486,665]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Second, quantification requires matrix-matched standards. Since even small impurities can affect ionization, standards need to be prepared with known ratios of chemical species and exist in a similar chemical environment to that of the films of interest [46]. Relative sensitivity factors can then be calculated to scale the integrated peak areas to atomic concentrations. We first attempt to quantify hydrogen content in our nickelate films by comparing to a mica standard, as used in Ding et al. [23]. The chemical formula for the mica (muscovite) crystals we used is $(\\mathrm{KF})_2(\\mathrm{Al}_2\\mathrm{O}_3)_3(\\mathrm{SiO}_2)_6(\\mathrm{H}_2\\mathrm{O})$ . Peak shapes as well as intensity measurements are shown in Fig. S1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[109,666,488,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To illustrate the importance of matrix-matched standards, we compare the levels of oxygen $(\\mathrm{O}^{-}$ and $\\mathrm{O}_2^-$ ) measured in the mica and in the SrTiO3 and NdGaO3 substrates prior to any film reduction. Although they have comparable oxygen number densities, we found that dissimilarities in the ionization efficiencies produced drastically different results (i.e., estimated stoichiometric ratios). A quick calculation revealed that the apparent oxygen concentration was significantly lower in the mica than in the SrTiO3 and NdGaO3 substrates, and this is due to the presence of different elements in the matrix. The same effect is observed for all elements of the periodic table, including H, which highlights the difficulty of quantification using SIMS. In addition, hydrogen is present in adventitious carbon contamination at surfaces and interfaces, and requires careful interpreta ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,90,679,106]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"tion of the profile data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,114,883,330]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Another complication is the effect of the reduction process on the chemical and physical properties of the film, which directly affects the sensitivity factor and the sputtering rate, respectively. A lower sputter rate means that fewer number of elements and molecules are being ejected at any given time, and even though the ionization efficiency may not have changed, the intensity appears to be lower. In our study, this apparent intensity of various molecular species within a single nickelate sample set varied dramatically as a function of reduction time and conditions, as discussed in further detail in Section VIE. This renders even samples cleaved from a single growth and reduced differently to not be quantitatively comparable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[537,409,857,436]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Disentangling Extrinsic and Intrinsic Hydrogen ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,462,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As mentioned earlier, SIMS can also detect surface adsorbates, and requires a way to distinguish hydrogen intrinsic to the sample from surface contamination. Surface adsorbates are often hydrocarbons, so we can compare carbon peaks such as $\\mathrm{C}_2^-$ , as well as other contaminant peaks, and see if hydrogen trends with these compounds. The rapid decay in signal at the surface is usually due to these hydrocarbons, and their contribution to the H and OH signals can be subtracted from those inside the film. We can further confidently attribute certain signals to measured hydrogen by isotope analysis. Metal oxides such as Ti will have the same ionization efficiency regardless of the isotope (e.g. $^{48}\\mathrm{TiO}_2$ vs. $^{49}\\mathrm{TiO}_2$ ). Species with isobaric interference, or those that overlap in mass, such as $^{49}\\mathrm{TiO}_2$ and $^{48}\\mathrm{TiO}_2\\mathrm{H}$ , can be distinguished by analyzing the natural isotopic distribution in the mass spectrum or profile shape, as shown in Fig. S3. In this figure, the less abundant $^{49}\\mathrm{TiO}_2^-$ has an overlapping mass with $^{48}\\mathrm{TiO}_2\\mathrm{H}^-$ at $m/z = 64.945$ that cannot be resolved. However, by constructing the depth profile and seeing their profile shapes, it is possible to identify which molecule the peak corresponds to. In this case, there is a contribution from the Ti hydroxide. Similarly for Ni oxides, comparison of the profiles show that $^{60}\\mathrm{NiO}_2^-$ is the likely assignment for this peak instead of the hydroxide. The sharp decay in peak intensity for $^{48}\\mathrm{TiO}_2\\mathrm{H}^-$ at the surface indicates that the Ti oxide of the $\\mathrm{SrTiO_3}$ cap has adsorbed some hydrogen, but that has not affected the nickelate film. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[864,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,87,934,324]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0444/0d1e18f445daadf149cc9942ef9b075cf7b1eb5c96258958b0a4f7a881594738.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":"<table><tr><td>Label</td><td>Material</td><td>Synthesis</td><td>Figures</td></tr><tr><td>As-grown (La,Ca)NiO3Superconducting (La,Ca)NiO2Over-reduced (La,Ca)NiO2</td><td>5.4 nm La0.78Ca0.22NiO3 / SrTiO329 nm SrTiO3 / 4 nm La0.78Ca0.22NiO2 / SrTiO33.2 nm SrTiO3 / 3.5 nm La0.78Ca0.22NiO2 / SrTiO3</td><td>VA1</td><td>2b,c,d, S52a,b,c,d,e,f, S5S5</td></tr><tr><td>As-grown (La,Sr)NiO3Superconducting (La,Sr)NiO2Over-reduced (La,Sr)NiO2</td><td>5.3 nm La0.8Sr0.2NiO3 / SrTiO36 nm SrTiO3 / 4.2 nm La0.8Sr0.2NiO2 / SrTiO331 nm SrTiO3 / 4.4 nm La0.8Sr0.2NiO2 / SrTiO3</td><td></td><td>2b, S62a,b,g,h, S3, S6</td></tr><tr><td>Superconducting Nd6Ni5O12</td><td>100 nm Pt / 10 nm Ti / 23 nm Nd6Ni5O12 / NdGaO3</td><td>VA2</td><td>1c, 3a,b,c,d, S7</td></tr><tr><td>As-grown NdNiO3Reduced NdNiO2</td><td>17.3 nm NdNiO3 / SrTiO317.3 nm NdNiO2 / SrTiO3</td><td>VA2</td><td>4a,c,d, S8, S104a,e,f, S2, S8, S10</td></tr><tr><td>Reduced NdNiO2</td><td>16 nm NdNiO2 / SrTiO3</td><td></td><td>4b</td></tr><tr><td>As-grown (Nd,Sr)NiO3</td><td>10 nm Nd0.8Sr0.2NiO3 / SrTiO3</td><td>VA3</td><td>5a,c,d, 7a, S9, S11</td></tr><tr><td>As-grown capped (Nd,Sr)NiO3</td><td>10 nm SrTiO3 / 10 nm Nd0.8Sr0.2NiO3 / SrTiO3</td><td></td><td>5a, 7b, S11</td></tr><tr><td>Reduced (Nd,Sr)NiO2</td><td>10 nm Nd0.8Sr0.2NiO2 / SrTiO3</td><td></td><td>5a, S11</td></tr><tr><td>Reduced capped (Nd,Sr)NiO2</td><td>10 nm SrTiO3 / 10 nm Nd0.8Sr0.2NiO2 / SrTiO3</td><td></td><td>5b,e,f, S9, S11, S12, S13</td></tr><tr><td>Mica</td><td>(KF)2(Al2O3)3(SiO2)6(H2O)</td><td>MTI Corp.</td><td>S1</td></tr></table>","table_caption":"[\"TABLE I. Table of samples and where they are referenced in this paper. Grouped samples are pieces split from the same deposited film. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[120,383,488,529]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0831/78536834c6697d77bc98e3ff5db7882f5130cd876eb5f1b2536c722363c54362.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[127,518,488,666]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0643/81bda40ae5e337f113263f0edeadcf0c6a2c7f799bf14e2941c163b5b4f459a9.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[498,385,867,667]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S1. a. SIMS showing the spectral peak shapes of $\\\\mathrm{H}^{\\\\pm}$ , $\\\\mathrm{O}^{\\\\pm}$ , $\\\\mathrm{OH}^{\\\\pm}$ , and $\\\\mathrm{O}_2^{\\\\pm}$ ions. The broad peaks centered around $m/z = 1.02$ and $m/z = 17.03$ are attributed to charging effects, and were not included for the construction of the depth profile. b. SIMS depth profiles showing the integrated peak intensities as a function of sputtered depth for both elemental and molecular ions from a mica substrate. \"]","image_footnote":"[]","img_path":"images/0075/2d0bb9985969646e94f7b0708a5855804b8a9861284ab859300d08cfc148d036.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[112,772,485,787]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"D. Previous detection of hydrogen using SIMS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[109,810,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to place our observations into context, it is helpful to consider previous studies which used the ToF-SIMS instrument employed in this study to examine oxide films with large degrees of hydrogen incorporation, such as humidity-treated $\\mathrm{GdO}_x\\mathrm{H}_y$ , $\\mathrm{LaMnO_3}$ membranes exposed to water, and $\\mathrm{CaH_2}$ -reduced $\\mathrm{BaZrO_3}$ [31, 47, 48]. In Fig. S4, we show re ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,772,883,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"produced $\\mathrm{H}^{-}$ intensity curves from a $\\mathrm{LaMnO}_3$ fre-standing membrane with incorporated water due to the dissolution of $\\mathrm{Sr}_3\\mathrm{Al}_2\\mathrm{O}_6$ during processing[48]. Also shown is a film of $\\mathrm{GdO}_x\\mathrm{H}_y$ which is very near the $\\mathrm{Gd(OH)}_3$ composition[47]. In these systems, we found enhancements of the $\\mathrm{H}^{+}$ , $\\mathrm{H}^{-}$ , and $\\mathrm{OH}^{-}$ intensities which were 1 to 3 orders of magnitude above the substrate background, and were able to establish the high hydrogen concentrations based on the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[862,59,882,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,99,473,270]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S2. Comparison of ToF-SIMS hydrogen signals in reduced non-superconducting $\\\\mathrm{NdNiO_2}$ with surface adsorbate signals. Intensities have been normalized to the surface value. The slower decay of hydrogen intensities indicate that some of the hydrogen signal is intrinsic to the sample. \"]","image_footnote":"[]","img_path":"images/0498/809ff979d881e1bfe2341ce861cfe4635e5ef452fd8549d46a35a2656aca0f0f.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[111,401,488,532]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"effects on the material properties. This prior experience provides reasonable upper and lower boundaries for expected effects and demonstrates our sensitivity to intrinsic hydrogen. Interestingly, the results from Ding et al. fell between these limits. We conclude therefore that hydrogen would readily have been detected in our measurements of layered square-planar nickelate samples if it were present at previously reported levels. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[153,560,444,574]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E. Extended SIMS Characterization ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[111,592,486,694]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For each sample, we have replotted SIMS depth profiles by scaling all intensities to an appropriate steady-state ion in the substrate to compare between sample types. Certain compounds with much higher $(\\mathrm{OH}^{-})$ or lower $(\\mathrm{H}^{-})$ intensities have been scaled for visualization clarity. These are shown in Figures S5, S6, S7, S8, and S9. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[111,694,486,867]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The layer interfaces are identified as halfway up the transitions of ions unique to each layer $(\\mathrm{TiO}_2^-)$ in the $\\mathrm{SrTiO_3}$ , $\\mathrm{NiO^{-}}$ in the nickelate film, $\\mathrm{GaO}_2^-$ in the $\\mathrm{NdGaO_3}$ , noting that heavier ions have broader depth profiles due to redeposition into the sputter crater. We also note that the sputter rate is faster for lower crystallinity layers, including amorphous $\\mathrm{SrTiO_3}$ caps, as well as lower-crystallinity reduced films. In fact, attempted measurements of the aggressively reduced $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_2$ without protection of the $\\mathrm{SrTiO_3}$ cap sputtered through the film so quickly that no depth profile could be obtained. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[111,867,486,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SIMS reveals dramatic differences between as-grown, superconducting, and non-superconducting reduced samples. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,118,852,364]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S3. Comparison of the isotopic distributions of Ti and Ni oxides in superconducting $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ . The less abundant isotopic oxides have an overlapping mass with the more abundant isotopic hydroxides. By scaling the depth profiles by the natural isotopic abundance, we can separate out these contributions. In this case, there is a contribution from the Ti hydroxide, but no evidence of Ni hydroxide. The sharp decay in peak intensity for $^{48}\\\\mathrm{TiO}_2\\\\mathrm{H}^-$ at the surface indicates that the Ti oxide of the $\\\\mathrm{SrTiO_3}$ cap has adsorbed some hydrogen, but that has not affected the nickelate film. \"]","image_footnote":"[]","img_path":"images/0981/a8b4376656dc614eafc335c0533bb9f596cb2b6eac547bb8a8ef93b70fd55a4c.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[594,551,802,702]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S4. Examples of previously measured and published SIMS depth profiles for the $\\\\mathrm{H}^{-}$ ion in the hydrogen containing oxides $\\\\mathrm{LaMnO}_3\\\\mathrm{H}_x$ and $\\\\mathrm{GdO}_x\\\\mathrm{H}_y$ [47, 48], normalized to 1 in the substrate. \"]","image_footnote":"[]","img_path":"images/0014/e151e45916b3e6d71891a1b01f5281172f0d021cedb04ed53efb53e70d1bab24.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[506,808,882,866]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"First, changes in $\\mathrm{O}_2^-$ intensity within the films can be seen after reduction, confirming preferential removal of oxygen from the nickelate layers using $\\mathrm{CaH}_2$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,867,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Next, the $\\mathrm{NiO^{-}}$ and $\\mathrm{NiO_2^-}$ intensities and their ratio vary dramatically between samples, even when originating from the same as-grown sample. In par ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[862,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,98,880,385]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S5. ToF-SIMS depth profiles for the as-grown, superconducting and over-reduced $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_{3\\\\rightarrow 2}}$ films, including those shown in 2. \"]","image_footnote":"[]","img_path":"images/0801/39e24ee80c4e861e0cd2a57bc0d996a69cac1986d0f32f6fbd328d2ad52a2ca9.jpg","list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[120,450,880,738]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S6. ToF-SIMS depth profiles for the as-grown and superconducting $\\\\mathrm{La}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_{3\\\\rightarrow 2}$ films including, those shown in 2. \"]","image_footnote":"[]","img_path":"images/0972/3610d08e345a595432eb6a034a48963e793e5d96a1e380660c140074c91d2eeb.jpg","list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[111,806,488,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ticular, though the intensities of these nickel oxides drops after reduction, they are not monotonic with reduction. In particular, we see that the $\\mathrm{TiO}_2$ -normalized intensities are an order of magnitude lower in the superconducting $\\mathrm{La}_{0.78}\\mathrm{Ca}_{0.22}\\mathrm{NiO}_2$ but increase again in the over-reduced film (Fig. S5). Furthermore, this effect is not seen in all samples ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,806,882,866]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Fig. S8). We conclude that the Ni valence and electronic state significantly affect the measured intensities of many ions [49, 50], making even quantitative sample-to-sample comparisons difficult. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,867,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, though we see no evidence for extensive hydrogen incorporation in any of these samples, the hydrogen signals which are measured are primarily ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[862,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,98,872,378]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S7. ToF-SIMS depth profile for the $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ film shown in 3. Intensities are normalized to the steady-state $\\\\mathrm{GaO}_2^-$ in the $\\\\mathrm{NdGaO_3}$ substrate. \"]","image_footnote":"[]","img_path":"images/0202/fdcc8296a45fcd2b24120ba244a8f8cbf877ae439318fe455d29d50f269f07b0.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[112,448,880,739]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S8. ToF-SIMS depth profiles for the $\\\\mathrm{NdNiO_3}$ and non-superconducting $\\\\mathrm{NdNiO_2}$ films shown in 4. Intensities are normalized to steady-state $\\\\mathrm{TiO_2^-}$ or $\\\\mathrm{Sr^{+}}$ in the $\\\\mathrm{SrTiO_3}$ substrate. \"]","image_footnote":"[]","img_path":"images/0854/f56fee29873a6d4294a4414a41972947b6929173bc39aa78b0faf287e2734f88.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[111,811,488,853]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"present as $\\mathrm{OH}^{-}$ , and secondarily $\\mathrm{H}^{-}$ . The $\\mathrm{H}^{+}$ peak is orders of magnitude smaller, and in many cases undetectable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[568,811,826,840]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"F. Electrical characterization of non-superconducting films ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,867,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. S10 shows resistance vs. temperature for the non-superconducting, undoped $\\mathrm{NdNiO_3 / SrTiO_3}$ shown in Fig. 4. These electrical transport mea ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[864,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[120,90,880,385]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S9. ToF-SIMS depth profiles for the $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ and $\\\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ shown in 5. Intensities are normalized to steady-state $\\\\mathrm{TiO}_2^-$ in the substrate. \"]","image_footnote":"[]","img_path":"images/0110/2dfba6098e4980b2e98ea3a273cf909cac6b7a8d0633171b5c51f699ea9c6ca4.jpg","list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[127,463,488,642]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S10. Two-point resistance measurements of as-grown and reduced $\\\\mathrm{NdNiO}_{3\\\\rightarrow 2}$ shown in Fig. 4. \"]","image_footnote":"[]","img_path":"images/0917/a5994f566079b6f5a9be8f9444a4fa082440de40f23e22ca14255abe0742fdb1.jpg","list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,722,486,881]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"surements were taken using a home-built electrical \"dipstick probe\" compatible with a helium dewar. Indium contacts were soldered on the four corners of each sample in a van der Pauw (VDP) configuration. AC transport measurements were taken at $17.777\\mathrm{Hz}$ using an SR-830 lock-in amplifier. The voltage and current were measured simultaneously to determine the resistance. Note that values shown are the measured resistance of a single VDP channel of these $5\\mathrm{mm} \\times 10\\mathrm{mm}$ samples, not sheet resistance or resistivity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[111,882,486,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The original as-grown film shows the hysteretic metal-insulator transition expected for a stoichi-","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,455,882,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"metric $\\mathrm{NdNiO_3}$ film, while the reduced infinite-layer film exhibits the metallic behavior expected for undoped $\\mathrm{NdNiO_2}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,500,883,643]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_2$ films were insulating enough that two-point resistances were measured only at room temperature. As-grown, without significant growth optimization, uncapped films started with resistances between $500\\mathrm{k}\\Omega$ to $700\\mathrm{k}\\Omega$ , while capped films started with resistances between $6\\mathrm{k}\\Omega$ to $8\\mathrm{k}\\Omega$ . After reduction, the resistance of uncapped films actually increased and was not measurable using a standard multimeter, while capped films had a lower resistance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[542,676,849,690]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"G. Further structural characterization ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,708,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure S11 shows complementary XRD measurements of the capped and uncapped $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_{3\\rightarrow 2}$ films taken using two configurations of a Rigaku SmartLab XRD. The top scans were measured in a high-intensity mode, using a parallel beam (PB) selection slit, and a parallel slit analyzer (PSA). Cu $\\mathrm{K}\\alpha$ lines were selected using a Ni filter. The lighter color scans were measured in a high-resolution mode, using a Ge $(220)\\times 2$ monochromator to select Cu $\\mathrm{K}\\alpha_{1}$ radiation on the incident side. The Diffracted Beam Monochromator assembly was installed on the receiving side containing a Ni filter, Ge $(400)\\times 2$ analyzer, and $0.5^{\\circ}$ PSA. While the high-resolution measurements allow ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[862,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[200,95,803,554]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S11. Full XRD scans of samples in Figure 5a taken using two instrument configurations. On top are high-intensity, low-resolution measurements used to survey for impurity phases, while on bottom are the same scans taken using a lower-intensity, high-resolution mode. \"]","image_footnote":"[]","img_path":"images/0217/5b804b39a0e0ae29e6d4eef2ffff758f850e90c58ba8af4ba9ab5f035e0ef5b0.jpg","list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[111,645,485,718]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"us to measure the as-grown NSNO (002) film peak at $47.485^{\\circ}$ , and confirms the much lower intensity of the corresponding (001) peak, the peaks of the reduced film are so low in intensity that they cannot be seen at all. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[111,722,485,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The crystalline quality and nature of defects in the reduced $\\mathrm{SrTiO_3}$ -capped $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_2$ films is studied by cross-sectional HAADF-STEM studies and is observed to be highly defective as shown in Fig. 5b. Mosaicity is observed in the $(\\mathrm{Nd},\\mathrm{Sr})\\mathrm{NiO}_2$ layer, appearing as a mixture of amorphous-like and crystalline domains, marked by the circles in 5b. Particularly, two different atomic arrangements deviating from the projected [100] perovskite structure is observed in the crystalline regions marked as 2 and 3 in 5b. Similar defects are present uniformly throughout the observed thin region ( $\\sim 5\\mu \\mathrm{m}$ ) of the FIB foil. The Fast Fourier Transform (FFT) of the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,645,883,849]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"atomic resolution HAADF-STEM image is shown in the inset of Fig. S12a. The sharp spots with the 4-fold symmetry corresponds to the $\\mathrm{SrTiO_3}$ perovskite structure along the [100] orientation. The FFT also shows the presence of additional spots corresponding to periodicities deviating from the STO structure (marked by the green arrows in inset of Fig. S12a), indicating the occurrence of a phase transformation, most likely during the reduction process. The presence of weak diffused rings corresponds to the presence of the amorphous regions (marked by the dashed circle in inset of Fig. S12a). The $\\mathrm{SrTiO_3}$ capping layer is also observed to consist of defects as shown in Fig. S12b-d. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,853,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Further, the chemical nature of the film was studied using STEM-EDS mapping. The elemental maps show chemical segregation in the reduced $\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ film in the form of Ni-rich ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[864,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"18 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[116,87,880,395]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0182/d6b3ba9e9a58426f9105c1c697fbba9ed56d4285f1ebdb17f60f3801b8f99053.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[114,396,359,614]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0294/87b1c579a28254b2a6fbc5b8015f90ed8ae8b7beae7e033a19958c07f80c9ba1.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[361,396,650,614]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0285/3d4fdea86ecab4737414e4fcd79f333c6bdb17d43bfd62c090bcbfcdbbe10d57.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[651,396,877,614]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S12. (a) The larger field of view of the image shown in 5b, showing the presence of defects in the STO capping layer as well. The inset shows the FFT pattern of the image. The spots corresponding to the cubic STO substrate (and cap) is denoted by the square, the extra spots and the diffused ring indicate the presence of additional crystalline and amorphous regions in the films, as respectively shown by the arrows and dashed semi-circle. (b-d) Magnified regions of the $\\\\mathrm{SrTiO_3}$ capping layer showing the presence of various forms of defects, with a schematic structural model overlaid ( $\\\\mathrm{Sr} = \\\\mathrm{green}$ , $\\\\mathrm{Ti} = \\\\mathrm{blue}$ , $\\\\mathrm{O} = \\\\mathrm{red}$ spheres). (b) Region 1 shows a Ruddlesden-Popper-like phase at the nickelate-cap interface. (c) Region 2 shows strong signal from the oxygen columns, which cannot be only due to O as low Z elements cannot to scatter to the high collection angle used in this experiment. (d) Region 3 shows the planes in the $\\\\mathrm{SrTiO_3}$ cap are highly distorted. \"]","image_footnote":"[]","img_path":"images/0134/2f692c1350baed5392334091ca4ec2a1e211c027f1b3dd66e3d174598006d6fc.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[109,775,486,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and Nd-rich regions and shown in Fig. S13a-d. By correlating the chemical maps with the high-resolution HAADF image, it is observed that the Nd-rich regions correspond to the amorphous-like regions, while the Ni-rich region correspond to the crystalline regions. Finally, Sr was not observed to be concentrated in this film. The STEM results thus provide a direct proof for the crystalline and chemical disorder in the $\\mathrm{Nd}_{0.8}\\mathrm{Sr}_{0.2}\\mathrm{NiO}_2$ film after the ag ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,776,702,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"gressive reduction process. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[594,821,797,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"H. Additional DFT data ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,853,883,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We provide here the structural data obtained from DFT-based structural relaxations for two choices of exchange-correlation functional: GGA-PBE and GGA-PBEsol. The optimized lattice constants for ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[864,59,883,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"19 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,89,553,224]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0988/5270d04aca8ab3166543274f07bc17cbcb8820fbd9630cb7bd73b38c8bfea6c5.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[122,224,553,349]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0722/e42fcee7ce8a4a52e577b6c153c0b2ae39ce8467fbf5c62118ee821e9d3f2dd8.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[122,351,553,474]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0310/af2870b7c032e55c1f2164a8f4068b141108fcd5b439a7cd8ad9fd10ff0e4858.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[122,474,553,598]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0363/0459cfdc5e72d2ea64c4bd07498c808b62b7c6e72956c94844d0ff892313adc4.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[557,90,883,343]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0715/4f35f6561cdead91f4553654ec38d26259398101c2f51b2de9c0d27bf15a65b6.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[557,345,883,598]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S13. (a-d) HAADF-STEM image and the corresponding EDS elemental maps obtained from the reduced $\\\\mathrm{SrTiO_3}$ -capped $(\\\\mathrm{Nd},\\\\mathrm{Sr})\\\\mathrm{NiO}_2$ film. A clear segregation of Ni and Nd is observed in the nickelate film. (e, f) The amorphous-like and crystalline domains correspond to the Nd-rich and Ni-rich region, respectively. \"]","image_footnote":"[]","img_path":"images/0748/ac72c1aae501bec5f5260a1aaadac02ad4797714cd2bedbb011cfe38d0d57605.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[111,681,488,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"all the nickelates considered in the main text within these two functionals are summarized in Fig. S14. We find good agreement with the experimental lattice constants for the undoped infinite-layer compounds $(R = \\mathrm{La},\\mathrm{Nd})$ is obtained with the GGA-PBE functional, which serves as a benchmark for our DFT-optimized lattice constants $(a_{exp} = 3.92\\AA ,$ $c_{exp} = 3.28\\AA$ for $\\mathrm{NdNiO_2}$ and $a_{exp} = 3.96\\AA$ $c_{exp} =$ 3.38 Å for $\\mathrm{LaNiO_2}$ [22, 51]). Previous works have used PBEsol to obtain H-binding energies in infinitelayer nickelates [26, 52], but we find that the GGA-PBEsol functional gives rise to optimized lattice constants that are quite far from the experimental values. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[862,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"20 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[119,95,464,276]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0151/7c5538a96776996b89fec4076e7f67c0e3b0a53c03cf1327418fae6444415ba7.jpg","list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[117,284,480,470]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. S14. Structural data from the DFT-optimized structures. (a) In-plane $(a)$ lattice constants. (b) Out-of-plane $(c)$ lattice constants (right axis corresponds to $\\\\mathrm{Nd}_6\\\\mathrm{Ni}5\\\\mathrm{O}_{12}$ ). \"]","image_footnote":"[]","img_path":"images/0822/038a8ba75784164c706d50f449156be212898e0df2e26e7a7d78f54617e799c0.jpg","list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[862,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"21 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[116,128,485,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] Anisimov, V. I., Bukhvalov, D. & Rice, T. M. Electronic structure of possible nickelate analogs to the cuprates. Phys. Rev. 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URL https://link.aps.org/doi/10.1103/PhysRevLett.107.206804. \",\"[6] Li, D. et al. Superconductivity in an infinite-layer nickelate. Nature 572, 624-627 (2019). URL https://doi.org/10.1038/s41586-019-1496-5. \",\"[7] Osada, M. et al. A superconducting praseodymium nickelate with infinite layer structure. Nano Letters 20, 5735-5740 (2020). URL https://doi.org/10.1021/acs.nanolett.0c01392. PMID: 32574061. \",\"[8] Osada, M., Wang, B. Y., Lee, K., Li, D. & Hwang, H. Y. Phase diagram of infinite layer praseodymium nickelate $\\\\mathrm{Pr}_{1 - x}\\\\mathrm{Sr}_x\\\\mathrm{NiO}_2$ thin films. Phys. Rev. Mater. 4, 121801 (2020). URL https://link.aps.org/doi/10.1103/PhysRevMaterials.4.121801. \",\"[9] Wei, W., Vu, D., Zhang, Z., Walker, F. J. & Ahn, C. H. Superconducting $\\\\mathrm{Nd}_{1 - x}\\\\mathrm{Eu}_x\\\\mathrm{NiO}_2$ thin films using in situ synthesis. Science Advances 9, eadh3327 (2023). URL https://www.science.org/doi/abs/10.1126/sciadv.adh3327. \",\"[10] Pan, G. A. et al. Superconductivity in a quintuple-layer square-planar nickelate. Nature materials 21, 160-164 (2022). URL https://doi.org/10.1038/s41563-021-01142-9. \",\"[11] Fowlie, J. et al. Intrinsic magnetism in superconducting infinite-layer nickelates. Nature Physics 18, 1043-1047 (2022). 2201.11943. \",\"[12] Lee, K. et al. Linear-in-temperature resistivity for optimally superconducting (Nd,Sr)NiO $_2$ . Nature 619, 288–292 (2023). URL https://doi.org/10.1038/s41586-023-06129-x. \",\"[13] Lane, C. et al. Competing incommensurate spin fluctuations and magnetic excitations in infinite-layer nickelate superconductors. Communications Physics 6 (2023). URL https://doi.org/10.1038/s42005-023-01213-0. \"]","page_idx":"21","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[511,128,882,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[14] Lu, H. et al. Magnetic excitations in infinite-layer nickelates. Science 373, 213-216 (2021). \",\"[15] Zhou, X. et al. Experimental progress on the emergent infinite-layer ni-based superconductors. Materials Today 55, 170-185 (2022). URL https://www.sciencedirect.com/science/article/pii/S1369702122000591. \",\"[16] Ferenc Segedin, D. et al. Limits to the strain engineering of layered square-planar nickelate thin films. Nature communications 14, 1468 (2023). \",\"[17] Lee, K. et al. Aspects of the synthesis of thin film superconducting infinite-layer nickelates. *Apl Materials* 8 (2020). \",\"[18] Parzyck, C. T. et al. Synthesis of thin film infinite-layerNickelates by atomic hydrogen reduction: clarifying the role of the capping layer (2024). 2401.07129. \",\"[19] Pan, G. A. et al. Synthesis and electronic properties of $\\\\mathrm{Nd}_{n+1}\\\\mathrm{Ni}_n\\\\mathrm{O}_{3n+1}$ ruddlesden-popper nickelate thin films. Phys. Rev. Mater. 6, 055003 (2022). URL https://link.aps.org/doi/10.1103/PhysRevMaterials.6.055003. \",\"[20] Parzyck, C. T. et al. Absence of 3 a 0 charge density wave order in the infinite-layer nickelate $\\\\mathrm{NdNiO}_2$ . Nature materials 1-6 (2024). \",\"[21] Wei, W. et al. Solid state reduction of nickel-ate thin films. Phys. Rev. Mater. 7, 013802 (2023). URL https://link.aps.org/doi/10.1103/PhysRevMaterials.7.013802. \",\"[22] Hayward, M. A., Green, M. A., Rosseinsky, M. J. & Sloan, J. Sodium hydride as a powerful reducing agent for topotactic oxide deintercalation: synthesis and characterization of the nickel(i) oxide LaNiO $_2$ . Journal of the American Chemical Society 121, 8843-8854 (1999). URL https://doi.org/10.1021/ja991573i. \",\"[23] Ding, X. et al. Critical role of hydrogen for superconductivity in nickelates. Nature 615, 50-55 (2023). URL https://doi.org/10.1038/s41586-022-05657-2. \",\"[24] Qin, C., Jiang, M. & Si, L. Effects of different concentrations of topotactic hydrogen impurities on the electronic structure of nickelate superconductors. Phys. Rev. B 108, 155147 (2023). URL https://link.aps.org/doi/10.1103/PhysRevB.108.155147. \",\"[25] Di Cataldo, S., Worm, P., Si, L. & Held, K. Absence of electron-phonon-mediated superconductivity in hydrogen-intercalated nickelates. Phys. Rev. B 108, 174512 (2023). URL https://link.aps.org/doi/10.1103/PhysRevB.108.174512. \",\"[26] Si, L. et al. Topotactic hydrogen in nickellate superconductors and akin infinite-layer oxides $ABO_{2}$ . Phys. Rev. Lett. 124, 166402 (2020). URL https://link.aps.org/doi/10.1103/PhysRevLett.124.166402. \",\"[27] Chow, L. E. et al. Pairing symmetry in infinite-layer nickelate superconductor (2023). 2201.10038. \"]","page_idx":"21","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[862,59,882,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[114,90,486,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[28] Chow, L. E. et al. Pauli-limit violation in lanthanide infinite-layer nickelate superconductors (2022). 2204.12606. \",\"[29] Sun, W. et al. Evidence for anisotropic superconductivity beyond pauli limit in infinite-layer lanthanum nickelates. Advanced Materials 35, 2303400 (2023). URL https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.202303400. \",\"[30] Eltes, F. et al. Low-loss $\\\\mathrm{BaTiO_3 - Si}$ waveguides for nonlinear integrated photonics. ACS Photonics 3, 1698-1703 (2016). URL https://doi.org/10.1021/acsphotonics.6b00350. https://doi.org/10.1021/acsphotonics.6b00350. \",\"[31] Orvis, T. et al. Electron doping $\\\\mathrm{BaZrO_3}$ via topochemical reduction. ACS applied materials & interfaces 11, 21720-21726 (2019). URL https://doi.org/10.1021/acsami.9b06370. \",\"[32] Pan, G. A. et al. Synthesis and electronic properties of $\\\\mathrm{Nd}_{n + 1}\\\\mathrm{Ni}_n\\\\mathrm{O}_{3n + 1}$ Ruddlesden-Popper nickellate thin films. Physical Review Materials 6, 055003 (2022). \",\"[33] Li, Z. et al. Epitaxial growth and electronic structure of Ruddlesden-Popper nickelates $(\\\\mathrm{La}_{n+1}\\\\mathrm{Ni}_n\\\\mathrm{O}_{3n+1}, n = 1-5)$ . APL Materials 8, 091112 (2020). \",\"[34] Sun, W. et al. Electronic and transport properties in Ruddlesden-Popper neodymium nickelates $\\\\mathrm{Nd}_{n+1}\\\\mathrm{Ni}_n\\\\mathrm{O}_{3n+1}$ ( $n=1-5$ ). Physical Review B 104, 184518 (2021). \",\"[35] Lee, K. et al. Aspects of the synthesis of thin film superconducting infinite-layer nickelates. *APL Materials* 8, 041107 (2020). \",\"[36] Li, Y. et al. Impact of Cation Stoichiometry on the Crystalline Structure and Superconductivity in Nickelates. Frontiers in Physics 9, 719534 (2021). \",\"[37] Patel, R. K. et al. Hole doping in a negative charge transfer insulator. Communications Physics 5, 216 (2022). URL https://doi.org/10.1038/s42005-022-00993-1. \",\"[38] Patel, R. K. et al. Epitaxial stabilization of ultra thin films of high entropy perovskite. Applied Physics Letters 116, 071601 (2020). URL https://doi.org/10.1063/1.5133710. \",\"[39] Maranville, B., Ratcliff II, W. & Kienzle, P. reductus: a stateless Python data reduction service with a browser front end. Journal of Applied Crystallography 51, 1500-1506 (2018). URL https://doi.org/10.1107/S1600576718011974. \",\"[40] Kirby, B. J. et al. Phase-sensitive specular neutron reflectometry for imaging the nanometer scale composition depth profile of thin-film materials. Current Opinion in Colloid & Interface Science 17, 44-53 (2012). \",\"[41] Kresse, G. & Furthmüller, J. Efficient iterative schemes for ab initio total-energy calculations using a plane-wave basis set. Physical Review B 54, \"]","page_idx":"22","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[513,92,880,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"11169-11186 (1996). URL https://link.aps.org/doi/10.1103/PhysRevB.54.11169. \",\"[42] Kresse, G. & Hafner, J. Ab initio molecular dynamics for liquid metals. Physical Review B 47, 558-561 (1993). URL https://link.aps.org/doi/10.1103/PhysRevB.47.558. \",\"[43] Kresse, G. & Joubert, D. From ultrasoft pseudopotentials to the projector augmented-wave method. Physical Review B 59, 1758-1775 (1999). URL https://link.aps.org/doi/10.1103/PhysRevB.59.1758. \",\"[44] Perdew, J. P., Burke, K. & Ernzerhof, M. Generalized gradient approximation made simple. Phys. Rev. Lett. 77, 3865-3868 (1996). URL https://link.aps.org/doi/10.1103/PhysRevLett.77.3865. \",\"[45] Wehbe, N., Pireaux, J.-J. & Houssiau, L. Xps evidence for negative ion formation in SIMs depth profiling of organic material with cesium. The Journal of Physical Chemistry C 118, 26613-26620 (2014). \",\"[46] Stevie, F. & Griffiths, D. Quantification in dynamic Sims: current status and future needs. Applied Surface Science 255, 1364-1367 (2008). \",\"[47] Sheffels, S. et al. Insight on hydrogen injection and gdox/co interface chemistry from in operando neutron reflectometry and secondary ion mass spectrometry. Applied Physics Letters 122 (2023). \",\"[48] Lu, Q. et al. Engineering magnetic anisotropy and emergent multidirectional soft ferromagnetism in ultrathin freestanding LaMnO₃ films. ACS Nano 16, 7580-7588 (2022). \",\"[49] Swart, H. C., Nagpure, I. M., Ntwaeborwa, O. M., Fisher, G. L. & Terblans, J. J. Identification of Eu oxidation states in a doped $\\\\mathrm{Sr}_5(\\\\mathrm{PO}_4)_3\\\\mathrm{F}$ phosphor by tof-sims imaging. Opt. Express 20, 17119-17125 (2012). URL https://opg.optica.org/oe/abstract.cfm?URI=oe-20-15-17119. \",\"[50] Seed Ahmed, H., Swart, H. & Kroon, R. Investigating the capability of ToF-SIMS to determine the oxidation state of Ce. Physica B: Condensed Matter 535, 124-127 (2018). URL https://www.sciencedirect.com/science/article/pii/S0921452617303824. 7th South African Conference on Photonic Materials SACPM 2017. \",\"[51] Hayward, M. & Rosseinsky, M. Synthesis of the infinite layer ni(i) phase $\\\\mathrm{NdNiO}_{2+x}$ by low temperature reduction of $\\\\mathrm{NdNiO}_3$ with sodium hydride. Solid State Sciences 5, 839-850 (2003). URL https://www.sciencedirect.com/science/article/pii/S1293255803001110. International Conference on Inorganic Materials 2002. \",\"[52] Si, L., Worm, P., Chen, D. & Held, K. Topotactic hydrogen forms chains in $ABO_2$ nickelate superconductors. Physical Review B 107, 49-51 (2023). \"]","page_idx":"22","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[862,59,880,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"23 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[138,87,854,122]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Hydrogen is not necessary for superconductivity in topotactically reduced nickelates \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,137,805,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Purnima P. Balakrishnan, $^{1, *}$ Dan Ferenc Segedin, $^{2}$ Lin Er Chow, $^{3}$ P. Quarterman, $^{1}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[186,154,810,167]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Shin Muramoto, $^{4}$ Mythili Surendran, $^{5,6}$ Ranjan K. 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Goodge, $^{10,11}$ Lena F. Kourkoutis, $^{10,11}$ Srimanta Midley, $^{7}$ Antia S. Botana, $^{8}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[160,200,834,215]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Jayakanth Ravichandran, $^{5,6,12}$ A. Ariando, $^{3}$ Julia A. Mundy, $^{2,\\\\dagger}$ and Alexander J. 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University, Cambridge, MA 02138, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[140,247,854,260]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{3}$ Department of Physics, Faculty of Science, National University of Singapore, Singapore 117551, Singapore \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[116,260,880,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{4}$ Material Measurement Laboratory, 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{\n \"bbox\": \"[207,352,787,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"<sup>9</sup>The Rowland Institute at Harvard, Harvard University, Cambridge, MA 02138, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[343,366,653,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{10}$ School of Applied and Engineering Physics, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[330,380,666,392]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cornell University, Ithaca, New York 14853, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[222,392,774,405]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{11}$ Kavli Institute at Cornell for Nanoscale Science, Ithaca, New York 14853, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,405,725,417]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{12}$ Ming Hsieh Department of Electrical and Computer Engineering, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[279,419,718,431]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"University of Southern California, Los Angeles, CA 90089, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[419,431,576,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Dated: March 5, 2024) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[166,452,826,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A key open question in the study of layered superconducting nickelate films is the role that hydrogen incorporation into the lattice plays in the appearance of the superconducting state. Due to the challenges of stabilizing highly crystalline square planar nickelate films, films are prepared by the deposition of a more stable parent compound which is then transformed into the target phase via a topotactic reaction with a strongly reducing agent such as $\\\\mathrm{CaH_2}$ . Recent studies, both experimental and theoretical, have introduced the possibility that the incorporation of hydrogen from the reducing agent into the nickelate lattice may be critical for the superconductivity. In this work, we use secondary ion mass spectrometry to examine superconducting $\\\\mathrm{La}_{1 - x}X_x\\\\mathrm{NiO}_2 / \\\\mathrm{SrTiO}_3$ ( $X = \\\\mathrm{Ca}$ and $\\\\mathrm{Sr}$ ) and $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12} / \\\\mathrm{NdGaO}_3$ films, along with non-superconducting $\\\\mathrm{NdNiO}_2 / \\\\mathrm{SrTiO}_3$ and $(\\\\mathrm{Nd},\\\\mathrm{Sr})\\\\mathrm{NiO}_2 / \\\\mathrm{SrTiO}_3$ . We find no evidence for extensive hydrogen incorporation across a broad range of samples, including both superconducting and non-superconducting films. Theoretical calculations indicate that hydrogen incorporation is broadly energetically unfavorable in these systems, supporting our conclusion that hydrogen incorporation is not generally required to achieve a superconducting state in layered square-planarNickelates. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,662,486,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Superconductivity in nickelates has been pursued ever since the discovery of the cuprates [1-5], but it was not until 2019 that it was demonstrated in thin films of the infinite-layer compound $\\\\mathrm{NdNiO_2}$ via hole doping with Sr [6]. This discovery introduced a novel family of layered nickelate superconductors that has now been extended to include the Pr- and La- analogs of the infinite-layer compound as well as the five-layer material $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ [7-10]. While superconducting nickelates exhibit many interesting phenomena [11-14], they also represent a unique materials synthesis challenge [15-19]. In gen \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,662,883,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"eral, layered square-planar nickelates cannot be synthesized directly, instead requiring a two-step fabrication method wherein an oxygen-rich precursor material is grown by traditional thin film deposition methods and then topotactically reduced, as illustrated in Fig. 1a,b. Typically, reduction is performed via a thermal anneal employing a chemical reducing agent and oxygen sink, such as $\\\\mathrm{H}_{2}$ , $\\\\mathrm{NaH}$ , or $\\\\mathrm{CaH}_{2}$ [6, 20-22]. One of the most pressing open questions is the degree to which the reduction process incorporates hydrogen into the nickelate film, and whether hydrogen is important in stabilizing superconductivity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,854,883,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A notable recent study by X. Ding et al. reported that hydrogen is critical for the emergence of superconductivity, requiring a stoichiometry around $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2\\\\mathrm{H}_{0.25}$ [23]. However, in this study, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[22,210,60,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"arXiv:2403.01796v1 [cond-mat.supr-con] 4 Mar 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[114,872,321,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"* purnima.balakrishnan@nist.gov \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[117,885,276,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"† mundy@fas.harvard.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[117,896,292,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\ddagger$ alexander.grutter@nist.gov \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[124,95,442,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0964/c824fb3f073bcef1e1dc56534c5d93b889a71028dabe64342ac7ff23899ad59b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[464,95,826,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0270/5e3882ca9d7c7e02ad6675fb54a8042620266f68621a1313b75e71450bf3db12.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,215,444,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0463/45792427230e0cb9453e5a4bf751139f1504fa57730ba2e429b32c573b37cac0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[464,287,870,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 1. Schematic crystal structures for precursor phase and reduced a. $n = \\\\\\\\infty$ and b. $n = 5$ layered square-planar nickelate compounds. c. Schematic of the ToF-SIMS measurement technique. d. SIMS spectra measured separately for positive and negative ions are analyzed by identifying peaks by mass to charge ratio $(m / z)$ and extracting integrated area. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0361/4ffd8dfefbec53b205e1ab3ba332dbebfb65aea1651d133e8fbe0c87a030a2ef.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,580,485,727]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the precursor films are hydrogen-rich, while hydrogen and oxygen stoichiometry are highly correlated through reduction. Furthermore, recent results using alternative reduction processes with no hydrogen source have cast doubt on the role of incorporated hydrogen on the electronic state [9, 21]. Theoretical investigations yield widely varying results, with conclusions ranging from hydrogen incorporation promoting [24], having no effect [25], or suppressing superconductivity altogether [26]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,737,486,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Given the differing conclusions in the literature, a comprehensive examination of the role of hydrogen incorporation in superconducting nickelates is urgently needed. To understand more broadly applicable trends rather than the specifics of one sample type or fabrication protocol, we used time-of-flight secondary ion mass spectrometry (ToF-SIMS) to study the relationship between hydrogen incorporation and superconductivity in a broad range of nickelate films grown and reduced by three different research groups. The films used in this study were grown via either molecular beam epitaxy (MBE) or \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,580,883,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"pulsed laser deposition (PLD), in a variety of geometries, and reduced with $\\\\mathrm{CaH_2}$ at different conditions. As the energetics of incorporating hydrogen may vary greatly depending on stoichiometry and structure [26], we compared multiple nickellate systems, including superconducting examples of $\\\\mathrm{La}_{1 - x}\\\\mathrm{Ca}_x\\\\mathrm{NiO}_2$ , $\\\\mathrm{La}_{1 - x}\\\\mathrm{Sr}_x\\\\mathrm{NiO}_2$ , and $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ . We also examined non-superconducting $\\\\mathrm{NdNiO_2}$ and $\\\\mathrm{Nd}_{1 - x}\\\\mathrm{Sr}_x\\\\mathrm{NiO}_2$ . We find no evidence that a large concentration of incorporated hydrogen is necessary to observe superconductivity. Instead, a wide range of films, superconducting and non-superconducting, exhibit $\\\\mathrm{H}^-$ intensities which are similar to the substrate background. Theoretical calculations support this picture, revealing that hydrogen incorporation is energetically unfavorable across all materials studied in this work. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,838,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As illustrated in Fig. 1c, ToF-SIMS is a destructive technique in which an ion beam sputters through the film, and ejected molecular ions are analyzed using a mass spectrometer to provide a depth-and element-resolved picture of the ejected species, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[109,90,486,207]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and thereby chemical composition. ToF-SIMS allows the isolation and identification of elemental $\\\\mathrm{H}^{\\\\pm}$ , and $\\\\mathrm{O}^{\\\\pm}$ as well as larger ejected molecules such as $\\\\mathrm{OH}^{\\\\pm}$ , $\\\\mathrm{O}_2^{\\\\pm}$ , and $\\\\mathrm{TiO}_2^{\\\\pm}$ , as shown in Fig. 1d. The change in molecular species intensity over time as the sample is sputtered results in a nanometer-resolved understanding of the chemical composition with depth. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,207,486,426]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However, the measured intensity depends significantly on the sputtering conditions, chemical environment, film composition, density, electronic state, and prevalence of structural defects. Absolute scaling of stoichiometry and depth therefore requires calibration standards with known stoichiometry and similar chemical environment to the films of interest. Since the defect levels and chemistry in superconducting nickelates evolves extensively during the reduction process, such standards are nearly impossible to obtain, and we instead adopt the convention of Ding et al., in which the hydrogen level observed in the $\\\\mathrm{SrTiO_3}$ or $\\\\mathrm{NdGaO_3}$ substrate is considered to be the \\\"background\\\" level representing minimal hydrogen [23]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,457,480,472]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. SUPERCONDUCTING $\\\\mathrm{La}_{1 - x}(\\\\mathrm{Sr},\\\\mathrm{Ca})_x\\\\mathrm{NiO}_2$ \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,491,486,895]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We first present results from two doped superconducting infinite-layer systems: $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ grown by pulsed laser deposition on $\\\\mathrm{SrTiO_3}$ substrates, as described in section VA1. The quality of representative samples has been previously demonstrated through x-ray diffraction (XRD), cross-sectional scanning transmission electron microscopy (STEM), and electron energy loss spectroscopy (EELS) analysis [27, 28]. To ensure depth-wise uniformity, the film thickness was limited to below $6\\\\mathrm{nm}$ . Fig. 2a shows the superconducting transitions for these samples, which have a residual resistivity ratio $\\\\approx 4.1$ , comparable to the highest reported values so far [18, 29]. After reduction, an amorphous $\\\\mathrm{SrTiO_3}$ cap is deposited to act as an oxidation barrier, with varying thickness due to the challenges associated with the room-temperature growth. Film and cap thicknesses were verified using x-ray reflectometry (XRR), shown in Fig. 2b, which reveals that the initial perovskite phase is uniform with the expected scattering length densities. After reduction, the sharp interfaces slight roughen, likely linked to the energetic deposition of the caps. While we focus on superconducting films, we also measured the as-grown perovskite and over-reduced (non-superconducting) films from the same growth, the details of which can be found in the supplemental information section VIE. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[129,896,483,911]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To understand the sensitivity of this experiment \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,90,883,454]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"to hydrogen, we first compare the overall hydrogen content of as-grown $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ samples in Fig. 2c. Here, we show the $\\\\mathrm{H^{-}}$ peak for both samples integrated across all sputtering times. The as-grown sample contains negligible hydrogen within either the film or substrate, indicating an extremely clean growth and handling process. The superconducting sample, in contrast, exhibits a clearly-resolved $\\\\mathrm{H^{-}}$ peak much larger than the measurement background. The additional hydrogen introduced into the reduced superconducting sample is easily detectable. We next compare the integrated peak intensity, indicated by the shaded region, over sputter time (depth). For this same pair of samples, Fig. 2d shows the $\\\\mathrm{H^{-}}$ intensity in just the $\\\\mathrm{SrTiO_3}$ substrate. Interestingly, while the substrate intensity of the as-grown sample is less than 40 counts per frame, the $\\\\mathrm{SrTiO_3}$ substrate associated with the superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ is an excellent match for the samples in Ding et al. [23], with approximately 200 counts per frame of $\\\\mathrm{H^{-}}$ . Thus we may be confident that the observed hydrogen levels in the substrates are above the instrumental detection limit and closely match previous observations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,457,883,734]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Having firmly established that the hydrogen levels reported previously in superconducting films are readily detectable with the instrument used in this study, we show SIMS data from superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ in Fig. 2e,f. Here the $\\\\mathrm{NiO_2}$ and $\\\\mathrm{TiO_2}$ intensities are normalized to their maximum values while the $\\\\mathrm{H^{-}}$ and $\\\\mathrm{OH^{-}}$ intensities are normalized to the steady-state value within the substrate, while alternative normalizations and raw counts are shown in the supplemental information section VIE. The film and substrate positions are indicated by the peak and dip in $\\\\mathrm{NiO_2^{-}}$ and $\\\\mathrm{TiO_2^{-}}$ intensities, respectively. The trends in $\\\\mathrm{H^{-}}$ and $\\\\mathrm{OH^{-}}$ intensities quite clearly disagree with prior reports: the superconducting $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ films do not exhibit the large 1 to 3 order of magnitude increases in $\\\\mathrm{H^{-}}$ or $\\\\mathrm{OH^{-}}$ signal which would be expected for extensive, multiplepercent hydrogen incorporation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,737,885,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Instead, apart from the quickly decaying signal associated with surface adsorbates, the $\\\\mathrm{H^{-}}$ and $\\\\mathrm{OH^{-}}$ signals within the $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ film are invariant within a factor of two of the signal within the substrate. Interestingly, the $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ sample, with a thicker amorphous $\\\\mathrm{SrTiO_3}$ cap (29 nm), exhibits higher $\\\\mathrm{H^{-}}$ intensity within the cap than within the nickelate film, concentrated near the interface. In the $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ sample with a thinner $\\\\mathrm{SrTiO_3}$ cap (approximately 6 nm), $\\\\mathrm{H^{-}}$ is much lower in the nickelate film than either the $\\\\mathrm{SrTiO_3}$ substrate or the other superconducting film. We speculate \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,85,344,253]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0538/c91c178402c1b8171bc367f7cc211a8b475d8a1832c195a227a78d9f7e7166e4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[346,85,826,253]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0444/584200cd1de3428e238f350a902ab06c584ec01bc4c6d3409ebca920d884814d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,263,442,431]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0435/9a3f38f729bde42ca2a7b06c5dad4f996e56ac2d5532fc1335be406fbab34ad5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[467,263,823,431]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0685/a1a109f4617a02e7e3fd512f83e53398dd789925e716ceef97ec598b30cec511.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,441,452,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0741/dea0056a1fff5784442c174dda7d5921f9a98e81f0623d4497f90dd511d59851.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[465,441,883,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 2. a. Resistivity vs. temperature for the superconducting $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\\\\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ samples, showing a clear transition and large RRR. b. XRR depth profiles of the as-grown and superconducting films, specifically the real component of the scattering length density (SLD). c. Intensity vs. mass to charge ratio near the $\\\\\\\\mathrm{H^{-}}$ peak for an as-grown $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and superconducting $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ film, integrated over the entire measurement time. d. Raw intensity (counts) of the $\\\\\\\\mathrm{H^{-}}$ peak in the substrate region for the same as-grown $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and superconducting $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ . e. SIMS depth profile of superconducting $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ . f. SIMS depth profile of superconducting $\\\\\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0325/f7d057b73cfb434c28a0a1236f316afcf72d238e5c273de9540782c0c34b7afa.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,743,486,830]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"that the $\\\\mathrm{SrTiO_3}$ cap may play a role in hydrogen capture or transport [30]. Most importantly, the coexistence of different low hydrogen concentrations with superconductivity definitively demonstrates that hydrogen doping is not required for superconductivity in the infinite-layer nickelates. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[540,744,849,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"II. SUPERCONDUCTING $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,780,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To test whether our findings are applicable more broadly within the square-planar nickelate family, beyond the infinite-layer structure, we examine the $n = 5$ member: superconducting $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ . This film consists of $23~\\\\mathrm{nm}$ $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ synthesized on $\\\\mathrm{NdGaO_3}$ (110) (see section V A 2 for details), with 10 nm titanium followed by $100~\\\\mathrm{nm}$ platinum patterned on the film surface as electrodes. Fig. 3a shows the zero-field superconducting transition of this sample \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,60,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[143,95,405,220]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0717/b9dd955c59fa310ac169877cd22f5869008f4a6cf5fac5afd09e20f2328c60a3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[143,232,401,367]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0098/507b37d77329d098c3e61a6a67a19e6228488749850f10543fc687f73bad7d9f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[143,386,472,551]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 3. a. Temperature-dependent resistivity of reduced $\\\\\\\\mathrm{Nd_6Ni_5O_{12}}$ / $\\\\\\\\mathrm{NdGaO_3}$ showing a clear superconducting transition. Reproduced from Ref. [10]. b. STEM image of the reduced, superconducting $\\\\\\\\mathrm{Nd_6Ni_5O_{12}}$ film and $\\\\\\\\mathrm{NdGaO_3}$ substrate. c. SIMS depth profiles of superconducting $\\\\\\\\mathrm{Nd_6Ni_5O_{12}}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0826/8bbcf3fd41d5a284bd69c5612e93570d7e2163da9fc7fe04e80b6d05444fda0e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[111,691,486,763]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"from reference [10], with a residual resistivity ratio of 3.8. Further characterization of this sample can be found in Ref. [10]. Fig. 3(b) shows a representative STEM image of this sample, revealing the $n = 5$ square-planar structure. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,766,486,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 3c plots the SIMS depth profile of this superconducting sample. $\\\\mathrm{NiO}_2^-$ and $\\\\mathrm{GaO}_2^-$ peaks are normalized to their maximum values, and clearly identify the electrode, film, and substrate regions. As before, we obtain information regarding the hydrogen concentration by examining the relative intensity of the $\\\\mathrm{H}^-$ and $\\\\mathrm{OH}^-$ peaks in the film and substrate. An advantage of the relatively thick electrode is the removal of surface contaminant effects from the measurement. Both the $\\\\mathrm{H}^-$ and $\\\\mathrm{OH}^-$ intensities are low \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,90,882,220]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in the platinum and titanium, increase slowly in the $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ film, and further increase deeper into the $\\\\mathrm{NdGaO_3}$ substrate. Similar to the superconducting $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ sample, we find that the hydrogen content appears to be highest in the substrate, although again the nickelate film and substrate intensities are very similar. Once again there is no evidence of an order of magnitude increase in hydrogen intensity in the film. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[527,253,864,268]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"III. NON-SUPERCONDUCTING FILMS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,287,882,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With little evidence of extensive hydrogen incorporation in high-quality superconducting samples, the question remains whether some structures or processes are more susceptible to hydrogen. We speculate that films with increased defect densities, whether due to growth conditions or from long or overly aggressive reduction treatments, may incorporate additional hydrogen as a defect compensation mechanism. These films do not exhibit superconductivity, but do provide a mechanism for understanding the extent to which hydrogen can be incorporated during reduction and whether it might inhibit the fabrication of superconducting films. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,476,883,635]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We first consider $17\\\\mathrm{nm}$ $\\\\mathrm{NdNiO_3}$ / $\\\\mathrm{SrTiO_3}$ (001) films grown by MBE and subjected to an incomplete reduction, at a lower temperature but for longer times compared to the optimized treatment for achieving high-quality $\\\\mathrm{NdNiO_2}$ . XRD scans shown in Fig. 4a indicate reduction towards the infinite-layer $\\\\mathrm{NdNiO_2}$ phase, but with a modest decrease in crystallinity. Electron microscopy measurements on an equivalent sister sample, shown in Fig. 4b, reveals the presence of defects and phase boundaries, as expected. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,636,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The film was cut in half before reduction, and both as-grown and reduced samples were measured using ToF-SIMS, yielding the intensity depth profiles in Figures 4c,d. As before, the NiO, $\\\\mathrm{NiO}_2$ , and $\\\\mathrm{TiO}_2$ peaks are normalized to their maximum value while the $\\\\mathrm{H}^{-}$ and $\\\\mathrm{OH}^{-}$ are normalized to the steady-state values in the substrate. The $\\\\mathrm{H}^{-}$ and $\\\\mathrm{OH}^{-}$ signals are slightly higher in the $\\\\mathrm{SrTiO_3}$ substrate than in the as-grown $\\\\mathrm{NdNiO_3}$ film. Upon reduction, $\\\\mathrm{H}^{-}$ and $\\\\mathrm{OH}^{-}$ increase at the surface of the films, and the lineshape of this increase only partially matches that of various peaks including $\\\\mathrm{C}_2^-$ and $\\\\mathrm{Ca^{+}}$ (see supplemental section VIC), indicating that they do not solely originate from surface adsorbates introduced during the reduction process. Near the substrate interface, which has previously been shown to be the highest-quality region of the film [17, 27], the $\\\\mathrm{H}^{-}$ intensity remains lower than in the $\\\\mathrm{SrTiO_3}$ substrate. Thus, while some insignificant hydrogen \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[133,106,553,299]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0738/52edf8fe3b5bd31b1b681e948d9446c1a73adc43bd142e60a58d83cc05e5d86a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[571,104,843,304]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0826/1bb6b9708fb55b721a660d591ca480c1a2698cd6fd4c80c7f1a942fd39fd5982.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[133,316,459,539]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0523/df46246666b85149f21dde3f1bd47e4b2101e4f52ccd586e93049e1a30470909.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[460,316,844,539]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 4. a. XRD of as-grown and $\\\\\\\\mathrm{NdNiO_3}$ and reduced $\\\\\\\\mathrm{NdNiO_2}$ films showing partial reduction to the infinite-layer phase. b. STEM of an equivalent sister $\\\\\\\\mathrm{NdNiO_2}$ sample revealing extended defects concentrated near the surface. c. SIMS depth profile of the as-grown film $\\\\\\\\mathrm{NdNiO_3}$ film. d. SIMS depth profile of the $\\\\\\\\mathrm{NdNiO_2}$ film, reduced for an extended time of $6\\\\\\\\mathrm{h}$ at $290^{\\\\\\\\circ}\\\\\\\\mathrm{C}$ . SIMS shows increased hydrogen concentration at the surface even without full oxygen removal. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0602/abef16c0866a93c579a85cd4b0a5ebaa232b3b6ce77badd4f25b54fafccab9c8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,647,485,691]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"content may be introduced during the reduction process, it seems to be limited near the surface of these uncapped films. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,694,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We next present our findings on non-superconducting infinite-layer films $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ / $\\\\mathrm{SrTiO_3}$ films, which are appropriately doped to result in superconductivity, but which were reduced aggressively at high temperatures $(600^{\\\\circ}\\\\mathrm{C}$ compared to $\\\\sim 300^{\\\\circ}\\\\mathrm{C})$ ; this reduction is enough to significantly hydrogen-dope a similar perovskite material, $\\\\mathrm{BaZrO_3}$ [31]. Furthermore, a common practice is to cap perovskite nickelate films with $\\\\mathrm{SrTiO_3}$ prior to reduction to provide balanced strain for structural stability of the film throughout its entire thickness [6, 17]. We therefore compare samples with and without an $\\\\mathrm{SrTiO_3}$ capping layer grown in situ on the $10~\\\\mathrm{nm}$ $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ before reduction. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,647,883,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"XRD measurements, shown in Figure 5a, reveal that the crystalline quality of both capped and uncapped films prior to reduction is lower, with broader, lower intensity film peaks. Importantly, while the (002) $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ peak is sharp, the expected perovskite (001) film peak is suppressed; further higher-resolution measurements, shown in the Supplemental Fig. S11, resolve the presence of an unidentified potential RP phase. As before, the topotactic reduction process reduces the $c$ -axis lattice parameter, but the peak intensity drops dramatically. Transmission electron micrographs of these samples, such as that shown in Fig. 5b, reveal the segregation of the film into multiple crystalline phases and amorphous-like regions. Thus, the aggressive reduction of these films is non-uniform and disordered rather than controlled, resulting in increased mosaicity and a loss of crystalline qual \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,143,472,321]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0423/18cc79aa5696c44cb6c1961ffcae4d67754119aa927e59856b286f6e03857759.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[480,143,803,309]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0221/f8bcd156921e7c1a5eccacabadfec1b3e6a4eaec065495826fbfefd567e62f65.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[133,330,467,570]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0912/22aa8123c886fef7bfda9ac285b72a58b58bd936bddf60075bfc0cc924d622de.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[478,327,870,571]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 5. a. XRD on $\\\\\\\\mathrm{Nd}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_3$ films grown by PLD, with and without a $10\\\\\\\\mathrm{nm}$ $\\\\\\\\mathrm{SrTiO_3}$ cap, showing a weak film (001) peak both before and after reduction, indicating a low-crystallinity as-grown film. Reduction further lowers crystallinity. b. Atomic-resolution cross-sectional HAADF-STEM micrograph from the reduced $\\\\\\\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ film showing amorphous (marked as 1) and crystalline regions (marked as 2 and 3). The low-crystalline quality of the film after reduction is clearly visible and agrees with the XRD data. c. SIMS depth profile of the as-grown $\\\\\\\\mathrm{Nd}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_3$ film indicates a separate surface layer. d. SIMS depth profile of the reduced $\\\\\\\\mathrm{Nd}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_2$ film with a $\\\\\\\\mathrm{SrTiO_3}$ cap, showing non-negligible but small hydrogen incorporation at the $\\\\\\\\mathrm{SrTiO_3}$ cap / $\\\\\\\\mathrm{Nd}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_2$ interface. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0044/051d90b5c99542a6ce73a53377a468d888958fcc39d2f4e91b6a7e60f0c27974.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,729,485,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ity. This is corroborated by electronic transport, as discussed further in the supplemental information, which indicates that capped and uncapped films exhibit sharply different resistivities. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,795,485,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As shown in Fig. 5c, which plots SIMS measurements from the as-grown, uncapped $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NO}_3$ film, the initial transient region shows much higher yields of all ions which may indicate differences in crystallinity near the surface, potentially from the emergence of a polycrystalline scale layer in uncapped samples over time [18]. In the bulk region, the $\\\\mathrm{H}^{-}$ and $\\\\mathrm{OH}^{-}$ intensities are similar to the sub \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,731,558,742]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"strate. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,752,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Despite the significant difference in crystalline quality and reduction conditions, the effects of reduction are startlingly similar to our other observations. Figure 5d shows the integrated peak intensities in the reduced $\\\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ bilayer. Once again, $\\\\mathrm{H^{-}}$ and $\\\\mathrm{OH^{-}}$ intensities are elevated at the film/cap interface - though over a broader spatial extent - with almost a $50\\\\%$ increase over the baseline in the substrate. Thus, while the $\\\\mathrm{SrTiO_3}$ cap appears to trap hydrogen, this enhancement is again far below the orders of magnitude which would \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[111,90,485,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"be expected for significant hydrogen incorporation, remaining within a factor of two of the substrate values. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[138,167,459,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IV. THEORETICAL CALCULATIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,200,485,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To further understand the lack of hydrogen incorporation in the nickelates analyzed above via SIMS (both superconducting and non-superconducting), density-functional theory (DFT)-based calculations were performed to explore the energetics of topotactic hydrogen in infinite-layer $R\\\\mathrm{NiO}_2$ ( $R =$ rare-earth, both doped and undoped) as well as in the quintuple-layer nickelate $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ . To investigate whether it is energetically favorable to intercalate hydrogen, we compute the hydrogen binding energy $(E_b)$ for the topotactic process as: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[120,375,485,391]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nE _ {b} = \\\\left\\\\{E \\\\left[ R \\\\mathrm {N i O} _ {2} \\\\right] + n \\\\times \\\\mu [ H ] - E \\\\left[ R \\\\mathrm {N i O} _ {2} \\\\mathrm {H} \\\\right] \\\\right\\\\} / n, \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[111,402,485,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $E[R\\\\mathrm{NiO}_2]$ and $E[R\\\\mathrm{NiO}_2\\\\mathrm{H}]$ are the total energies for the infinite-layer $R\\\\mathrm{NiO}_2$ and hydride-oxide $R\\\\mathrm{NiO}_2\\\\mathrm{H}$ compounds, $\\\\mu[H] = E[\\\\mathrm{H}_2]/2$ is the chemical potential of H, and $n$ are the number of H atoms in the (super)cell. Analogous expressions are used for $R_{0.75}(\\\\mathrm{Sr},\\\\mathrm{Ca})_{0.25}\\\\mathrm{NiO}_2$ and $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ . A positive (negative) $E_b$ indicates that the topotatic hydrogen intercalation is favorable (unfavorable). The calculated binding energies are summarized in Fig. 6. We find that the incorporation of H into $R\\\\mathrm{NiO}_2$ , $R_{0.75}(\\\\mathrm{Sr},\\\\mathrm{Ca})_{0.25}\\\\mathrm{NiO}_2$ , $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ is systematically unfavorable, in agreement with experiments. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,579,485,911]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In summary, we searched for hydrogen across a wide range of superconducting and nonsuperconducting nickelate films, with different cation and dopant chemistry, structures, growth methods, reduction conditions, and crystalline quality. Not only did we find no significant concentrations of hydrogen in superconducting films, we were also unable to use excessive reduction temperature or time to force significant amounts of hydrogen into these structures. These results are consistent with first-principles calculations which show that hydrogen incorporation is energetically unfavorable in both infinite-layer and layered square-planar compounds. At most, we observed increased concentrations by a factor of two from the trace amounts already present within the substrates. Furthermore, hydrogen, as hydride or hydroxide ions $\\\\mathrm{(H^{-}}$ and $\\\\mathrm{OH}^{-}$ ), was more likely to be found in $\\\\mathrm{SrTiO_3}$ caps or in the substrates than in the nickelate films themselves. This propensity for hydrogen to appear in higher concentrations in $\\\\mathrm{SrTiO_3}$ capping layers and $\\\\mathrm{SrTiO_3 / }$ nickelate interfaces is interesting in the context of recent work showing the important role such \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,90,700,239]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0007/479b1969db105765e61fdb112bc961a54d88fec154a9769819145e18448b89ab.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[511,244,684,353]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0027/70cf5d27249364229e0176968f7c2175fe4364d55211ca71685a6cbde1ad691f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[511,358,759,489]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"d \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0267/318ec71358f331d140b8679cce11b1b346cd334e25ce7d262eddf38e4826b1d2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[754,107,880,460]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 6. Topotatic-H energetics for superconducting nickelates. Crystal structures indicating the positions of topotatic-H used for (a) $(\\\\\\\\mathrm{La,Nd})\\\\\\\\mathrm{NiO}_2$ (b) $(\\\\\\\\mathrm{La,Nd})_{0.75}(\\\\\\\\mathrm{Sr},\\\\\\\\mathrm{Ca})_{0.25}\\\\\\\\mathrm{NiO}_2$ and (c) $\\\\\\\\mathrm{Nd_6Ni_5O_{12}}$ (d) Binding energies for superconducting layered nickalates, where a positive (negative) binding energy indicates favoring (disfavoring) H-intercalation. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0502/83ecebc02783511836632826e3a98833ce4468afbc16172ec8542d016f7b4619.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[506,650,882,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"capping layers can play in facilitating the reduction process [18]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,680,883,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It should be noted that our measurements generally reveal as-grown samples which are almost completely devoid of hydrogen prior to reduction. $\\\\mathrm{CaH_2}$ does appear to introduce hydrogen into the system, as evidenced by changes in both film and substrate levels in as-grown $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3}$ and reduced $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ films, for example. However, topotactic reduction appears unable to introduce hydrogen into these nickelates at the levels near $25\\\\%$ previously cited as critical doping for superconductivity [23]. At such high levels of incorporated hydrogen, Ding et al. observed $\\\\mathrm{H^{-}}$ intensities approximately $40\\\\times$ to $60\\\\times$ the substrate concentration, and approaching a factor of $200\\\\times$ to $600\\\\times$ near the film surface. We find no evidence of such large relative $\\\\mathrm{H^{-}}$ intensities in the films studied in this work. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[109,90,486,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Therefore, although superconductivity is highly sensitive to reduction optimization, this is likely due to the crystalline quality and oxygen stoichiometry, and not hydrogen stoichiometry. Of course, this study does not demonstrate that superconductivity requires the absence of incorporated hydrogen. The results of Ding et al. clearly demonstrate that it is possible to realize the superconducting state in samples which contain significant hydrogen concentrations. This work instead indicates that many films appear resistant to hydrogen infiltration, and most importantly, superconductivity may be readily realized without it. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[160,313,437,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"V. EXPERIMENTAL METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[125,345,473,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. Sample Synthesis: Thin Film Deposition and Reduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[197,391,403,405]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. $L a_{1 - x}(C a,S r)_{x}N i O_{2}$ Films \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,424,486,583]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thin films, $\\\\sim 6\\\\mathrm{nm}$ thick, of the infinite-layer nickelates $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_2}$ and $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ were grown on $\\\\mathrm{SrTiO_3}$ (001) substrates using pulsed laser deposition (PLD) and $\\\\mathrm{CaH_2}$ topotactic reduction under conditions as previously reported [27, 28]. Notably, reduction was performed using $0.1\\\\mathrm{g}$ of $\\\\mathrm{CaH_2}$ powder at $340^{\\\\circ}\\\\mathrm{C}$ to $360^{\\\\circ}\\\\mathrm{C}$ for $1\\\\mathrm{h}$ (2 h for overreduced samples). After reduction, samples were capped ex-situ, at room temperature, with amorphous $\\\\mathrm{SrTiO_3}$ to protect the surface from reoxidation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[181,618,418,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. $Nd_{6}Ni_{5}O_{12}$ and $NdNiO_{2}$ Films \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,650,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We use ozone-assisted molecular beam epitaxy (MBE) to synthesize the precursor $\\\\mathrm{NdNiO_3}$ / $\\\\mathrm{SrTiO_3}$ (001) and $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{16} / \\\\mathrm{NdGaO}_3$ (110) films in Fig. 4 and Fig. 3, respectively. To calibrate the nickel and neodymium elemental fluxes, we synthesize NiO on MgO (001) and $\\\\mathrm{Nd}_2\\\\mathrm{O}_3$ on yttria-stabilized zirconia (YSZ (111)), then measure the film thickness via x-ray reflectivity. Next, we synthesize $\\\\mathrm{NdNiO_3}$ / $\\\\mathrm{LaAlO_3}$ (001) and use the $c$ -axis lattice constant and film thickness to refine the Nd / Ni ratio and monolayer dose, respectively. Using the optimized neodymium and nickel shutter times from the synthesis of $\\\\mathrm{NdNiO_3}$ / $\\\\mathrm{LaAlO_3}$ , we synthesize the Ruddlesden-Popper nickelates via monolayer shuttering. Both $\\\\mathrm{NdNiO_3}$ and Ruddlesden-Popper nickelates are synthesized at a substrate temperature of $500^{\\\\circ}\\\\mathrm{C}$ to $600^{\\\\circ}\\\\mathrm{C}$ with $\\\\sim 1.0\\\\times 10^{-6}$ Torr distilled ozone (Heeg Vacuum Engineering). The MBE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,88,700,186]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0299/b51e5ad03b283651bf44a0f89aa4c165bfb36a12ef3c7b1a0c50f6a9e8b69c65.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[705,88,897,186]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 7. RHEED image of the $\\\\\\\\mathrm{Nd}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_3$ (NSNO) films (a) with out and (b) with $\\\\\\\\mathrm{SrTiO_3}$ (STO) capping layer after cooling the samples to room temperature. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0231/75049f42e26ac6f1e63c9e29d7cfaf52ad6c76ef0c5da0af38d06699a40eef2b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[506,268,880,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"synthesis conditions and calibration scheme are described in Refs. [10, 32]; similar techniques were also used in Refs. [33, 34]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,313,883,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The perovskite and Ruddlesden-Popper films are reduced to the square-planar phase via $\\\\mathrm{CaH_2}$ topotactic reduction. The following methods are similar to those used elsewhere [10, 35, 36]. First, the as-grown films are cut into identical pieces, and the pieces to be reduced are tightly wrapped in aluminum foil (All- Foils) to avoid direct contact between the film and $\\\\mathrm{CaH_2}$ . Each film is then placed in a borosilicate tube (Chemglass Life Sciences) with $\\\\sim 0.1\\\\mathrm{g}$ of $\\\\mathrm{CaH_2}$ pieces ( $>92\\\\%$ , Alfa Aesar). The borosilicate tube is pumped down to $< 0.5\\\\mathrm{mTorr}$ , sealed, and then heated for several hours at $\\\\sim 290^{\\\\circ}\\\\mathrm{C}$ in a convection oven (Heratherm, Thermo Fisher Scientific) with a $10^{\\\\circ}\\\\mathrm{Cmin}^{-1}$ heating rate. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[609,546,785,559]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. $N d_{0.8} S r_{0.2} N i O_{3}$ Films \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,577,883,881]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polycrystalline targets of $\\\\mathrm{NdNiO_3}$ and $\\\\mathrm{Nd_{0.8}Sr_{0.2}NiO_3}$ were prepared by the liquid-mix technique [37, 38]. $10\\\\mathrm{nm}$ thick $\\\\mathrm{Nd_{0.8}Sr_{0.2}NiO_3}$ films were grown on (001) $\\\\mathrm{SrTiO_3}$ substrates using a Neocera PLD system equipped with an in-situ RHEED (Staub Instruments, Germany). The depositions were conducted using a KrF excimer laser operating at $2\\\\mathrm{Hz}$ with a fluence of $1.5\\\\mathrm{Jcm}^{-2}$ . During the deposition, a dynamic oxygen pressure of $150\\\\mathrm{mTorr}$ was maintained, and the substrate temperature was $735^{\\\\circ}\\\\mathrm{C}$ . The optional $10\\\\mathrm{nm}$ thick $\\\\mathrm{SrTiO_3}$ capping layer was grown at the same condition as the film. After the deposition, all samples were in-situ annealed at the deposition temperature in an oxygen atmosphere of $500\\\\mathrm{Torr}$ for $30\\\\mathrm{min}$ and subsequently cooled to room temperature at a rate of $15^{\\\\circ}\\\\mathrm{Cmin}^{-1}$ . The streaky RHEED pattern of specular (0 0) and off-specular (0 1), (0 -1) spots, recorded after cooling the samples to room temperature confirm the excellent surface morphology of the films (Figure 7). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,882,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The as-grown films were sealed in evacuated $(\\\\sim 1\\\\mathrm{mTorr})$ quartz ampoules with $0.1\\\\mathrm{g}$ $\\\\mathrm{CaH_2}$ pow \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[870,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[111,90,486,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"der (90-95%, Thermo Scientific Chemicals). The ampoules were then baked in a muffle furnace at $600^{\\\\circ}\\\\mathrm{C}$ for up to $10\\\\mathrm{h}$ . The temperature ramp rate was fixed at $10^{\\\\circ}\\\\mathrm{C}\\\\mathrm{min}^{-1}$ . Once the ampoules were opened, the reduced films were immediately rinsed in $n$ -butanol and isopropanol in an ultrasonic bath for $3\\\\mathrm{min}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[214,224,385,239]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. X-ray Diffraction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,257,486,330]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"X-ray diffraction (XRD) measurements were performed at room temperature before and after reduction by each group on commercially available x-ray diffractometers using $\\\\mathrm{CuK}\\\\alpha_{1}$ ( $\\\\lambda = 1.5406\\\\AA$ ) radiation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[200,363,398,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. X-ray Reflectometry \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,396,486,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"X-ray reflectometry (XRR) measurements were performed at ambient conditions in a horizontal configuration using a Rigaku SmartLab diffractometer. The incident beam was collimated using the parallel beam slit and an incident slit of $30\\\\mu \\\\mathrm{m}$ height to improve $Q$ -resolution. The Cu $\\\\mathrm{K}\\\\alpha_{1}$ wavelength $(\\\\lambda = 1.5406\\\\AA)$ was isolated by using a Ge- $(220)\\\\times 2$ monochromator. The scattered beam was further collimated by a $0.2\\\\mathrm{mm}$ receiving slit. The data were reduced using the reductus web-service [39] and fit to a slab model using Ref1D [40]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[143,588,454,617]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"D. Time-of-Flight Secondary Ion Mass Spectroscopy \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,633,486,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Time-of-flight SIMS was performed using an IONTOF IV (Münster, Germany) equipped with a $20\\\\mathrm{keV}\\\\mathrm{Ar}_{2600\\\\pm 1000}^{+}$ cluster source for sputtering, a $30\\\\mathrm{keV}\\\\mathrm{Bi}_3^+$ liquid metal ion source for analysis, and a time-of-flight mass analyzer. Depth profiling was performed in non-interlaced mode with 1 scan of analysis with a resolution of $(128\\\\times 128)$ pixels, 10 scans of sputtering, and at least $0.5\\\\mathrm{s}$ of charge compensation per cycle, where both the analysis and sputter rasters were kept inside a $(500\\\\times 500)\\\\mu \\\\mathrm{m}$ area. The corresponding ion doses were $1.9\\\\times 10^{9}$ ions/cm $^2$ (0.12 pA) for $\\\\mathrm{Bi}_3^+$ , and between $2.1\\\\times 10^{14}$ ions/cm $^2$ to $2.6\\\\times 10^{14}$ ions/cm $^2$ (5.1 nA to 6.4 nA) per cycle for the cluster source due to day-to-day fluctuations in the beam current. On especially insulating samples or substrates, a small drop of silver paint was used to electrically contact the sample surface to the sample holder for further charge compensation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,90,883,193]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For reliable detection of $\\\\mathrm{H}^-$ ions, contributions from residual gases were minimized by keeping the chamber pressure below $5\\\\times 10^{-7}\\\\mathrm{Pa}$ . Both negative and positive ions were analyzed at separate spots, and the signal rastered over multiple spots was averaged after normalizing for the highest intensity ion unique to the substrate $(\\\\mathrm{TiO}_2^-$ or $\\\\mathrm{GaO}_2^-)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,193,883,325]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Spectra were analyzed using SurfaceLab to perform mass calibrations, identify peaks with the appropriate compounds, and extract the total integrated peak intensity as a function of sputter time. As many molecular compounds can have similar mass, peak assignments were made carefully, considering factors such as mass offset, isotopic distribution, and similarity in profile shape to other known oxide and hydroxide species. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[599,356,794,371]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E. Electron Microscopy \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,388,883,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{Nd}_{6}\\\\mathrm{Ni}_{5}\\\\mathrm{O}_{12}$ cross-sectional STEM specimens were prepared by the standard focussed ion beam (FIB) lift-out process on a Thermo Fisher Scientific Helios G4 UX or FEI Helios 660 FIB. HAADF-STEM was performed on a probe-corrected Thermo Fisher Scientific Spectra 300 X-CFEG operating at $300\\\\mathrm{kV}$ with a 30 mrad convergence semi-angle. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,491,883,665]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The reduced $\\\\mathrm{NiNdO_2}$ cross-sectional scanning transmission electron microscope (STEM) specimens were prepared using focused ion beam (FIB) liftout and thinning. Samples were first thinned down using an accelerating voltage of $30\\\\mathrm{kV}$ with a decreasing current from $100\\\\mathrm{pA}$ to $40\\\\mathrm{pA}$ , and then with a fine polishing process using an accelerating voltage of $5\\\\mathrm{kV}$ and a current of $41\\\\mathrm{pA}$ . STEM-HAADF images were acquired using Thermo Fisher Scientific Titan Themis Z G3 operated at $200\\\\mathrm{kV}$ . The convergence angle was $18.9\\\\mathrm{mrad}$ and the collection angles ranged from $68\\\\mathrm{mrad}$ to $280\\\\mathrm{mrad}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,665,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The reduced $\\\\mathrm{SrTiO_3}$ -capped $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_3$ cross-sectional STEM specimens were prepared using a Thermo Fisher Scientific Helios G4 UXe PFIB Dual Beam system, using a standard lift-out procedure. The film surface was protected by depositing protective C and W layers to prevent damage to the film surface during ion beam milling. The foil was first thinned down to $\\\\sim 200\\\\mathrm{nm}$ using the $30\\\\mathrm{kV}$ ion-beam, and then with a final polishing process using a $5\\\\mathrm{kV}$ ion-beam. The high-resolution STEM-HAADF imaging was carried out using a Thermo Fisher Scientific Spectra 200 operated at $200\\\\mathrm{kV}$ , with a probe semi-convergence angle of $25\\\\mathrm{mrad}$ and current of $\\\\sim 20\\\\mathrm{pA}$ , and the collection angles ranged from $54\\\\mathrm{mrad}$ to $200\\\\mathrm{mrad}$ . The energy dispersive X-ray spectroscopy (EDS) chemical mapping was performed using the same instrument \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[864,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,90,486,122]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"utilizing the Bruker Dual-X X-ray detectors, using an electron beam current of $\\\\sim 100\\\\mathrm{pA}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[187,150,410,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"F. Computational methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,183,485,588]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Density-functional theory (DFT)-based calculations were performed to theoretically explore the energetics of topotactic hydrogen in the infinite-layer nickelate $R\\\\mathrm{NiO}_2$ ( $R = \\\\mathrm{La}$ , Nd, both doped and undoped) as well as in the quintuple-layer nickelate $\\\\mathrm{Nd}_{6}\\\\mathrm{Ni}_{5}\\\\mathrm{O}_{12}$ . For $R\\\\mathrm{NiO}_2\\\\mathrm{H}_{\\\\delta}$ , $R_{0.75}(\\\\mathrm{Sr},\\\\mathrm{Ca})_{0.25}\\\\mathrm{NiO}_2\\\\mathrm{H}_{\\\\delta}$ , and $\\\\mathrm{Nd}_{6}\\\\mathrm{Ni}_{5}\\\\mathrm{O}_{12}\\\\mathrm{H}_{\\\\delta}$ ( $\\\\delta = 0,1$ ) structural relaxations were performed using the VASP code [41-43] with the Perdew-Burke-Ernzerhof version of the generalized gradient approximation (GGA-PBE) [44]. For the infinite-layer materials ( $R\\\\mathrm{NiO}_2$ and $R_{0.75}(\\\\mathrm{Sr},\\\\mathrm{Ca})_{0.25}\\\\mathrm{NiO}_2$ ) up to a $2\\\\times 2\\\\times 2$ supercell was used to accommodate the appropriate H content and/or ( $\\\\mathrm{Sr},\\\\mathrm{Ca}$ ) doping level. GGA-PBE was chosen as it provides lattice constants in close agreement with experimental data, as shown in Supplementary Note H. A Γ-centered $13\\\\times 13\\\\times 15$ ( $9\\\\times 9\\\\times 11$ ) $k$ -mesh was used for the $1\\\\times 1\\\\times 1$ unit cells ( $2\\\\times 2\\\\times 2$ supercells) with a $0.05\\\\mathrm{eV}$ Gaussian smearing. For $\\\\mathrm{Nd}_{6}\\\\mathrm{Ni}_{5}\\\\mathrm{O}_{12}$ , a Γ-centered $9\\\\times 9\\\\times 9$ $k$ -mesh with a $0.05\\\\mathrm{eV}$ Gaussian smearing was used. The size of the plane-wave basis sets was set with a kinetic energy cut-off of $520\\\\mathrm{eV}$ . For $R = \\\\mathrm{Nd}$ , we have used a pseudopotential where the $\\\\mathrm{Nd}(4f)$ electrons are frozen in the core. To compute the chemical potential of hydrogen ( $\\\\mu [\\\\mathrm{H}]$ ), we optimized an $\\\\mathrm{H}_2$ dimer in $15^3\\\\mathring{\\\\mathrm{A}}^3$ box with energy cutoff set to $325\\\\mathrm{eV}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[179,618,419,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHOR CONTRIBUTIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,650,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PPB, S. Muramoto, and AJG performed and analyzed ToF-SIMS measurements. PPB, AJG, and PQ performed XRR and analyzed and interpreted all reflectometry data. LEC deposited and reduced $\\\\mathrm{La_{0.8}Sr_{0.2}NiO_3 / La_{0.8}Sr_{0.2}NiO_2}$ and $\\\\mathrm{La_{0.78}Ca_{0.22}NiO_3 / La_{0.78}Ca_{0.22}NiO_2}$ films, and performed electronic characterization. $\\\\mathrm{NdNiO_3}$ and $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ films were fabricated deposited by GAP, DFS, and QS, while GAP and DFS performed reduction and electronic characterization. TEM of $\\\\mathrm{Nd}_6\\\\mathrm{Ni}_5\\\\mathrm{O}_{12}$ and $\\\\mathrm{NdNiO_2}$ films were performed by BHG and YTS, respectively. $\\\\mathrm{Nd_{0.8}Sr_{0.2}NiO_3}$ films were deposited and initially characterized by RKP and S. Middey, reduced by MS, and imaged via TEM by KJ and YTS. HL and ASB performed theoretical calculations for all film compositions. The study was designed by AJG, PPB, PQ, DFS, JAM, AA, and JR. The paper was written by PPB and AJG \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,90,714,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"with input from all authors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[596,135,795,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,167,882,224]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We thank Kyuho Lee for insightful discussions. We also thank Kerry Sieben for x-ray assistance. We thank Hanjong Paik for supporting the growth of the $n = 5$ superconducting sample. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,224,883,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Certain commercial equipment, instruments, software, or materials are identified in this paper in order to specify the experimental procedure adequately. Such identifications are not intended to imply recommendation or endorsement by NIST, nor it is intended to imply that the materials or equipment identified are necessarily the best available for the purpose. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,340,883,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Research was performed in part at the NIST Center for Nanoscale Science and Technology. Electron microscopy was performed at the Cornell Center for Materials Research (CCMR) Shared Facilities, which are supported by the NSF MRSEC Program (No. DMR-1719875). B.H.G. and L.F.K acknowledge support from PARADIM and the Packard Foundation. S. Midney acknowledges MHRD, Government of India for financial support under the STARS research funding scheme (grant number: STARS/APR2019/PS/156/FS). PPB and PQ received funding from the NRC RAP. JAM, ASB, and HL acknowledge support from NSF grant no. DMR2323971. JR and MS acknowledge support from an ARO MURI program with award no. W911NF-21-1-0327, and the National Science Foundation of the United States under grant number DMR-2122071. Materials growth and electron microscopy were supported in part by the Platform for the Accelerated Realization, Analysis, and Discovery of Interface Materials (PARADIM) under NSF Cooperative Agreement no. DMR-2039380. KJ and YTS acknowledge support from USC Viterbi startup funding and the USC Research and Innovation Instrumentation Award. Electron microscopy data were acquired at the Core Center of Excellence in Nano Imaging at USC. LEC and AA acknowledge support from the Ministry of Education (MOE), Singapore, under its Tier-2 Academic Research Fund (AcRF), Grants No. MOET2EP50121-0018 and MOE-T2EP50123-0013. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[532,818,859,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"VI. SUPPLEMENTAL INFORMATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[609,849,782,864]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. Sample Summary \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,882,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table VIA lists details of all samples referenced in this paper, along with their fabrication details and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[862,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,90,354,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which figures they correspond to. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[138,138,460,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. Hydrogen Quantification using SIMS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,171,485,460]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although ToF-SIMS is very sensitive to mass and depth, extracting quantitative information (e.g., chemical stoichiometries) can be challenging due to so-called matrix effects where the chemical and electronic environment of the material (matrix) affects the ionization of the sputtered species. First, the choice of the sputtering beam can change the matrix. For example, the use of a $\\\\mathrm{Cs^{+}}$ sputter beam results in Cs implantation into the film, lowering the work function and dramatically increasing the yield of negative ions [45]. Because different ions can interact differently with the implanted Cs, the ion yield ratios can vary drastically. To minimize potential chemical interactions with the sample, we chose to use an $\\\\mathrm{Ar^{+}}$ noble gas cluster source for sputtering, which is also volatile and escapes to vacuum after bombardment. The type of analysis beam $(\\\\mathrm{Bi}_{3}^{+},\\\\mathrm{O}_{2}^{+},\\\\mathrm{Ga}^{+}$ etc.) also has an effect on ionization, and this needs to be specified when comparing quantitative results. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,462,486,665]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Second, quantification requires matrix-matched standards. Since even small impurities can affect ionization, standards need to be prepared with known ratios of chemical species and exist in a similar chemical environment to that of the films of interest [46]. Relative sensitivity factors can then be calculated to scale the integrated peak areas to atomic concentrations. We first attempt to quantify hydrogen content in our nickelate films by comparing to a mica standard, as used in Ding et al. [23]. The chemical formula for the mica (muscovite) crystals we used is $(\\\\mathrm{KF})_2(\\\\mathrm{Al}_2\\\\mathrm{O}_3)_3(\\\\mathrm{SiO}_2)_6(\\\\mathrm{H}_2\\\\mathrm{O})$ . Peak shapes as well as intensity measurements are shown in Fig. S1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,666,488,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To illustrate the importance of matrix-matched standards, we compare the levels of oxygen $(\\\\mathrm{O}^{-}$ and $\\\\mathrm{O}_2^-$ ) measured in the mica and in the SrTiO3 and NdGaO3 substrates prior to any film reduction. Although they have comparable oxygen number densities, we found that dissimilarities in the ionization efficiencies produced drastically different results (i.e., estimated stoichiometric ratios). A quick calculation revealed that the apparent oxygen concentration was significantly lower in the mica than in the SrTiO3 and NdGaO3 substrates, and this is due to the presence of different elements in the matrix. The same effect is observed for all elements of the periodic table, including H, which highlights the difficulty of quantification using SIMS. In addition, hydrogen is present in adventitious carbon contamination at surfaces and interfaces, and requires careful interpreta \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,90,679,106]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"tion of the profile data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,114,883,330]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Another complication is the effect of the reduction process on the chemical and physical properties of the film, which directly affects the sensitivity factor and the sputtering rate, respectively. A lower sputter rate means that fewer number of elements and molecules are being ejected at any given time, and even though the ionization efficiency may not have changed, the intensity appears to be lower. In our study, this apparent intensity of various molecular species within a single nickelate sample set varied dramatically as a function of reduction time and conditions, as discussed in further detail in Section VIE. This renders even samples cleaved from a single growth and reduced differently to not be quantitatively comparable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[537,409,857,436]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Disentangling Extrinsic and Intrinsic Hydrogen \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,462,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As mentioned earlier, SIMS can also detect surface adsorbates, and requires a way to distinguish hydrogen intrinsic to the sample from surface contamination. Surface adsorbates are often hydrocarbons, so we can compare carbon peaks such as $\\\\mathrm{C}_2^-$ , as well as other contaminant peaks, and see if hydrogen trends with these compounds. The rapid decay in signal at the surface is usually due to these hydrocarbons, and their contribution to the H and OH signals can be subtracted from those inside the film. We can further confidently attribute certain signals to measured hydrogen by isotope analysis. Metal oxides such as Ti will have the same ionization efficiency regardless of the isotope (e.g. $^{48}\\\\mathrm{TiO}_2$ vs. $^{49}\\\\mathrm{TiO}_2$ ). Species with isobaric interference, or those that overlap in mass, such as $^{49}\\\\mathrm{TiO}_2$ and $^{48}\\\\mathrm{TiO}_2\\\\mathrm{H}$ , can be distinguished by analyzing the natural isotopic distribution in the mass spectrum or profile shape, as shown in Fig. S3. In this figure, the less abundant $^{49}\\\\mathrm{TiO}_2^-$ has an overlapping mass with $^{48}\\\\mathrm{TiO}_2\\\\mathrm{H}^-$ at $m/z = 64.945$ that cannot be resolved. However, by constructing the depth profile and seeing their profile shapes, it is possible to identify which molecule the peak corresponds to. In this case, there is a contribution from the Ti hydroxide. Similarly for Ni oxides, comparison of the profiles show that $^{60}\\\\mathrm{NiO}_2^-$ is the likely assignment for this peak instead of the hydroxide. The sharp decay in peak intensity for $^{48}\\\\mathrm{TiO}_2\\\\mathrm{H}^-$ at the surface indicates that the Ti oxide of the $\\\\mathrm{SrTiO_3}$ cap has adsorbed some hydrogen, but that has not affected the nickelate film. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[864,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,87,934,324]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0444/0d1e18f445daadf149cc9942ef9b075cf7b1eb5c96258958b0a4f7a881594738.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Label</td><td>Material</td><td>Synthesis</td><td>Figures</td></tr><tr><td>As-grown (La,Ca)NiO3Superconducting (La,Ca)NiO2Over-reduced (La,Ca)NiO2</td><td>5.4 nm La0.78Ca0.22NiO3 / SrTiO329 nm SrTiO3 / 4 nm La0.78Ca0.22NiO2 / SrTiO33.2 nm SrTiO3 / 3.5 nm La0.78Ca0.22NiO2 / SrTiO3</td><td>VA1</td><td>2b,c,d, S52a,b,c,d,e,f, S5S5</td></tr><tr><td>As-grown (La,Sr)NiO3Superconducting (La,Sr)NiO2Over-reduced (La,Sr)NiO2</td><td>5.3 nm La0.8Sr0.2NiO3 / SrTiO36 nm SrTiO3 / 4.2 nm La0.8Sr0.2NiO2 / SrTiO331 nm SrTiO3 / 4.4 nm La0.8Sr0.2NiO2 / SrTiO3</td><td></td><td>2b, S62a,b,g,h, S3, S6</td></tr><tr><td>Superconducting Nd6Ni5O12</td><td>100 nm Pt / 10 nm Ti / 23 nm Nd6Ni5O12 / NdGaO3</td><td>VA2</td><td>1c, 3a,b,c,d, S7</td></tr><tr><td>As-grown NdNiO3Reduced NdNiO2</td><td>17.3 nm NdNiO3 / SrTiO317.3 nm NdNiO2 / SrTiO3</td><td>VA2</td><td>4a,c,d, S8, S104a,e,f, S2, S8, S10</td></tr><tr><td>Reduced NdNiO2</td><td>16 nm NdNiO2 / SrTiO3</td><td></td><td>4b</td></tr><tr><td>As-grown (Nd,Sr)NiO3</td><td>10 nm Nd0.8Sr0.2NiO3 / SrTiO3</td><td>VA3</td><td>5a,c,d, 7a, S9, S11</td></tr><tr><td>As-grown capped (Nd,Sr)NiO3</td><td>10 nm SrTiO3 / 10 nm Nd0.8Sr0.2NiO3 / SrTiO3</td><td></td><td>5a, 7b, S11</td></tr><tr><td>Reduced (Nd,Sr)NiO2</td><td>10 nm Nd0.8Sr0.2NiO2 / SrTiO3</td><td></td><td>5a, S11</td></tr><tr><td>Reduced capped (Nd,Sr)NiO2</td><td>10 nm SrTiO3 / 10 nm Nd0.8Sr0.2NiO2 / SrTiO3</td><td></td><td>5b,e,f, S9, S11, S12, S13</td></tr><tr><td>Mica</td><td>(KF)2(Al2O3)3(SiO2)6(H2O)</td><td>MTI Corp.</td><td>S1</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE I. Table of samples and where they are referenced in this paper. Grouped samples are pieces split from the same deposited film. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[120,383,488,529]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0831/78536834c6697d77bc98e3ff5db7882f5130cd876eb5f1b2536c722363c54362.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[127,518,488,666]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0643/81bda40ae5e337f113263f0edeadcf0c6a2c7f799bf14e2941c163b5b4f459a9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[498,385,867,667]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S1. a. SIMS showing the spectral peak shapes of $\\\\\\\\mathrm{H}^{\\\\\\\\pm}$ , $\\\\\\\\mathrm{O}^{\\\\\\\\pm}$ , $\\\\\\\\mathrm{OH}^{\\\\\\\\pm}$ , and $\\\\\\\\mathrm{O}_2^{\\\\\\\\pm}$ ions. The broad peaks centered around $m/z = 1.02$ and $m/z = 17.03$ are attributed to charging effects, and were not included for the construction of the depth profile. b. SIMS depth profiles showing the integrated peak intensities as a function of sputtered depth for both elemental and molecular ions from a mica substrate. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0075/2d0bb9985969646e94f7b0708a5855804b8a9861284ab859300d08cfc148d036.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[112,772,485,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"D. Previous detection of hydrogen using SIMS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[109,810,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to place our observations into context, it is helpful to consider previous studies which used the ToF-SIMS instrument employed in this study to examine oxide films with large degrees of hydrogen incorporation, such as humidity-treated $\\\\mathrm{GdO}_x\\\\mathrm{H}_y$ , $\\\\mathrm{LaMnO_3}$ membranes exposed to water, and $\\\\mathrm{CaH_2}$ -reduced $\\\\mathrm{BaZrO_3}$ [31, 47, 48]. In Fig. S4, we show re \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,772,883,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"produced $\\\\mathrm{H}^{-}$ intensity curves from a $\\\\mathrm{LaMnO}_3$ fre-standing membrane with incorporated water due to the dissolution of $\\\\mathrm{Sr}_3\\\\mathrm{Al}_2\\\\mathrm{O}_6$ during processing[48]. Also shown is a film of $\\\\mathrm{GdO}_x\\\\mathrm{H}_y$ which is very near the $\\\\mathrm{Gd(OH)}_3$ composition[47]. In these systems, we found enhancements of the $\\\\mathrm{H}^{+}$ , $\\\\mathrm{H}^{-}$ , and $\\\\mathrm{OH}^{-}$ intensities which were 1 to 3 orders of magnitude above the substrate background, and were able to establish the high hydrogen concentrations based on the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[862,59,882,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,99,473,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S2. Comparison of ToF-SIMS hydrogen signals in reduced non-superconducting $\\\\\\\\mathrm{NdNiO_2}$ with surface adsorbate signals. Intensities have been normalized to the surface value. The slower decay of hydrogen intensities indicate that some of the hydrogen signal is intrinsic to the sample. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0498/809ff979d881e1bfe2341ce861cfe4635e5ef452fd8549d46a35a2656aca0f0f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[111,401,488,532]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"effects on the material properties. This prior experience provides reasonable upper and lower boundaries for expected effects and demonstrates our sensitivity to intrinsic hydrogen. Interestingly, the results from Ding et al. fell between these limits. We conclude therefore that hydrogen would readily have been detected in our measurements of layered square-planar nickelate samples if it were present at previously reported levels. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[153,560,444,574]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E. Extended SIMS Characterization \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,592,486,694]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For each sample, we have replotted SIMS depth profiles by scaling all intensities to an appropriate steady-state ion in the substrate to compare between sample types. Certain compounds with much higher $(\\\\mathrm{OH}^{-})$ or lower $(\\\\mathrm{H}^{-})$ intensities have been scaled for visualization clarity. These are shown in Figures S5, S6, S7, S8, and S9. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,694,486,867]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The layer interfaces are identified as halfway up the transitions of ions unique to each layer $(\\\\mathrm{TiO}_2^-)$ in the $\\\\mathrm{SrTiO_3}$ , $\\\\mathrm{NiO^{-}}$ in the nickelate film, $\\\\mathrm{GaO}_2^-$ in the $\\\\mathrm{NdGaO_3}$ , noting that heavier ions have broader depth profiles due to redeposition into the sputter crater. We also note that the sputter rate is faster for lower crystallinity layers, including amorphous $\\\\mathrm{SrTiO_3}$ caps, as well as lower-crystallinity reduced films. In fact, attempted measurements of the aggressively reduced $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ without protection of the $\\\\mathrm{SrTiO_3}$ cap sputtered through the film so quickly that no depth profile could be obtained. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,867,486,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SIMS reveals dramatic differences between as-grown, superconducting, and non-superconducting reduced samples. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,118,852,364]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S3. Comparison of the isotopic distributions of Ti and Ni oxides in superconducting $\\\\\\\\mathrm{La_{0.8}Sr_{0.2}NiO_2}$ . The less abundant isotopic oxides have an overlapping mass with the more abundant isotopic hydroxides. By scaling the depth profiles by the natural isotopic abundance, we can separate out these contributions. In this case, there is a contribution from the Ti hydroxide, but no evidence of Ni hydroxide. The sharp decay in peak intensity for $^{48}\\\\\\\\mathrm{TiO}_2\\\\\\\\mathrm{H}^-$ at the surface indicates that the Ti oxide of the $\\\\\\\\mathrm{SrTiO_3}$ cap has adsorbed some hydrogen, but that has not affected the nickelate film. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0981/a8b4376656dc614eafc335c0533bb9f596cb2b6eac547bb8a8ef93b70fd55a4c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[594,551,802,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S4. Examples of previously measured and published SIMS depth profiles for the $\\\\\\\\mathrm{H}^{-}$ ion in the hydrogen containing oxides $\\\\\\\\mathrm{LaMnO}_3\\\\\\\\mathrm{H}_x$ and $\\\\\\\\mathrm{GdO}_x\\\\\\\\mathrm{H}_y$ [47, 48], normalized to 1 in the substrate. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0014/e151e45916b3e6d71891a1b01f5281172f0d021cedb04ed53efb53e70d1bab24.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[506,808,882,866]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"First, changes in $\\\\mathrm{O}_2^-$ intensity within the films can be seen after reduction, confirming preferential removal of oxygen from the nickelate layers using $\\\\mathrm{CaH}_2$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,867,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Next, the $\\\\mathrm{NiO^{-}}$ and $\\\\mathrm{NiO_2^-}$ intensities and their ratio vary dramatically between samples, even when originating from the same as-grown sample. In par \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[862,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,98,880,385]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S5. ToF-SIMS depth profiles for the as-grown, superconducting and over-reduced $\\\\\\\\mathrm{La_{0.78}Ca_{0.22}NiO_{3\\\\\\\\rightarrow 2}}$ films, including those shown in 2. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0801/39e24ee80c4e861e0cd2a57bc0d996a69cac1986d0f32f6fbd328d2ad52a2ca9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[120,450,880,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S6. ToF-SIMS depth profiles for the as-grown and superconducting $\\\\\\\\mathrm{La}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_{3\\\\\\\\rightarrow 2}$ films including, those shown in 2. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0972/3610d08e345a595432eb6a034a48963e793e5d96a1e380660c140074c91d2eeb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[111,806,488,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ticular, though the intensities of these nickel oxides drops after reduction, they are not monotonic with reduction. In particular, we see that the $\\\\mathrm{TiO}_2$ -normalized intensities are an order of magnitude lower in the superconducting $\\\\mathrm{La}_{0.78}\\\\mathrm{Ca}_{0.22}\\\\mathrm{NiO}_2$ but increase again in the over-reduced film (Fig. S5). Furthermore, this effect is not seen in all samples \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,806,882,866]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Fig. S8). We conclude that the Ni valence and electronic state significantly affect the measured intensities of many ions [49, 50], making even quantitative sample-to-sample comparisons difficult. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,867,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, though we see no evidence for extensive hydrogen incorporation in any of these samples, the hydrogen signals which are measured are primarily \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[862,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,98,872,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S7. ToF-SIMS depth profile for the $\\\\\\\\mathrm{Nd}_6\\\\\\\\mathrm{Ni}_5\\\\\\\\mathrm{O}_{12}$ film shown in 3. Intensities are normalized to the steady-state $\\\\\\\\mathrm{GaO}_2^-$ in the $\\\\\\\\mathrm{NdGaO_3}$ substrate. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0202/fdcc8296a45fcd2b24120ba244a8f8cbf877ae439318fe455d29d50f269f07b0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[112,448,880,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S8. ToF-SIMS depth profiles for the $\\\\\\\\mathrm{NdNiO_3}$ and non-superconducting $\\\\\\\\mathrm{NdNiO_2}$ films shown in 4. Intensities are normalized to steady-state $\\\\\\\\mathrm{TiO_2^-}$ or $\\\\\\\\mathrm{Sr^{+}}$ in the $\\\\\\\\mathrm{SrTiO_3}$ substrate. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0854/f56fee29873a6d4294a4414a41972947b6929173bc39aa78b0faf287e2734f88.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[111,811,488,853]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"present as $\\\\mathrm{OH}^{-}$ , and secondarily $\\\\mathrm{H}^{-}$ . The $\\\\mathrm{H}^{+}$ peak is orders of magnitude smaller, and in many cases undetectable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[568,811,826,840]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"F. Electrical characterization of non-superconducting films \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,867,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. S10 shows resistance vs. temperature for the non-superconducting, undoped $\\\\mathrm{NdNiO_3 / SrTiO_3}$ shown in Fig. 4. These electrical transport mea \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[864,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[120,90,880,385]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S9. ToF-SIMS depth profiles for the $\\\\\\\\mathrm{Nd}_{0.8}\\\\\\\\mathrm{Sr}_{0.2}\\\\\\\\mathrm{NiO}_3$ and $\\\\\\\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ shown in 5. Intensities are normalized to steady-state $\\\\\\\\mathrm{TiO}_2^-$ in the substrate. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0110/2dfba6098e4980b2e98ea3a273cf909cac6b7a8d0633171b5c51f699ea9c6ca4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[127,463,488,642]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S10. Two-point resistance measurements of as-grown and reduced $\\\\\\\\mathrm{NdNiO}_{3\\\\\\\\rightarrow 2}$ shown in Fig. 4. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0917/a5994f566079b6f5a9be8f9444a4fa082440de40f23e22ca14255abe0742fdb1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,722,486,881]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"surements were taken using a home-built electrical \\\"dipstick probe\\\" compatible with a helium dewar. Indium contacts were soldered on the four corners of each sample in a van der Pauw (VDP) configuration. AC transport measurements were taken at $17.777\\\\mathrm{Hz}$ using an SR-830 lock-in amplifier. The voltage and current were measured simultaneously to determine the resistance. Note that values shown are the measured resistance of a single VDP channel of these $5\\\\mathrm{mm} \\\\times 10\\\\mathrm{mm}$ samples, not sheet resistance or resistivity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,882,486,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The original as-grown film shows the hysteretic metal-insulator transition expected for a stoichi-\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,455,882,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"metric $\\\\mathrm{NdNiO_3}$ film, while the reduced infinite-layer film exhibits the metallic behavior expected for undoped $\\\\mathrm{NdNiO_2}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,500,883,643]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ films were insulating enough that two-point resistances were measured only at room temperature. As-grown, without significant growth optimization, uncapped films started with resistances between $500\\\\mathrm{k}\\\\Omega$ to $700\\\\mathrm{k}\\\\Omega$ , while capped films started with resistances between $6\\\\mathrm{k}\\\\Omega$ to $8\\\\mathrm{k}\\\\Omega$ . After reduction, the resistance of uncapped films actually increased and was not measurable using a standard multimeter, while capped films had a lower resistance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[542,676,849,690]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"G. Further structural characterization \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,708,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure S11 shows complementary XRD measurements of the capped and uncapped $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_{3\\\\rightarrow 2}$ films taken using two configurations of a Rigaku SmartLab XRD. The top scans were measured in a high-intensity mode, using a parallel beam (PB) selection slit, and a parallel slit analyzer (PSA). Cu $\\\\mathrm{K}\\\\alpha$ lines were selected using a Ni filter. The lighter color scans were measured in a high-resolution mode, using a Ge $(220)\\\\times 2$ monochromator to select Cu $\\\\mathrm{K}\\\\alpha_{1}$ radiation on the incident side. The Diffracted Beam Monochromator assembly was installed on the receiving side containing a Ni filter, Ge $(400)\\\\times 2$ analyzer, and $0.5^{\\\\circ}$ PSA. While the high-resolution measurements allow \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[862,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[200,95,803,554]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S11. Full XRD scans of samples in Figure 5a taken using two instrument configurations. On top are high-intensity, low-resolution measurements used to survey for impurity phases, while on bottom are the same scans taken using a lower-intensity, high-resolution mode. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0217/5b804b39a0e0ae29e6d4eef2ffff758f850e90c58ba8af4ba9ab5f035e0ef5b0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[111,645,485,718]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"us to measure the as-grown NSNO (002) film peak at $47.485^{\\\\circ}$ , and confirms the much lower intensity of the corresponding (001) peak, the peaks of the reduced film are so low in intensity that they cannot be seen at all. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[111,722,485,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The crystalline quality and nature of defects in the reduced $\\\\mathrm{SrTiO_3}$ -capped $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ films is studied by cross-sectional HAADF-STEM studies and is observed to be highly defective as shown in Fig. 5b. Mosaicity is observed in the $(\\\\mathrm{Nd},\\\\mathrm{Sr})\\\\mathrm{NiO}_2$ layer, appearing as a mixture of amorphous-like and crystalline domains, marked by the circles in 5b. Particularly, two different atomic arrangements deviating from the projected [100] perovskite structure is observed in the crystalline regions marked as 2 and 3 in 5b. Similar defects are present uniformly throughout the observed thin region ( $\\\\sim 5\\\\mu \\\\mathrm{m}$ ) of the FIB foil. The Fast Fourier Transform (FFT) of the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,645,883,849]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"atomic resolution HAADF-STEM image is shown in the inset of Fig. S12a. The sharp spots with the 4-fold symmetry corresponds to the $\\\\mathrm{SrTiO_3}$ perovskite structure along the [100] orientation. The FFT also shows the presence of additional spots corresponding to periodicities deviating from the STO structure (marked by the green arrows in inset of Fig. S12a), indicating the occurrence of a phase transformation, most likely during the reduction process. The presence of weak diffused rings corresponds to the presence of the amorphous regions (marked by the dashed circle in inset of Fig. S12a). The $\\\\mathrm{SrTiO_3}$ capping layer is also observed to consist of defects as shown in Fig. S12b-d. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,853,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Further, the chemical nature of the film was studied using STEM-EDS mapping. The elemental maps show chemical segregation in the reduced $\\\\mathrm{SrTiO_3 / Nd_{0.8}Sr_{0.2}NiO_2}$ film in the form of Ni-rich \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[864,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"18 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[116,87,880,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0182/d6b3ba9e9a58426f9105c1c697fbba9ed56d4285f1ebdb17f60f3801b8f99053.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[114,396,359,614]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0294/87b1c579a28254b2a6fbc5b8015f90ed8ae8b7beae7e033a19958c07f80c9ba1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[361,396,650,614]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0285/3d4fdea86ecab4737414e4fcd79f333c6bdb17d43bfd62c090bcbfcdbbe10d57.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[651,396,877,614]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S12. (a) The larger field of view of the image shown in 5b, showing the presence of defects in the STO capping layer as well. The inset shows the FFT pattern of the image. The spots corresponding to the cubic STO substrate (and cap) is denoted by the square, the extra spots and the diffused ring indicate the presence of additional crystalline and amorphous regions in the films, as respectively shown by the arrows and dashed semi-circle. (b-d) Magnified regions of the $\\\\\\\\mathrm{SrTiO_3}$ capping layer showing the presence of various forms of defects, with a schematic structural model overlaid ( $\\\\\\\\mathrm{Sr} = \\\\\\\\mathrm{green}$ , $\\\\\\\\mathrm{Ti} = \\\\\\\\mathrm{blue}$ , $\\\\\\\\mathrm{O} = \\\\\\\\mathrm{red}$ spheres). (b) Region 1 shows a Ruddlesden-Popper-like phase at the nickelate-cap interface. (c) Region 2 shows strong signal from the oxygen columns, which cannot be only due to O as low Z elements cannot to scatter to the high collection angle used in this experiment. (d) Region 3 shows the planes in the $\\\\\\\\mathrm{SrTiO_3}$ cap are highly distorted. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0134/2f692c1350baed5392334091ca4ec2a1e211c027f1b3dd66e3d174598006d6fc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[109,775,486,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and Nd-rich regions and shown in Fig. S13a-d. By correlating the chemical maps with the high-resolution HAADF image, it is observed that the Nd-rich regions correspond to the amorphous-like regions, while the Ni-rich region correspond to the crystalline regions. Finally, Sr was not observed to be concentrated in this film. The STEM results thus provide a direct proof for the crystalline and chemical disorder in the $\\\\mathrm{Nd}_{0.8}\\\\mathrm{Sr}_{0.2}\\\\mathrm{NiO}_2$ film after the ag \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,776,702,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"gressive reduction process. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[594,821,797,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"H. Additional DFT data \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,853,883,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We provide here the structural data obtained from DFT-based structural relaxations for two choices of exchange-correlation functional: GGA-PBE and GGA-PBEsol. The optimized lattice constants for \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[864,59,883,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"19 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,89,553,224]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0988/5270d04aca8ab3166543274f07bc17cbcb8820fbd9630cb7bd73b38c8bfea6c5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[122,224,553,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0722/e42fcee7ce8a4a52e577b6c153c0b2ae39ce8467fbf5c62118ee821e9d3f2dd8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[122,351,553,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0310/af2870b7c032e55c1f2164a8f4068b141108fcd5b439a7cd8ad9fd10ff0e4858.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[122,474,553,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0363/0459cfdc5e72d2ea64c4bd07498c808b62b7c6e72956c94844d0ff892313adc4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[557,90,883,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0715/4f35f6561cdead91f4553654ec38d26259398101c2f51b2de9c0d27bf15a65b6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[557,345,883,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S13. (a-d) HAADF-STEM image and the corresponding EDS elemental maps obtained from the reduced $\\\\\\\\mathrm{SrTiO_3}$ -capped $(\\\\\\\\mathrm{Nd},\\\\\\\\mathrm{Sr})\\\\\\\\mathrm{NiO}_2$ film. A clear segregation of Ni and Nd is observed in the nickelate film. (e, f) The amorphous-like and crystalline domains correspond to the Nd-rich and Ni-rich region, respectively. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0748/ac72c1aae501bec5f5260a1aaadac02ad4797714cd2bedbb011cfe38d0d57605.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[111,681,488,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"all the nickelates considered in the main text within these two functionals are summarized in Fig. S14. We find good agreement with the experimental lattice constants for the undoped infinite-layer compounds $(R = \\\\mathrm{La},\\\\mathrm{Nd})$ is obtained with the GGA-PBE functional, which serves as a benchmark for our DFT-optimized lattice constants $(a_{exp} = 3.92\\\\AA ,$ $c_{exp} = 3.28\\\\AA$ for $\\\\mathrm{NdNiO_2}$ and $a_{exp} = 3.96\\\\AA$ $c_{exp} =$ 3.38 Å for $\\\\mathrm{LaNiO_2}$ [22, 51]). Previous works have used PBEsol to obtain H-binding energies in infinitelayer nickelates [26, 52], but we find that the GGA-PBEsol functional gives rise to optimized lattice constants that are quite far from the experimental values. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[862,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"20 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[119,95,464,276]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0151/7c5538a96776996b89fec4076e7f67c0e3b0a53c03cf1327418fae6444415ba7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[117,284,480,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. S14. Structural data from the DFT-optimized structures. (a) In-plane $(a)$ lattice constants. (b) Out-of-plane $(c)$ lattice constants (right axis corresponds to $\\\\\\\\mathrm{Nd}_6\\\\\\\\mathrm{Ni}5\\\\\\\\mathrm{O}_{12}$ ). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0822/038a8ba75784164c706d50f449156be212898e0df2e26e7a7d78f54617e799c0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[862,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"21 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[116,128,485,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] Anisimov, V. 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URL https://doi.org/10.1038/s42005-023-01213-0. \\\"]\",\n \"page_idx\": \"21\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[511,128,882,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[14] Lu, H. et al. Magnetic excitations in infinite-layer nickelates. Science 373, 213-216 (2021). \\\",\\\"[15] Zhou, X. et al. Experimental progress on the emergent infinite-layer ni-based superconductors. Materials Today 55, 170-185 (2022). URL https://www.sciencedirect.com/science/article/pii/S1369702122000591. \\\",\\\"[16] Ferenc Segedin, D. et al. Limits to the strain engineering of layered square-planar nickelate thin films. Nature communications 14, 1468 (2023). \\\",\\\"[17] Lee, K. et al. 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Identification of Eu oxidation states in a doped $\\\\\\\\mathrm{Sr}_5(\\\\\\\\mathrm{PO}_4)_3\\\\\\\\mathrm{F}$ phosphor by tof-sims imaging. Opt. Express 20, 17119-17125 (2012). URL https://opg.optica.org/oe/abstract.cfm?URI=oe-20-15-17119. \\\",\\\"[50] Seed Ahmed, H., Swart, H. & Kroon, R. Investigating the capability of ToF-SIMS to determine the oxidation state of Ce. Physica B: Condensed Matter 535, 124-127 (2018). URL https://www.sciencedirect.com/science/article/pii/S0921452617303824. 7th South African Conference on Photonic Materials SACPM 2017. \\\",\\\"[51] Hayward, M. & Rosseinsky, M. Synthesis of the infinite layer ni(i) phase $\\\\\\\\mathrm{NdNiO}_{2+x}$ by low temperature reduction of $\\\\\\\\mathrm{NdNiO}_3$ with sodium hydride. Solid State Sciences 5, 839-850 (2003). URL https://www.sciencedirect.com/science/article/pii/S1293255803001110. International Conference on Inorganic Materials 2002. \\\",\\\"[52] Si, L., Worm, P., Chen, D. & Held, K. Topotactic hydrogen forms chains in $ABO_2$ nickelate superconductors. Physical Review B 107, 49-51 (2023). \\\"]\",\n \"page_idx\": \"22\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[862,59,880,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"23 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.48550/arxiv.2403.01796"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences/Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"9d78953bc80a859d4b44272908c46a6605d6fd835f760b9ba9ccff2bec90b46b"},"title":{"kind":"string","value":"Hydrogen is not necessary for superconductivity in topotactically reduced nickelates"}}},{"rowIdx":168,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Rakesh K Tandon|Rajiv Baijal"},"content_list":{"kind":"list like","value":[{"bbox":"[87,76,270,90]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORIGINAL ARTICLE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[87,99,894,145]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of lactase on symptoms and hydrogen breath levels in lactose intolerance: A crossover placebo-controlled study ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[87,149,374,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rajiv Baijal and Rakesh K Tandon ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,173,620,185]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Institute of Gastroenterology, Pushpawati Singhania Hospital and Research Institute, New Delhi, India ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,235,157,246]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Key words ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[85,249,347,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"lactase enzyme, lactose hydrogen breath test, lactose intolerance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,289,341,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted for publication 18 November 2020. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,315,189,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Correspondence ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[85,329,342,381]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dr Rajiv Baijal, Institute of Gastroenterology, Pushpawati Singhania Hospital and Research Institute, Sheikh Sarai, Phase 2, New Delhi 110017, India. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,383,257,395]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Email: endolife99@gmail.com ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,409,326,421]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Declaration of conflict of interest: None ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,436,374,448]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding support: Walter Bushnell Private Limited ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[389,232,480,246]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[388,253,919,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background and Aim: The absence of lactase in the intestinal villi due to mucosal injury or genetic factors causes undigested lactose to reach the colon where it is fermented. Lactose intolerance is diagnosed based on clinical symptoms like bloating, abdominal pain and flatulence, lactose hydrogen breath test (HBT), and lactose tolerance test. No Indian studies are available on the use of lactase supplements. The aim was to study the effect of lactase chewable tablets on clinical symptoms and hydrogen breath excretion in patients with lactose intolerance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[388,352,919,448]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: This was a randomized, double-blind, crossover placebo-controlled trial to study the effect of lactase tablets on symptoms and hydrogen breath levels in adults with lactose intolerance, confirmed by Lactose HBT. Clinical symptom severity was recorded using a visual analog scale, and HBT was performed every $30\\mathrm{min}$ for $180\\mathrm{min}$ . As it was a crossover design, the same patients were tested with both lactase and placebo, acting as their own controls with a washout period of 1 week between visits. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[388,451,919,521]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Forty-seven patients (mean age 33.6 years; 30 males) with lactose intolerance formed the study group. Clinical symptoms, mean clinical score $(P < 0.05)$ , and mean hydrogen breath levels $(P < 0.05)$ were improved when the patients were given lactase. Reduction in cumulative hydrogen breath level over $180\\mathrm{min}$ was $55\\%$ when patients received lactase compared to placebo. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[388,521,919,549]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions: Orally supplemented lactase enzyme significantly reduced the clinical symptoms and hydrogen breath excretion in patients with lactose intolerance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,575,213,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[85,598,490,725]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lactase in the small intestinal villi breaks down lactose into glucose and galactose. In the absence of lactase due to mucosal injury or, more commonly, due to reduced genetic expression of the enzyme lactase-phlorizin hydrolase, $^{1}$ undigested lactose reaches the colon, where bacteria ferment it, generating $\\mathrm{H}_2$ , $\\mathrm{CO}_2$ , lactic acid, and acetic acid, drawing water into the colon by osmosis. This results in clinical symptoms like diarrhea, abdominal pain, bloating, borborygmi, nausea, and flatulence after ingestion of milk or dairy products. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,725,490,781]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Often, at birth, there is insufficient lactase available in the intestinal villi. By 5-6 months, sufficient lactase starts being produced. The production of lactase enzyme starts decreasing after the age of 5-8 years.[2] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,782,490,881]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is suggested that only about $35\\%$ of people worldwide are lactase-persistent, who continue to produce lactase throughout adulthood, and thus are able to digest the sugar in milk without discomfort. Lactase deficiency can be seen in up to $15\\%$ of persons of Northern European descent, up to $80\\%$ of Blacks and Latinos, and up to $100\\%$ of American Indians and Asians. An Indian study conducted by Babu et al. indicated that the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,576,919,634]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frequency and degree of lactose malabsorption is higher in South Indians compared to North Indians because of genetic differences in the population. The reported incidence was the highest in the south at $82\\%$ and $66\\%$ in the north.[5] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,635,919,691]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tandon et al. suggested that the lower incidence of lactose intolerance in North Indian subjects may perhaps be because they are descendants of the Aryans who have been dairying for long and are known to be lactose tolerant.[6] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,693,919,780]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is a common practice for clinicians to advise lactose-intolerant patients to avoid milk and dairy products, but that may cause calcium, vitamin D, and riboflavin deficiency states; decrease quality of life; and lead to osteoporosis and depression. Lactase-pretreated food products and external lactase enzyme are two of the dietetic treatments for lactose-intolerant patients. $^{1}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,780,919,823]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is therefore logical to coadminister lactase enzyme along with milk/dairy products so that the latter are digested and assimilated and yet do not produce the symptoms of intolerance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,823,919,881]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present study aimed to test this hypothesis. It was a randomized, double-blind, placebo-controlled trial to observe the effect of marketed lactase supplement on patients with lactose intolerance. The source of this lactase is Aspergillus oryzae, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,3,346,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open An open access journal of gastroenterology and hepatology Open Access ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[805,6,894,35]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGHF Journal of Gastroenterology and Hepatology Foundation ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[779,40,919,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"doi:10.1002/jgh3.12463 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[85,906,489,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[85,918,897,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[85,945,917,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[907,906,917,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[73,78,480,136]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which is presently marketed in India as a food supplement. Although there are numerous international trials available, no trials on lactase enzyme have been conducted in India despite the supplement being used by many. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,136,480,180]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The aim was to study the effect of lactase chewable tablets (Yamoo) on clinical symptoms and hydrogen breath excretion in patients with lactose malabsorption and intolerance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,210,164,226]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[73,232,478,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study was a randomized, crossover, double-blind, placebo-controlled trial, in which we studied the effect of an orally administered marketed lactase supplement (Lactase 4500 FCC chewable tablets) on hydrogen breath levels and intestinal symptoms in patients with lactose intolerance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,303,478,332]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The trial was registered at Clinical Trials Registry India (ICMR-NIMS) with registration number: CTRI/2018/03/012295. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,332,478,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study was conducted at the Department of Gastroenterology, Pushpawati Singhania Research Institute for Liver, Renal & Digestive Diseases, New Delhi, in accordance with the ethical principles outlined in the Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical Practice Guidelines, and local regulatory requirements. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,416,480,599]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An earlier study had shown that the hydrogen breath level was reduced from $31.8 \\pm 8.3$ ppm to $14.7 \\pm 8.0$ ppm on treatment with lactase (a decrease of $17.1$ ppm). The placebo arm had shown a slight increase from $30.7 \\pm 8.7$ ppm to $31.9 \\pm 8.0$ ppm. An effect size of 0.5 was fixed under the assumption that similar results would be obtained for the present study. With statistical significance of $5\\%$ , a minimum study power of $80\\%$ and a patient dropout rate of $2\\%$ , each group would have 40 subjects. The study would have two arms—the experimental arm and the placebo arm—into which the patients would be randomly divided. To improve the statistical validity of the study, a crossover design would be used. Thus, we conducted a crossover, double-blind, placebo-controlled study with 50 patients. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,599,480,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Patients were randomized into two groups—A and B—such that half of them received treatment, and the other half received placebo, coded as Alpha and Beta, respectively. The randomization sequence was generated in advance by a computerized random number generator. Lactase and placebo tablets were identical in shape, size, color, taste, and smell. After a washout period of 1 week, the treatment assigned to each group was interchanged. We decided on an interceding period of 1 week to remove any residual effects of the previous treatment. All patients received both therapies, that is, lactase and placebo. Participants, investigators, and outcome assessors were blinded to the treatment assigned. The code was stored in a sealed envelope and retained under lock and was broken and disclosed to the investigators only after complete data entry was performed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,796,480,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study population consisted of patients between 18 and 65 years of age with a medical history consistent with lactose intolerance, confirmed by the lactose hydrogen breath test (HBT). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,852,480,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Patients were included if they were able to comprehend the study instructions, complete the requisite visits, consensually participate in the study, and sign the informed consent form (ICF). We included patients from Delhi and NCR (National ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,78,907,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Capital Region) because of the need for a minimum of three visits, 1 week apart. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,107,907,246]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Patients were excluded from the study group if they had diverticular disease, diabetic gastroparesis, HIV, immunosuppression of any origin, or cancer under treatment. Patients with conditions that could compromise participation in the study—such as hypersensitivity or previous laboratory or clinical adverse events related to the use of lactase or any of the components of the formulations used in the study, systemic infection during the study or use of antibiotics in the last 4 weeks, diabetes mellitus, uncontrolled hypertension or renal failure, pregnancy, lactation, and chronic pulmonary disease—were also excluded. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,246,907,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study duration was 1 year, conducted from March 2018 to April 2019. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,274,907,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At the first visit, patients with a history of lactose intolerance fulfilling the inclusion criteria were clinically assessed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,304,907,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A baseline HBT using the Bedfont Gastrolyzer hand-held breath analyzer was performed. To minimize basal hydrogen excretion, patients were asked to have a carbohydrate-restricted dinner on the day before the test and fast for at least $12\\mathrm{h}$ on the day of the test. Before starting the test, patients washed their mouths with $20\\mathrm{ml}$ of $0.05\\%$ chlorhexidine. Smoking and physical exercise was not allowed for $30\\mathrm{min}$ before and during the test. End-alveolar breath samples were collected immediately before lactose ingestion, and then, a dose of $25\\mathrm{g}$ of lactose was administered, and breath samples were collected every $30\\mathrm{min}$ for $3\\mathrm{h}$ (0, 30, 60, 90, 120, 150, and $180\\mathrm{min}$ ). Symptom scores for abdominal pain, bloating, flatulence, borborygmi, and diarrhea were recorded at these intervals using the visual analog scale. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,500,907,528]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The test was considered positive (lactose malabsorption) if hydrogen concentrations were at least $20~\\mathrm{ppm}$ above baseline. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,529,907,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Patients were randomly allocated to two groups—A and B. Each patient was called a week later. At the second visit, a similar procedure was repeated, but this time, the patients in group A consumed three chewable lactase 4500 FCC tablets $5\\mathrm{min}$ before the $25 - \\mathrm{g}$ lactose load, while patients in group B were given a placebo. The HBT values and symptoms were recorded as previously described. One week later, at the third visit, patients of group A received placebo, while group B received lactase tablets. Hence, each patient from each group was exposed to the experimental product and the placebo, with a washout interval of 1 week. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[544,682,806,696]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study design is illustrated in Figure 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[544,698,873,710]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adverse events were monitored throughout the study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,712,907,753]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For each group, mean clinical score of symptoms and mean hydrogen levels (ppm) at each time interval for each visit were calculated. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,781,907,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Statistical analysis. Categorical variables were presented in number and percentage $(\\%)$ , and continuous variables were presented as mean. Normality of data was tested using the Kolmogorov-Smirnov test. If the normality was rejected, then a nonparametric test was used. Quantitative variables were compared using the Mann-Whitney Test (as the datasets were not normally distributed) between the two groups. A $P$ -value of $< 0.05$ was considered statistically significant. The data was entered into an MS Excel spreadsheet, and analysis was carried ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,40,349,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of lactase tablets on lactose intolerance ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[764,40,907,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"R Baijal and RK Tandon ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[77,934,87,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[507,934,907,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[99,947,907,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[742,960,907,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"John Wiley & Sons Australia, Ltd. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[201,79,794,474]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1 Flow chart showing the trial methodology. \"]","image_footnote":"[]","img_path":"images/0295/8d79ed81561c0cd87b80b20d17e0296b0e3f2811cfd5c74007cffbe484f66af5.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[85,529,490,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"out using Statistical Package for Social Sciences (SPSS) IBM version 21.0. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,557,490,612]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Area under the curve for cumulative hydrogen breath excretion over $180\\mathrm{min}$ was calculated and compared between the placebo-lactase crossover groups $(n = 47)$ using the trapezoid rule in MS Excel. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,613,490,725]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to account for errors in random sampling, the margin of error for difference of means in the HBT levels and overall symptom levels (expressed as the sum of each of the levels of abdominal pain, bloating, flatulence, borborygmi, and diarrhea using the visual analog scale) for the placebo and lactase groups was determined as the product of standard deviation and $z$ -value at $95\\%$ and $99\\%$ confidence intervals each. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,529,591,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,552,919,635]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sixty-seven patients were tested for lactose intolerance by HBT, of which 50 were found to have lactose intolerance. Three patients were lost to follow-up; hence, 47 (mean age 33.6 years; 30 males, 17 females) patients formed the study group. These were randomized into two groups, group A $(n = 23)$ and group B $(n = 24)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,636,919,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"No significant adverse events were detected throughout the study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,664,919,721]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There was no statistically significant difference in clinical symptoms and mean clinical score (abdominal pain, bloating, flatulence, borborygmi, diarrhea) and hydrogen breath levels between groups A and B at baseline (Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,758,921,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0192/1aceeb9a02dba083a9f6823dcde22233c4207e97cbe72ec29bc1e52e9ea0c1b8.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Time (minutes)</td><td colspan=\"3\">Baseline mean clinical score</td><td colspan=\"3\">Baseline mean hydrogen breath levels (ppm)</td></tr><tr><td>Group A (n = 23)</td><td>Group B (n = 24)</td><td>P value</td><td>Group A (n = 23)</td><td>Group B (n = 24)</td><td>P value</td></tr><tr><td>0</td><td>1.516</td><td>1.836</td><td>0.248</td><td>39.70</td><td>38.54</td><td>0.840</td></tr><tr><td>30</td><td>1.666</td><td>1.764</td><td>0.308</td><td>45.56</td><td>45.38</td><td>0.758</td></tr><tr><td>60</td><td>1.798</td><td>1.900</td><td>0.354</td><td>93.35</td><td>76.83</td><td>0.544</td></tr><tr><td>90</td><td>1.926</td><td>1.544</td><td>0.446</td><td>113.74</td><td>89.83</td><td>0.400</td></tr><tr><td>120</td><td>1.694</td><td>1.400</td><td>0.476</td><td>132.44</td><td>105.00</td><td>0.202</td></tr><tr><td>150</td><td>1.524</td><td>1.428</td><td>0.550</td><td>136.61</td><td>130.83</td><td>0.873</td></tr><tr><td>180</td><td>1.476</td><td>1.390</td><td>0.498</td><td>146.22</td><td>140.83</td><td>0.655</td></tr></table>","table_caption":"[\"Table 1 Baseline mean clinical score and hydrogen breath values at visit 1 \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[87,40,231,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"R Baijal and RK Tandon ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[645,40,919,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of lactase tablets on lactose intolerance ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[85,934,489,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[85,947,895,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[907,934,919,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[75,95,912,258]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0513/3d99fdf5a0fb649059cc5ca36bda051cef976dde2f19fcbc9de533b95115d4a2.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Time (minutes)</td><td colspan=\"3\">Mean clinical score</td><td colspan=\"3\">Mean hydrogen breath levels (ppm)</td></tr><tr><td>Group A (n = 23) (lactase)</td><td>Group B (n = 24) (placebo)</td><td>P value</td><td>Group A (n = 23) (lactase)</td><td>Group B (n = 24) (placebo)</td><td>P value</td></tr><tr><td>0</td><td>0.262</td><td>1.458</td><td>0.253</td><td>25.83</td><td>31.67</td><td>0.183</td></tr><tr><td>30</td><td>0.484</td><td>1.700</td><td>0.319</td><td>28.17</td><td>33.33</td><td>0.079</td></tr><tr><td>60</td><td>0.662</td><td>1.508</td><td>0.171</td><td>39.83</td><td>53.08</td><td>0.027</td></tr><tr><td>90</td><td>0.392</td><td>1.474</td><td>0.199</td><td>53.52</td><td>78.92</td><td>0.012</td></tr><tr><td>120</td><td>0.234</td><td>1.392</td><td>0.068</td><td>56.96</td><td>96.38</td><td>0.021</td></tr><tr><td>150</td><td>0.348</td><td>1.302</td><td>0.267</td><td>59.78</td><td>98.42</td><td>0.012</td></tr><tr><td>180</td><td>0.244</td><td>1.132</td><td>0.266</td><td>58.44</td><td>109.46</td><td>0.008</td></tr></table>","table_caption":"[\"Table 2 Mean clinical score and hydrogen breath values at visit 2 when group A received lactase and group B received placebo \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[73,297,478,381]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At visit 2, when group A received lactase and group B received placebo, clinical symptoms and mean clinical scores were lower in group A than in group B, and hydrogen breath levels were lower in group A compared to group B, and the difference was statistically significant at 60, 90, 120, 150, and $180\\mathrm{min}$ (Table 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,381,478,479]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At visit 3, when group B received lactase and group A received placebo, clinical symptoms and mean clinical score (abdominal pain, bloating, flatulence, borborygmi and diarrhea) were lower in group B than in group A. The difference between mean clinical score for groups B and A was statistically significant, with a $P$ -value of 0.041 at $120\\mathrm{min}$ specifically for abdominal pain, bloating, and flatulence (Table 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,480,478,535]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At visit 3, when group B received lactase tablets, the hydrogen breath levels were lower compared to group A, and the difference was statistically significant at $90\\mathrm{min}$ and subsequently till $180\\mathrm{min}$ (Table 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,535,478,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the crossover design, when a group of patients received lactase, the mean clinical score and the hydrogen breath levels were lower than when the same group of patients received placebo (Table 4, Figs 2,3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,593,480,677]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A difference in means of clinical symptom values that are lower than the margin of error is indicative of the action of the drug (Table S1, Supporting information). Margins of errors have been calculated at a $99\\%$ confidence interval. At time $t = 0$ , the difference between means of the clinical symptoms expressed by patients in the placebo and lactase groups is 1.04, of which 0.36 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,297,907,381]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is due to statistical error (with $99\\%$ confidence); the remaining is accounted for by the action of the drug. As time passes, the difference in means decreases monotonically along with the margins of error at a $99\\%$ confidence interval, indicating that, as time passes, the action of the drug accounts for a decrease in exhibited symptom. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,381,907,479]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As shown in Table S1, the difference of means for hydrogen breath levels that are lower than the margin of error is indicative of the action of drug rather than a difference due to sampling error. At $60\\mathrm{min}$ , the margin of error at $99\\%$ confidence is 5.195 (confidence interval 10.10-20.49), indicating that the action of lactase leads to an observable decline in hydrogen breath levels. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,480,907,563]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reduction in cumulative hydrogen breath level was $55\\%$ when patients received lactase compared to placebo. Maximum reduction took place in the final $30\\mathrm{min}$ of the 3-h period. The percentage reduction of hydrogen emitted in the breath monotonically increases with time, demonstrating that the efficacy of the drug increases over time (Table S2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,565,907,677]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"These results show that the clinical symptoms improved when patients received lactase compared to when they received placebo. The mean clinical score and mean and cumulative hydrogen breath values were significantly lower when the patients in either of the groups received lactase compared to placebo. As it was a crossover design, the same patients were tested with both lactase and placebo—indicating that clinical symptoms, mean clinical score, and mean and cumulative hydrogen ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,730,912,893]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0421/66e900eb4ae4b9ff2fbc2c84b544233cd7ebffec700cb40b2ea3cf3682e1affd.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Time (minutes)</td><td colspan=\"3\">Mean clinical score</td><td colspan=\"3\">Mean hydrogen breath levels (ppm)</td></tr><tr><td>Group A (n = 23) (placebo)</td><td>Group B (n = 24) (lactase)</td><td>P value</td><td>Group A (n = 23) (placebo)</td><td>Group B (n = 24) (lactase)</td><td>P value</td></tr><tr><td>0</td><td>1.148</td><td>0.268</td><td>0.293</td><td>24.39</td><td>29.75</td><td>0.966</td></tr><tr><td>30</td><td>1.268</td><td>0.400</td><td>0.279</td><td>27.70</td><td>26.96</td><td>0.348</td></tr><tr><td>60</td><td>1.380</td><td>0.368</td><td>0.246</td><td>56.44</td><td>39.04</td><td>0.198</td></tr><tr><td>90</td><td>1.068</td><td>0.158</td><td>0.257</td><td>82.56</td><td>43.83</td><td>0.019</td></tr><tr><td>120</td><td>1.010</td><td>0.056</td><td>0.041</td><td>85.17</td><td>48.92</td><td>0.009</td></tr><tr><td>150</td><td>0.766</td><td>0.048</td><td>0.255</td><td>94.91</td><td>56.33</td><td>0.022</td></tr><tr><td>180</td><td>0.688</td><td>0.056</td><td>0.117</td><td>95.52</td><td>57.88</td><td>0.022</td></tr></table>","table_caption":"[\"Table 3 Mean clinical score and hydrogen breath values at visit 3 when group A received placebo and group B received lactase \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[77,40,351,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of lactase tablets on lactose intolerance ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[764,40,907,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"R Baijal and RK Tandon ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[77,934,87,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[507,934,907,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[99,947,907,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[742,960,907,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"John Wiley & Sons Australia, Ltd. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[87,95,922,244]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0954/e02b66956621fd2107fb125af443cdac3dc47bc44c43539886e7483cc1e345bc.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Time (minutes)</td><td colspan=\"3\">Mean clinical score</td><td colspan=\"3\">Mean hydrogen breath levels (ppm)</td></tr><tr><td>Placebo (n = 47)</td><td>Lactase (n = 47)</td><td>P value</td><td>Placebo (n = 47)</td><td>Lactase (n = 47)</td><td>P value</td></tr><tr><td>0</td><td>1.306 (0.90)</td><td>0.265(0.13)</td><td>0.029</td><td>28.11(8.22)</td><td>27.83 (6.69)</td><td>0.398</td></tr><tr><td>30</td><td>1.488(0.85)</td><td>0.441(0.10)</td><td>0.021</td><td>30.57(8.92)</td><td>27.55 (7.05)</td><td>0.346</td></tr><tr><td>60</td><td>1.445(0.81)</td><td>0.512(0.19)</td><td>0.033</td><td>54.72(16.00)</td><td>39.43(11.19)</td><td>0.116</td></tr><tr><td>90</td><td>1.275(0.82)</td><td>0.273(0.16)</td><td>0.024</td><td>80.70(23.58)</td><td>48.57(16.61)</td><td>0.033</td></tr><tr><td>120</td><td>1.205(0.70)</td><td>0.143(0.14)</td><td>0.005</td><td>90.89(26.50)</td><td>52.85(20.24)</td><td>0.029</td></tr><tr><td>150</td><td>1.040(0.72)</td><td>0.195(0.19)</td><td>0.032</td><td>96.35(28.10)</td><td>58.02(20.67)</td><td>0.035</td></tr><tr><td>180</td><td>0.915(0.65)</td><td>0.148(0.16)</td><td>0.030</td><td>102.64(29.93)</td><td>58.15(22.95)</td><td>0.025</td></tr></table>","table_caption":"[\"Table 4 Crossover design analysis of mean clinical scores and hydrogen breath levels $\\\\left( {n = {47}}\\\\right)$ \"]","table_footnote":"[\"All values in mean (standard deviation). \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[85,283,490,310]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"breath levels were better whenever the patients were given lactase. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[87,340,200,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[85,363,490,433]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study showed that patients receiving lactase chewable tablets (Yamoo) had improvement in clinical symptoms of lactose intolerance after a lactose challenge. Their mean clinical score was better. Mean and cumulative hydrogen breath levels were also reduced when patients received lactase. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,434,490,475]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To ensure that any effects of the lactose intolerance test or lactase administration during visit 1 did not affect the results at visit 2, we set a gap of 1 week between the two visits. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,476,490,531]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The diagnosis of lactose intolerance can be based on clinical features, lactose tolerance test, and lactose HBT. Of them, the most reliable and convenient for the patient is indeed the lactose HBT that was used in the present study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,531,490,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In most studies on lactose intolerance, the dosage of lactose has been either $25\\mathrm{g}$ or $50\\mathrm{g}$ . A $50\\mathrm{-g}$ dose would likely have elicited a higher baseline score but is considered nonphysiological. Studies in India and elsewhere have found lower lactose doses to be acceptable for determining lactose malabsorption. Therefore, we have used $25\\mathrm{g}$ of lactose in this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[85,616,490,672]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The administration of exogenous lactase as pills has been used to treat lactose intolerance in children, adolescents, and adults, and enzymatic supplementation is an intermediate step between dairy restriction and the use of diets with low levels of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,685,495,865]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2 Comparison of mean clinical scores between lactase and placebo groups after crossover analysis $(n = 47)$ . Placebo; lactase. \"]","image_footnote":"[]","img_path":"images/0750/547cfd4e23d63440e910d710eff8c8a06ff877cdfd69c8f4c2475e70bf0e4d30.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[514,283,919,310]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) for the management of lactose intolerance. $^{7,8}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,310,919,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lactase administration or pretreated food product with lactase enzyme is a practical therapeutic approach to control symptoms of lactase deficiency and lactose intolerance. Such treatment is also likely to prevent complications of reduced calcium intake and vitamin deficiency and to ensure a better quality of life.[7] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,382,919,452]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the limitations of this study is that the reduction in clinical symptoms does not correspond with the reduction in hydrogen breath values. This is likely due to the subjective nature of the clinical symptoms, as well as the Likert scale used for measuring them. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,452,919,521]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In all earlier trials, the HBT was used to diagnose excess hydrogen gas postlactose intake and postlactose intake with lactase. These trials showed reduction of hydrogen in breath of between $40\\%$ and $50\\%$ . Symptom score reduction was from $45\\%$ to $88\\%$ .[9-12] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[514,521,919,579]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In conclusion, clinical symptoms like bloating, abdominal pain, diarrhea, flatulence, and borborygmi improved and hydrogen breath levels were reduced in lactose-intolerant patients when they were given the lactase supplement. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,599,705,616]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,621,919,650]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Mr Rishi Bajal and Ms Neha Bajal jointly conducted the statistical analysis. Ms. Neha Bajal was also responsible for editing ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[519,664,924,865]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3 Comparison of hydrogen breath levels between lactase and placebo groups after crossover analysis $(n = 47)$ . Placebo; lactase. \"]","image_footnote":"[]","img_path":"images/0062/6f5d1bdfa339fb9308e097fe0bfabff945f528506bea2a6025a0633254b780d9.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[89,40,233,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"R Baijal and RK Tandon ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[645,40,919,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of lactase tablets on lactose intolerance ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[85,934,489,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[85,947,897,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[907,934,919,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[73,79,480,205]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the article and graph preparation. We were assisted in our endeavor by our sponsor the Walter Bushnell Private Limited; it provided us with the Yamoo tablets—the oral chewable lactase enzyme tested in this trial—along with the placebo. The cost of the HBT was borne by the company. The authors are solely responsible for the data and the contents of the paper. In no way are the Honorary Editor-in-Chief, Editorial Board Members, or the printer/publishers responsible for the results/findings and content of this article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,231,191,246]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[84,255,480,524]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1 Suchy FJ, Brannon PM, Carpenter TO et al. National Institutes of Health Consensus Development Conference: lactose intolerance and health. Ann. Intern. Med. 2010; 152: 792-6. \",\"2 Di Rienzo T, D'Angelo G, D'aversa F et al. Lactose intolerance: from diagnosis to correct management. Eur. Rev. Med. Pharmacol. Sci. 2013; 17: 18-25. \",\"3 Leonardi M, Gerbault P, Thomas MG, Burger J. The evolution of lactase persistence in Europe. A synthesis of archaeological and genetic evidence. Int. Dairy J. 2012; 22: 88-97. \",\"4 Swagerty DL Jr, Walling AD, Klein RM. Lactose intolerance. Am. Fam. Physician. 2002; 65: 1845-50. \",\"5 Babu J, Kumar S, Babu P, Prasad JH, Ghoshal UC. Frequency of lactose malabsorption among healthy Southern and Northern Indian populations by genetic analysis and lactose hydrogen breath and tolerance tests. Am. J. Clin. Nutr. 2010; 91: 140-6. \",\"6 Tandon RK, Joshi YK, Singh DS, Narendranathan M, Balakrishnan V, Lal K. Lactose intolerance in North and South Indians. Am. J. Clin. Nutr. 1981; 34: 943-6. \",\"7 Medow MS, Thek KD, Newman LJ, Berezin SB, Glassman MS, Schwarz SM. b-Galactosidase tablets in the treatment of lactose intolerance in Pediatrics. Am. J. Dis. Child. 1990; 144: 1261-4. \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[507,79,909,295]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"8 Misselwitz B, Pohl D, Frahmauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterol. J. 2013; 1: 151-9. \",\"9 Sanders SW, Kolman KG, Reitberg DP. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactose-intolerant subjects. Clin. Pharm. 1992; 11: 533-8. \",\"10 Ojetti V, Gigante G, Gabrielli M et al. The effect of oral supplementation with Lactobacillus reuteri or tilactase in lactose intolerant patients: randomized trial. Eur. Rev. Med. Pharmacol. Sci. 2010; 14: 163-70. \",\"11 Portincasa P, Di Ciaula A, Vacca M, Montelli R, Q-H Wang D, Palasciano G. Beneficial effects of oral tilactase on patients with hypolactasia. Eur. J. Clin. Invest. 2008; 38: 835-44. \",\"12 Montalto M, Nucera G, Santoro L et al. Effect of exogenous beta-galactosidase in patients with lactose malabsorption and intolerance: a crossover double-blind placebo-controlled study. Eur. J. Clin. Nutr. 2005; 59: 489-93. \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[504,324,741,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supporting information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[502,347,907,375]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Additional supporting information may be found in the online version of this article at the publisher's website: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,388,907,430]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table S1 Variation of the impact of the drug with time as measured by difference in means, margin of error, and confidence intervals measured at $99\\%$ significance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[502,447,907,488]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table S2 Comparison of total hydrogen breath levels between placebo and lactase groups as measured using trapezoid rule $(n = 47)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,40,351,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of lactase tablets on lactose intolerance ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[764,40,907,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"R Baijal and RK Tandon ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[78,934,89,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[507,934,907,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[100,947,907,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[742,961,907,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"John Wiley & Sons Australia, Ltd. ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[87,76,270,90]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORIGINAL ARTICLE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,99,894,145]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of lactase on symptoms and hydrogen breath levels in lactose intolerance: A crossover placebo-controlled study \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,149,374,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rajiv Baijal and Rakesh K Tandon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,173,620,185]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Institute of Gastroenterology, Pushpawati Singhania Hospital and Research Institute, New Delhi, India \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,235,157,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Key words \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,249,347,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"lactase enzyme, lactose hydrogen breath test, lactose intolerance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,289,341,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted for publication 18 November 2020. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,315,189,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Correspondence \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,329,342,381]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dr Rajiv Baijal, Institute of Gastroenterology, Pushpawati Singhania Hospital and Research Institute, Sheikh Sarai, Phase 2, New Delhi 110017, India. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,383,257,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Email: endolife99@gmail.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,409,326,421]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Declaration of conflict of interest: None \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,436,374,448]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding support: Walter Bushnell Private Limited \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[389,232,480,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[388,253,919,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background and Aim: The absence of lactase in the intestinal villi due to mucosal injury or genetic factors causes undigested lactose to reach the colon where it is fermented. Lactose intolerance is diagnosed based on clinical symptoms like bloating, abdominal pain and flatulence, lactose hydrogen breath test (HBT), and lactose tolerance test. No Indian studies are available on the use of lactase supplements. The aim was to study the effect of lactase chewable tablets on clinical symptoms and hydrogen breath excretion in patients with lactose intolerance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[388,352,919,448]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: This was a randomized, double-blind, crossover placebo-controlled trial to study the effect of lactase tablets on symptoms and hydrogen breath levels in adults with lactose intolerance, confirmed by Lactose HBT. Clinical symptom severity was recorded using a visual analog scale, and HBT was performed every $30\\\\mathrm{min}$ for $180\\\\mathrm{min}$ . As it was a crossover design, the same patients were tested with both lactase and placebo, acting as their own controls with a washout period of 1 week between visits. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[388,451,919,521]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Forty-seven patients (mean age 33.6 years; 30 males) with lactose intolerance formed the study group. Clinical symptoms, mean clinical score $(P < 0.05)$ , and mean hydrogen breath levels $(P < 0.05)$ were improved when the patients were given lactase. Reduction in cumulative hydrogen breath level over $180\\\\mathrm{min}$ was $55\\\\%$ when patients received lactase compared to placebo. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[388,521,919,549]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions: Orally supplemented lactase enzyme significantly reduced the clinical symptoms and hydrogen breath excretion in patients with lactose intolerance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,575,213,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,598,490,725]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lactase in the small intestinal villi breaks down lactose into glucose and galactose. In the absence of lactase due to mucosal injury or, more commonly, due to reduced genetic expression of the enzyme lactase-phlorizin hydrolase, $^{1}$ undigested lactose reaches the colon, where bacteria ferment it, generating $\\\\mathrm{H}_2$ , $\\\\mathrm{CO}_2$ , lactic acid, and acetic acid, drawing water into the colon by osmosis. This results in clinical symptoms like diarrhea, abdominal pain, bloating, borborygmi, nausea, and flatulence after ingestion of milk or dairy products. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,725,490,781]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Often, at birth, there is insufficient lactase available in the intestinal villi. By 5-6 months, sufficient lactase starts being produced. The production of lactase enzyme starts decreasing after the age of 5-8 years.[2] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,782,490,881]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is suggested that only about $35\\\\%$ of people worldwide are lactase-persistent, who continue to produce lactase throughout adulthood, and thus are able to digest the sugar in milk without discomfort. Lactase deficiency can be seen in up to $15\\\\%$ of persons of Northern European descent, up to $80\\\\%$ of Blacks and Latinos, and up to $100\\\\%$ of American Indians and Asians. An Indian study conducted by Babu et al. indicated that the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,576,919,634]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frequency and degree of lactose malabsorption is higher in South Indians compared to North Indians because of genetic differences in the population. The reported incidence was the highest in the south at $82\\\\%$ and $66\\\\%$ in the north.[5] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,635,919,691]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tandon et al. suggested that the lower incidence of lactose intolerance in North Indian subjects may perhaps be because they are descendants of the Aryans who have been dairying for long and are known to be lactose tolerant.[6] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,693,919,780]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is a common practice for clinicians to advise lactose-intolerant patients to avoid milk and dairy products, but that may cause calcium, vitamin D, and riboflavin deficiency states; decrease quality of life; and lead to osteoporosis and depression. Lactase-pretreated food products and external lactase enzyme are two of the dietetic treatments for lactose-intolerant patients. $^{1}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,780,919,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is therefore logical to coadminister lactase enzyme along with milk/dairy products so that the latter are digested and assimilated and yet do not produce the symptoms of intolerance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,823,919,881]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The present study aimed to test this hypothesis. It was a randomized, double-blind, placebo-controlled trial to observe the effect of marketed lactase supplement on patients with lactose intolerance. The source of this lactase is Aspergillus oryzae, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,3,346,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open An open access journal of gastroenterology and hepatology Open Access \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[805,6,894,35]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGHF Journal of Gastroenterology and Hepatology Foundation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[779,40,919,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi:10.1002/jgh3.12463 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[85,906,489,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[85,918,897,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[85,945,917,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[907,906,917,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[73,78,480,136]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which is presently marketed in India as a food supplement. Although there are numerous international trials available, no trials on lactase enzyme have been conducted in India despite the supplement being used by many. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,136,480,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The aim was to study the effect of lactase chewable tablets (Yamoo) on clinical symptoms and hydrogen breath excretion in patients with lactose malabsorption and intolerance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,210,164,226]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,232,478,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study was a randomized, crossover, double-blind, placebo-controlled trial, in which we studied the effect of an orally administered marketed lactase supplement (Lactase 4500 FCC chewable tablets) on hydrogen breath levels and intestinal symptoms in patients with lactose intolerance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,303,478,332]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The trial was registered at Clinical Trials Registry India (ICMR-NIMS) with registration number: CTRI/2018/03/012295. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,332,478,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study was conducted at the Department of Gastroenterology, Pushpawati Singhania Research Institute for Liver, Renal & Digestive Diseases, New Delhi, in accordance with the ethical principles outlined in the Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical Practice Guidelines, and local regulatory requirements. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,416,480,599]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An earlier study had shown that the hydrogen breath level was reduced from $31.8 \\\\pm 8.3$ ppm to $14.7 \\\\pm 8.0$ ppm on treatment with lactase (a decrease of $17.1$ ppm). The placebo arm had shown a slight increase from $30.7 \\\\pm 8.7$ ppm to $31.9 \\\\pm 8.0$ ppm. An effect size of 0.5 was fixed under the assumption that similar results would be obtained for the present study. With statistical significance of $5\\\\%$ , a minimum study power of $80\\\\%$ and a patient dropout rate of $2\\\\%$ , each group would have 40 subjects. The study would have two arms—the experimental arm and the placebo arm—into which the patients would be randomly divided. To improve the statistical validity of the study, a crossover design would be used. Thus, we conducted a crossover, double-blind, placebo-controlled study with 50 patients. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,599,480,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Patients were randomized into two groups—A and B—such that half of them received treatment, and the other half received placebo, coded as Alpha and Beta, respectively. The randomization sequence was generated in advance by a computerized random number generator. Lactase and placebo tablets were identical in shape, size, color, taste, and smell. After a washout period of 1 week, the treatment assigned to each group was interchanged. We decided on an interceding period of 1 week to remove any residual effects of the previous treatment. All patients received both therapies, that is, lactase and placebo. Participants, investigators, and outcome assessors were blinded to the treatment assigned. The code was stored in a sealed envelope and retained under lock and was broken and disclosed to the investigators only after complete data entry was performed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,796,480,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study population consisted of patients between 18 and 65 years of age with a medical history consistent with lactose intolerance, confirmed by the lactose hydrogen breath test (HBT). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,852,480,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Patients were included if they were able to comprehend the study instructions, complete the requisite visits, consensually participate in the study, and sign the informed consent form (ICF). We included patients from Delhi and NCR (National \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,78,907,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Capital Region) because of the need for a minimum of three visits, 1 week apart. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,107,907,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Patients were excluded from the study group if they had diverticular disease, diabetic gastroparesis, HIV, immunosuppression of any origin, or cancer under treatment. Patients with conditions that could compromise participation in the study—such as hypersensitivity or previous laboratory or clinical adverse events related to the use of lactase or any of the components of the formulations used in the study, systemic infection during the study or use of antibiotics in the last 4 weeks, diabetes mellitus, uncontrolled hypertension or renal failure, pregnancy, lactation, and chronic pulmonary disease—were also excluded. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,246,907,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study duration was 1 year, conducted from March 2018 to April 2019. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,274,907,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At the first visit, patients with a history of lactose intolerance fulfilling the inclusion criteria were clinically assessed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,304,907,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A baseline HBT using the Bedfont Gastrolyzer hand-held breath analyzer was performed. To minimize basal hydrogen excretion, patients were asked to have a carbohydrate-restricted dinner on the day before the test and fast for at least $12\\\\mathrm{h}$ on the day of the test. Before starting the test, patients washed their mouths with $20\\\\mathrm{ml}$ of $0.05\\\\%$ chlorhexidine. Smoking and physical exercise was not allowed for $30\\\\mathrm{min}$ before and during the test. End-alveolar breath samples were collected immediately before lactose ingestion, and then, a dose of $25\\\\mathrm{g}$ of lactose was administered, and breath samples were collected every $30\\\\mathrm{min}$ for $3\\\\mathrm{h}$ (0, 30, 60, 90, 120, 150, and $180\\\\mathrm{min}$ ). Symptom scores for abdominal pain, bloating, flatulence, borborygmi, and diarrhea were recorded at these intervals using the visual analog scale. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,500,907,528]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The test was considered positive (lactose malabsorption) if hydrogen concentrations were at least $20~\\\\mathrm{ppm}$ above baseline. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,529,907,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Patients were randomly allocated to two groups—A and B. Each patient was called a week later. At the second visit, a similar procedure was repeated, but this time, the patients in group A consumed three chewable lactase 4500 FCC tablets $5\\\\mathrm{min}$ before the $25 - \\\\mathrm{g}$ lactose load, while patients in group B were given a placebo. The HBT values and symptoms were recorded as previously described. One week later, at the third visit, patients of group A received placebo, while group B received lactase tablets. Hence, each patient from each group was exposed to the experimental product and the placebo, with a washout interval of 1 week. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[544,682,806,696]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study design is illustrated in Figure 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[544,698,873,710]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adverse events were monitored throughout the study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,712,907,753]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For each group, mean clinical score of symptoms and mean hydrogen levels (ppm) at each time interval for each visit were calculated. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,781,907,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Statistical analysis. Categorical variables were presented in number and percentage $(\\\\%)$ , and continuous variables were presented as mean. Normality of data was tested using the Kolmogorov-Smirnov test. If the normality was rejected, then a nonparametric test was used. Quantitative variables were compared using the Mann-Whitney Test (as the datasets were not normally distributed) between the two groups. A $P$ -value of $< 0.05$ was considered statistically significant. The data was entered into an MS Excel spreadsheet, and analysis was carried \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,40,349,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of lactase tablets on lactose intolerance \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[764,40,907,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"R Baijal and RK Tandon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[77,934,87,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[507,934,907,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[99,947,907,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[742,960,907,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"John Wiley & Sons Australia, Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[201,79,794,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1 Flow chart showing the trial methodology. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0295/8d79ed81561c0cd87b80b20d17e0296b0e3f2811cfd5c74007cffbe484f66af5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[85,529,490,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"out using Statistical Package for Social Sciences (SPSS) IBM version 21.0. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,557,490,612]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Area under the curve for cumulative hydrogen breath excretion over $180\\\\mathrm{min}$ was calculated and compared between the placebo-lactase crossover groups $(n = 47)$ using the trapezoid rule in MS Excel. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,613,490,725]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to account for errors in random sampling, the margin of error for difference of means in the HBT levels and overall symptom levels (expressed as the sum of each of the levels of abdominal pain, bloating, flatulence, borborygmi, and diarrhea using the visual analog scale) for the placebo and lactase groups was determined as the product of standard deviation and $z$ -value at $95\\\\%$ and $99\\\\%$ confidence intervals each. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,529,591,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,552,919,635]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sixty-seven patients were tested for lactose intolerance by HBT, of which 50 were found to have lactose intolerance. Three patients were lost to follow-up; hence, 47 (mean age 33.6 years; 30 males, 17 females) patients formed the study group. These were randomized into two groups, group A $(n = 23)$ and group B $(n = 24)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,636,919,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"No significant adverse events were detected throughout the study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,664,919,721]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There was no statistically significant difference in clinical symptoms and mean clinical score (abdominal pain, bloating, flatulence, borborygmi, diarrhea) and hydrogen breath levels between groups A and B at baseline (Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,758,921,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0192/1aceeb9a02dba083a9f6823dcde22233c4207e97cbe72ec29bc1e52e9ea0c1b8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Time (minutes)</td><td colspan=\\\"3\\\">Baseline mean clinical score</td><td colspan=\\\"3\\\">Baseline mean hydrogen breath levels (ppm)</td></tr><tr><td>Group A (n = 23)</td><td>Group B (n = 24)</td><td>P value</td><td>Group A (n = 23)</td><td>Group B (n = 24)</td><td>P value</td></tr><tr><td>0</td><td>1.516</td><td>1.836</td><td>0.248</td><td>39.70</td><td>38.54</td><td>0.840</td></tr><tr><td>30</td><td>1.666</td><td>1.764</td><td>0.308</td><td>45.56</td><td>45.38</td><td>0.758</td></tr><tr><td>60</td><td>1.798</td><td>1.900</td><td>0.354</td><td>93.35</td><td>76.83</td><td>0.544</td></tr><tr><td>90</td><td>1.926</td><td>1.544</td><td>0.446</td><td>113.74</td><td>89.83</td><td>0.400</td></tr><tr><td>120</td><td>1.694</td><td>1.400</td><td>0.476</td><td>132.44</td><td>105.00</td><td>0.202</td></tr><tr><td>150</td><td>1.524</td><td>1.428</td><td>0.550</td><td>136.61</td><td>130.83</td><td>0.873</td></tr><tr><td>180</td><td>1.476</td><td>1.390</td><td>0.498</td><td>146.22</td><td>140.83</td><td>0.655</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1 Baseline mean clinical score and hydrogen breath values at visit 1 \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[87,40,231,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"R Baijal and RK Tandon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[645,40,919,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of lactase tablets on lactose intolerance \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[85,934,489,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[85,947,895,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[907,934,919,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[75,95,912,258]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0513/3d99fdf5a0fb649059cc5ca36bda051cef976dde2f19fcbc9de533b95115d4a2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Time (minutes)</td><td colspan=\\\"3\\\">Mean clinical score</td><td colspan=\\\"3\\\">Mean hydrogen breath levels (ppm)</td></tr><tr><td>Group A (n = 23) (lactase)</td><td>Group B (n = 24) (placebo)</td><td>P value</td><td>Group A (n = 23) (lactase)</td><td>Group B (n = 24) (placebo)</td><td>P value</td></tr><tr><td>0</td><td>0.262</td><td>1.458</td><td>0.253</td><td>25.83</td><td>31.67</td><td>0.183</td></tr><tr><td>30</td><td>0.484</td><td>1.700</td><td>0.319</td><td>28.17</td><td>33.33</td><td>0.079</td></tr><tr><td>60</td><td>0.662</td><td>1.508</td><td>0.171</td><td>39.83</td><td>53.08</td><td>0.027</td></tr><tr><td>90</td><td>0.392</td><td>1.474</td><td>0.199</td><td>53.52</td><td>78.92</td><td>0.012</td></tr><tr><td>120</td><td>0.234</td><td>1.392</td><td>0.068</td><td>56.96</td><td>96.38</td><td>0.021</td></tr><tr><td>150</td><td>0.348</td><td>1.302</td><td>0.267</td><td>59.78</td><td>98.42</td><td>0.012</td></tr><tr><td>180</td><td>0.244</td><td>1.132</td><td>0.266</td><td>58.44</td><td>109.46</td><td>0.008</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2 Mean clinical score and hydrogen breath values at visit 2 when group A received lactase and group B received placebo \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[73,297,478,381]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At visit 2, when group A received lactase and group B received placebo, clinical symptoms and mean clinical scores were lower in group A than in group B, and hydrogen breath levels were lower in group A compared to group B, and the difference was statistically significant at 60, 90, 120, 150, and $180\\\\mathrm{min}$ (Table 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,381,478,479]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At visit 3, when group B received lactase and group A received placebo, clinical symptoms and mean clinical score (abdominal pain, bloating, flatulence, borborygmi and diarrhea) were lower in group B than in group A. The difference between mean clinical score for groups B and A was statistically significant, with a $P$ -value of 0.041 at $120\\\\mathrm{min}$ specifically for abdominal pain, bloating, and flatulence (Table 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,480,478,535]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At visit 3, when group B received lactase tablets, the hydrogen breath levels were lower compared to group A, and the difference was statistically significant at $90\\\\mathrm{min}$ and subsequently till $180\\\\mathrm{min}$ (Table 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,535,478,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the crossover design, when a group of patients received lactase, the mean clinical score and the hydrogen breath levels were lower than when the same group of patients received placebo (Table 4, Figs 2,3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,593,480,677]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A difference in means of clinical symptom values that are lower than the margin of error is indicative of the action of the drug (Table S1, Supporting information). Margins of errors have been calculated at a $99\\\\%$ confidence interval. At time $t = 0$ , the difference between means of the clinical symptoms expressed by patients in the placebo and lactase groups is 1.04, of which 0.36 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,297,907,381]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is due to statistical error (with $99\\\\%$ confidence); the remaining is accounted for by the action of the drug. As time passes, the difference in means decreases monotonically along with the margins of error at a $99\\\\%$ confidence interval, indicating that, as time passes, the action of the drug accounts for a decrease in exhibited symptom. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,381,907,479]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As shown in Table S1, the difference of means for hydrogen breath levels that are lower than the margin of error is indicative of the action of drug rather than a difference due to sampling error. At $60\\\\mathrm{min}$ , the margin of error at $99\\\\%$ confidence is 5.195 (confidence interval 10.10-20.49), indicating that the action of lactase leads to an observable decline in hydrogen breath levels. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,480,907,563]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reduction in cumulative hydrogen breath level was $55\\\\%$ when patients received lactase compared to placebo. Maximum reduction took place in the final $30\\\\mathrm{min}$ of the 3-h period. The percentage reduction of hydrogen emitted in the breath monotonically increases with time, demonstrating that the efficacy of the drug increases over time (Table S2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,565,907,677]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"These results show that the clinical symptoms improved when patients received lactase compared to when they received placebo. The mean clinical score and mean and cumulative hydrogen breath values were significantly lower when the patients in either of the groups received lactase compared to placebo. As it was a crossover design, the same patients were tested with both lactase and placebo—indicating that clinical symptoms, mean clinical score, and mean and cumulative hydrogen \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,730,912,893]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0421/66e900eb4ae4b9ff2fbc2c84b544233cd7ebffec700cb40b2ea3cf3682e1affd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Time (minutes)</td><td colspan=\\\"3\\\">Mean clinical score</td><td colspan=\\\"3\\\">Mean hydrogen breath levels (ppm)</td></tr><tr><td>Group A (n = 23) (placebo)</td><td>Group B (n = 24) (lactase)</td><td>P value</td><td>Group A (n = 23) (placebo)</td><td>Group B (n = 24) (lactase)</td><td>P value</td></tr><tr><td>0</td><td>1.148</td><td>0.268</td><td>0.293</td><td>24.39</td><td>29.75</td><td>0.966</td></tr><tr><td>30</td><td>1.268</td><td>0.400</td><td>0.279</td><td>27.70</td><td>26.96</td><td>0.348</td></tr><tr><td>60</td><td>1.380</td><td>0.368</td><td>0.246</td><td>56.44</td><td>39.04</td><td>0.198</td></tr><tr><td>90</td><td>1.068</td><td>0.158</td><td>0.257</td><td>82.56</td><td>43.83</td><td>0.019</td></tr><tr><td>120</td><td>1.010</td><td>0.056</td><td>0.041</td><td>85.17</td><td>48.92</td><td>0.009</td></tr><tr><td>150</td><td>0.766</td><td>0.048</td><td>0.255</td><td>94.91</td><td>56.33</td><td>0.022</td></tr><tr><td>180</td><td>0.688</td><td>0.056</td><td>0.117</td><td>95.52</td><td>57.88</td><td>0.022</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3 Mean clinical score and hydrogen breath values at visit 3 when group A received placebo and group B received lactase \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[77,40,351,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of lactase tablets on lactose intolerance \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[764,40,907,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"R Baijal and RK Tandon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[77,934,87,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[507,934,907,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[99,947,907,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[742,960,907,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"John Wiley & Sons Australia, Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[87,95,922,244]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0954/e02b66956621fd2107fb125af443cdac3dc47bc44c43539886e7483cc1e345bc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Time (minutes)</td><td colspan=\\\"3\\\">Mean clinical score</td><td colspan=\\\"3\\\">Mean hydrogen breath levels (ppm)</td></tr><tr><td>Placebo (n = 47)</td><td>Lactase (n = 47)</td><td>P value</td><td>Placebo (n = 47)</td><td>Lactase (n = 47)</td><td>P value</td></tr><tr><td>0</td><td>1.306 (0.90)</td><td>0.265(0.13)</td><td>0.029</td><td>28.11(8.22)</td><td>27.83 (6.69)</td><td>0.398</td></tr><tr><td>30</td><td>1.488(0.85)</td><td>0.441(0.10)</td><td>0.021</td><td>30.57(8.92)</td><td>27.55 (7.05)</td><td>0.346</td></tr><tr><td>60</td><td>1.445(0.81)</td><td>0.512(0.19)</td><td>0.033</td><td>54.72(16.00)</td><td>39.43(11.19)</td><td>0.116</td></tr><tr><td>90</td><td>1.275(0.82)</td><td>0.273(0.16)</td><td>0.024</td><td>80.70(23.58)</td><td>48.57(16.61)</td><td>0.033</td></tr><tr><td>120</td><td>1.205(0.70)</td><td>0.143(0.14)</td><td>0.005</td><td>90.89(26.50)</td><td>52.85(20.24)</td><td>0.029</td></tr><tr><td>150</td><td>1.040(0.72)</td><td>0.195(0.19)</td><td>0.032</td><td>96.35(28.10)</td><td>58.02(20.67)</td><td>0.035</td></tr><tr><td>180</td><td>0.915(0.65)</td><td>0.148(0.16)</td><td>0.030</td><td>102.64(29.93)</td><td>58.15(22.95)</td><td>0.025</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 4 Crossover design analysis of mean clinical scores and hydrogen breath levels $\\\\\\\\left( {n = {47}}\\\\\\\\right)$ \\\"]\",\n \"table_footnote\": \"[\\\"All values in mean (standard deviation). \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[85,283,490,310]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"breath levels were better whenever the patients were given lactase. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[87,340,200,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,363,490,433]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study showed that patients receiving lactase chewable tablets (Yamoo) had improvement in clinical symptoms of lactose intolerance after a lactose challenge. Their mean clinical score was better. Mean and cumulative hydrogen breath levels were also reduced when patients received lactase. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,434,490,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To ensure that any effects of the lactose intolerance test or lactase administration during visit 1 did not affect the results at visit 2, we set a gap of 1 week between the two visits. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,476,490,531]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The diagnosis of lactose intolerance can be based on clinical features, lactose tolerance test, and lactose HBT. Of them, the most reliable and convenient for the patient is indeed the lactose HBT that was used in the present study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,531,490,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In most studies on lactose intolerance, the dosage of lactose has been either $25\\\\mathrm{g}$ or $50\\\\mathrm{g}$ . A $50\\\\mathrm{-g}$ dose would likely have elicited a higher baseline score but is considered nonphysiological. Studies in India and elsewhere have found lower lactose doses to be acceptable for determining lactose malabsorption. Therefore, we have used $25\\\\mathrm{g}$ of lactose in this study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[85,616,490,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The administration of exogenous lactase as pills has been used to treat lactose intolerance in children, adolescents, and adults, and enzymatic supplementation is an intermediate step between dairy restriction and the use of diets with low levels of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,685,495,865]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2 Comparison of mean clinical scores between lactase and placebo groups after crossover analysis $(n = 47)$ . Placebo; lactase. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0750/547cfd4e23d63440e910d710eff8c8a06ff877cdfd69c8f4c2475e70bf0e4d30.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[514,283,919,310]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) for the management of lactose intolerance. $^{7,8}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,310,919,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lactase administration or pretreated food product with lactase enzyme is a practical therapeutic approach to control symptoms of lactase deficiency and lactose intolerance. Such treatment is also likely to prevent complications of reduced calcium intake and vitamin deficiency and to ensure a better quality of life.[7] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,382,919,452]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the limitations of this study is that the reduction in clinical symptoms does not correspond with the reduction in hydrogen breath values. This is likely due to the subjective nature of the clinical symptoms, as well as the Likert scale used for measuring them. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,452,919,521]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In all earlier trials, the HBT was used to diagnose excess hydrogen gas postlactose intake and postlactose intake with lactase. These trials showed reduction of hydrogen in breath of between $40\\\\%$ and $50\\\\%$ . Symptom score reduction was from $45\\\\%$ to $88\\\\%$ .[9-12] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,521,919,579]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In conclusion, clinical symptoms like bloating, abdominal pain, diarrhea, flatulence, and borborygmi improved and hydrogen breath levels were reduced in lactose-intolerant patients when they were given the lactase supplement. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,599,705,616]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,621,919,650]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Mr Rishi Bajal and Ms Neha Bajal jointly conducted the statistical analysis. Ms. Neha Bajal was also responsible for editing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[519,664,924,865]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3 Comparison of hydrogen breath levels between lactase and placebo groups after crossover analysis $(n = 47)$ . Placebo; lactase. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0062/6f5d1bdfa339fb9308e097fe0bfabff945f528506bea2a6025a0633254b780d9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[89,40,233,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"R Baijal and RK Tandon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[645,40,919,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of lactase tablets on lactose intolerance \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[85,934,489,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[85,947,897,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[907,934,919,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[73,79,480,205]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the article and graph preparation. We were assisted in our endeavor by our sponsor the Walter Bushnell Private Limited; it provided us with the Yamoo tablets—the oral chewable lactase enzyme tested in this trial—along with the placebo. The cost of the HBT was borne by the company. The authors are solely responsible for the data and the contents of the paper. In no way are the Honorary Editor-in-Chief, Editorial Board Members, or the printer/publishers responsible for the results/findings and content of this article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,231,191,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,255,480,524]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1 Suchy FJ, Brannon PM, Carpenter TO et al. National Institutes of Health Consensus Development Conference: lactose intolerance and health. Ann. Intern. Med. 2010; 152: 792-6. \\\",\\\"2 Di Rienzo T, D'Angelo G, D'aversa F et al. Lactose intolerance: from diagnosis to correct management. Eur. Rev. Med. Pharmacol. Sci. 2013; 17: 18-25. \\\",\\\"3 Leonardi M, Gerbault P, Thomas MG, Burger J. The evolution of lactase persistence in Europe. A synthesis of archaeological and genetic evidence. Int. Dairy J. 2012; 22: 88-97. \\\",\\\"4 Swagerty DL Jr, Walling AD, Klein RM. Lactose intolerance. Am. Fam. Physician. 2002; 65: 1845-50. \\\",\\\"5 Babu J, Kumar S, Babu P, Prasad JH, Ghoshal UC. Frequency of lactose malabsorption among healthy Southern and Northern Indian populations by genetic analysis and lactose hydrogen breath and tolerance tests. Am. J. Clin. Nutr. 2010; 91: 140-6. \\\",\\\"6 Tandon RK, Joshi YK, Singh DS, Narendranathan M, Balakrishnan V, Lal K. Lactose intolerance in North and South Indians. Am. J. Clin. Nutr. 1981; 34: 943-6. \\\",\\\"7 Medow MS, Thek KD, Newman LJ, Berezin SB, Glassman MS, Schwarz SM. b-Galactosidase tablets in the treatment of lactose intolerance in Pediatrics. Am. J. Dis. Child. 1990; 144: 1261-4. \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[507,79,909,295]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"8 Misselwitz B, Pohl D, Frahmauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterol. J. 2013; 1: 151-9. \\\",\\\"9 Sanders SW, Kolman KG, Reitberg DP. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactose-intolerant subjects. Clin. Pharm. 1992; 11: 533-8. \\\",\\\"10 Ojetti V, Gigante G, Gabrielli M et al. The effect of oral supplementation with Lactobacillus reuteri or tilactase in lactose intolerant patients: randomized trial. Eur. Rev. Med. Pharmacol. Sci. 2010; 14: 163-70. \\\",\\\"11 Portincasa P, Di Ciaula A, Vacca M, Montelli R, Q-H Wang D, Palasciano G. Beneficial effects of oral tilactase on patients with hypolactasia. Eur. J. Clin. Invest. 2008; 38: 835-44. \\\",\\\"12 Montalto M, Nucera G, Santoro L et al. Effect of exogenous beta-galactosidase in patients with lactose malabsorption and intolerance: a crossover double-blind placebo-controlled study. Eur. J. Clin. Nutr. 2005; 59: 489-93. \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[504,324,741,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supporting information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,347,907,375]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Additional supporting information may be found in the online version of this article at the publisher's website: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,388,907,430]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table S1 Variation of the impact of the drug with time as measured by difference in means, margin of error, and confidence intervals measured at $99\\\\%$ significance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[502,447,907,488]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table S2 Comparison of total hydrogen breath levels between placebo and lactase groups as measured using trapezoid rule $(n = 47)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,40,351,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of lactase tablets on lactose intolerance \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[764,40,907,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"R Baijal and RK Tandon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[78,934,89,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[507,934,907,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JGH Open: An open access journal of gastroenterology and hepatology (2020) 1-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[100,947,907,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[742,961,907,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"John Wiley & Sons Australia, Ltd. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1002/jgh3.12463"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Life Sciences"},"sha256":{"kind":"string","value":"a4fb55b62e47d9c882a2293dfd13d60c00231f4dc56adccad432de12521fa412"},"title":{"kind":"string","value":"Effect of lactase on symptoms and hydrogen breath levels in lactose intolerance: A crossover placebo‐controlled study"}}},{"rowIdx":169,"cells":{"abstract":{"kind":"string","value":"The development of nanotools for chemical sensing and macromolecular modifications is a new challenge in the biomedical field, with emphasis on artificial peptidases designed to cleave peptide bonds at specific sites. In this landscape, metal porphyrins are attractive due to their ability to form stable complexes with amino acids and to generate reactive oxygen species when irradiated by light of appropriate wavelengths. The issues of hydrophobic behavior and aggregation in aqueous environments of porphyrins can be solved by using its PEGylated derivatives. This work proposes the design of an artificial photo-protease agent based on a PEGylated mercury porphyrin, able to form a stable complex with l-Tryptophan, an amino acid present also in the lysozyme structure (a well-known protein model). The sensing and photodegradation features of PEGylated mercury porphyrin were exploited to detect and degrade both l-Trp and lysozyme using ROS, generated under green (532 nm) and red (650 nm) light lasers. The obtained system (Star3600_Hg) and its behavior as a photo-protease agent were studied by means of several spectroscopies (UV-Vis, fluorescence and circular dichroism), and MALDI-TOF mass spectrometry, showing the cleavage of lysozyme and the appearance of several short-chain residues. The approach of this study paves the way for potential applications in theranostics and targeted bio-medical therapies."},"author":{"kind":"string","value":"Mezzina, Lidia|Nicosia, Angelo|Barone, Laura|Vento, Fabiana|Mineo, Placido Giuseppe"},"content_list":{"kind":"list like","value":[{"bbox":"[53,122,107,136]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[53,137,843,185]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Water-Soluble Star Polymer as a Potential Photoactivated Nanotool for Lysozyme Degradation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[53,197,915,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lidia Mezzina $^{1}$ , Angelo Nicosia $^{1, *}$ , Laura Barone $^{1}$ , Fabiana Vento $^{1}$ and Placido Giuseppe Mineo $^{1,2,3, *}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,237,937,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"$^{1}$ Department of Chemical Sciences and INSTM UdR of Catania, University of Catania, V.le A. Doria 6, I-95125 Catania, Italy; lidia.mezzina@phd.unict.it (L.M.); barone.laura@studium.unict.it (L.B.); fabianav2@libero.it (F.V.) \",\"$^{2}$ Institute for Chemical and Physical Processes, National Research Council (IPCF-CNR), Viale F. Stagno d'Alcomtres 37, I-98158 Messina, Italy \",\"3 Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Via P. Gaifami 18, I-95126 Catania, Italy \",\"* Correspondence: angelo.nicosia@unict.it (A.N.); placido.mineo@unict.it (P.G.M.) \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[272,357,941,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: The development of nanotools for chemical sensing and macromolecular modifications is a new challenge in the biomedical field, with emphasis on artificial peptidases designed to cleave peptide bonds at specific sites. In this landscape, metal porphyrins are attractive due to their ability to form stable complexes with amino acids and to generate reactive oxygen species when irradiated by light of appropriate wavelengths. The issues of hydrophobic behavior and aggregation in aqueous environments of porphyrins can be solved by using its PEGylated derivatives. This work proposes the design of an artificial photo-protease agent based on a PEGylated mercury porphyrin, able to form a stable complex with L-Tryptophan, an amino acid present also in the lysozyme structure (a well-known protein model). The sensing and photodegradation features of PEGylated mercury porphyrin were exploited to detect and degrade both L-Trp and lysozyme using ROS, generated under green $(532\\mathrm{nm})$ and red $(650\\mathrm{nm})$ light lasers. The obtained system (Star3600_Hg) and its behavior as a photo-protease agent were studied by means of several spectroscopies (UV-Vis, fluorescence and circular dichroism), and MALDI-TOF mass spectrometry, showing the cleavage of lysozyme and the appearance of several short-chain residues. The approach of this study paves the way for potential applications in theranostics and targeted bio-medical therapies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,554,146,576]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0477/f34aaa69525ee764b35ec806a4845a91656d6cae8111cd25c0a3afc71713576b.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[53,581,263,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Citation: Mezzina, L.; Nicosia, A.; ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,595,226,607]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Barone, L.; Vento, F.; Mineo, P.G.","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,609,226,621]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Water-Soluble Star Polymer as a ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,624,255,636]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Potential Photoactivated Nanotool for ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,638,231,650]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lysozyme Degradation. Polymers ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,652,221,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2024, 16, 301. https://doi.org/ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,665,184,678]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3390/polym16020301 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,688,245,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Academic Editor: Helena Felgueiras ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,709,206,722]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 23 December 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,724,189,736]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Revised: 18 January 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,738,196,750]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted: 19 January 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,753,200,764]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published: 22 January 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,777,154,804]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0716/d6ab8c3515a8d6def96967babc610cdebea2976e7dd6195055d8c928f61bebb2.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[53,808,257,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,602,870,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: porphyrin; protein degradation; photo-degradation; lysozyme; L-tryptophan ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,663,394,675]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,680,939,725]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the challenges in the biomedical field is to study new systems that act as nano-tools for chemical sensing or modifications at molecular levels, minimizing immune response or biodegradation problems [1]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,726,941,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"More focus has been placed on the creation of site-specific protein-cleaving agents, which is a remarkable challenge due to the exceptional stability of peptide bonds [2]. One of the advances in the use of artificial peptidases lies in the possibility of mapping and discerning binding sites on proteins and in the possibility of using them as molecular scissors to generate smaller fragments suitable for protein sequencing studies [3], the design of new DNA-targeted drugs [4] or even for the production of new biomaterials [5]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,816,941,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A commonly used approach is to design specific chemicals capable of binding to proteins at specific sites and cleaving their backbone when exposed to light irradiation [6]. This purpose could be pursued by using specific classes of chromophores that, in the presence of specific molecules, form complexes and modify their physicochemical properties as a result of structural modifications or binding processes [6]. Among these systems, porphyrins draw great attention because of the possibility of coordinating a metal in the center of the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,115,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[121,65,275,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"polymers ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,64,939,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MDPI ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[55,963,438,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301. https://doi.org/10.3390/polym16020301 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[675,963,939,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://www.mdpi.com/journal/polymers ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[278,102,939,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"tetra pyrrolic core, which can then interact with several kinds of biologically interesting molecules such as amino acids [7,8]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,131,939,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In recent years, porphyrins have been widely used in sensing in solid state [9,10], in solution [11,12], and in theranostics (a field of medicine that combines therapy and diagnostics) due to their unique properties and versatility [13-15]. In particular, porphyrins are among the best candidates for non-invasive diagnostics (such as imaging) since they can be used as contrast agents in techniques like magnetic resonance imaging (MRI), positron emission tomography (PET) and fluorescence imaging [16-18]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,222,941,355]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Furthermore, porphyrins are particularly suitable to be employed in targeted therapies, such as photodynamic therapy (PDT) [19]. This exploits the synergistic effect of a photosensitizer that, when irradiated with a proper light source, can react with oxygen in its fundamental state to initiate a well-known photochemical process that leads to the generation of reactive oxygen species (ROS) such as singlet oxygen, ${}^{1}\\mathrm{O}_{2}$ [20], a cytotoxic agent [15]. However, in PDT, the appropriate wavelength of the excitation source is important. In fact, a light range between 500 and $900\\mathrm{nm}$ is needed, since this is the light range where tissues are more optically transparent. Moreover, the use of high-energy ultraviolet (UV) and near-UV wavelengths can lead to DNA and cellular damage [21]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,356,939,594]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Even if porphyrins are excellent candidates for PDT, they suffer from hydrophobic behavior due to their highly conjugated structure and hence the tendency to aggregate in aqueous media, such as the cell environment [22]. To overcome this issue, a variety of approaches can be used [17], such as the loading of porphyrin onto nanoparticles [23], their incorporation into hydrogels [24] or coupling with cyclodextrins [25]. In this context, the use of ionic porphyrins (e.g., the meso-tetrakis(p-sulfonatophenyl)porphyrin) has many drawbacks, such as sensitivity to environmental conditions including the pH and ionic strength of a solution [26-28]. Moreover, the presence of charges in the porphyrin structure could determine the denaturation of proteins and/or hinder the penetration of the porphyrin itself inside cells, aside from the non-specific binding that can lead the porphyrin to be bound to proteins or biomolecules with complementary charges rather than the target protein [29]. An alternative viable option is the use of PEGylated porphyrins [30], where the presence of PEG chains in peripheral positions with an appropriate polymerization degree [30,31] renders the porphyrin suitable for biomedical applications (avoiding the aggregation phenomena), guaranteeing excellent water solubility, stealth behaviors towards the immune system and biocompatibility [30]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,595,939,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lysozyme is one of the most studied proteins, since it has several valuable properties and is widespread [32]. Moreover, it shows bacteriostatic and bactericidal properties [33] and could be used as a food preservative to prevent the growth of food spoilage microorganisms, carrying out its antibacterial activity by acting as a catalyst for the hydrolysis of specific polysaccharides contained in bacteria's cell walls [34]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,669,939,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this work, we designed an artificial photo-protease agent able to form a complex with L-Tryptophan (L-Trp) residue that, when irradiated by light with a suitable wavelength, determines the amino acid/protein degradation. In particular, several metal porphyrin derivatives were investigated as L-Trp sensors and photosensitizers. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,728,941,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Taking into account the sensing and the photochemical features of a PEGylated porphyrin with a mercury atom complexed into the tetrapyrrolic core (Star3600_Hg), and the capability of L-Trp to act as an intermediate in the photo-oxidation mechanism involving the production of singlet oxygen, the above features were exploited to determine the selective degradation of lysozyme polypeptide. The synthesized systems and photodegradation features were investigated by means of MALDI-TOF mass spectrometry and UV-Vis, fluorescence and circular dichroism spectroscopies. To the best of our knowledge, this is the first case reported about a water-soluble mercury porphyrin suitable to be used as an artificial protease. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[273,102,475,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Materials and Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,120,939,151]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Metal acetates, chloroform, ethanol, triethylamine, LC-MS-grade water and pyridine were purchased from Sigma Aldrich (Merck Group, Milan, Italy). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,162,801,189]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1. Synthesis of 5,10,15,20-Tetrakis- $p$ -(ω-methoxy-poly-oxyethylene phenyl) Porphyrin (Star3600_2H) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,193,941,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Briefly, a solution of $1.57\\mathrm{g}$ of PEGMEC $(2.15\\mathrm{mmol})$ solubilized in $9\\mathrm{mL}$ of $\\mathrm{H}_2\\mathrm{O}$ :THF solution (1:1) was added to $0.18\\mathrm{g}$ of P4OH $(0.27\\mathrm{mmol})$ previously solubilized in $2.2\\mathrm{mL}$ of an aqueous solution of NaOH $0.5\\mathrm{M}$ , and stirred for $24\\mathrm{h}$ . Then, a further $2.2\\mathrm{mL}$ of NaOH $0.5\\mathrm{M}$ and $2\\mathrm{mL}$ of THF were added to the mixture and allowed to react for $24\\mathrm{h}$ more. The reaction product was acidified and dried under a nitrogen stream and then in a vacuum oven $(80^{\\circ}\\mathrm{C}$ for $48\\mathrm{h}$ ). The residue was solubilized in $\\mathrm{CHCl}_3$ and purified via chromatography using silica gel as the stationary phase and the mixture $\\mathrm{CHCl}_3:\\mathrm{EtOH}:\\mathrm{N}(\\mathrm{C}_2\\mathrm{H}_5)_3$ (96.5:2.0:1.5) as the eluent, resulting in a yield of $30\\%$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,324,828,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2. Synthesis of the 5,10,15,20-Tetrakis- $p$ -(ω-methoxy-poly-oxyethylene phenyl) Metal-Porphyrins (Star3600_Me) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,355,941,533]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The synthesis of metal porphyrins involved the reaction between Star3600_2H and the acetate of the chosen metal. Briefly, $100\\mu \\mathrm{mol}$ of the desired metal salt (acetate of nickel, zinc, tin, manganese, rhodium, copper, erbium, mercury, iron) and $10\\mu \\mathrm{mol}$ of Star3600_2H (about $36\\mathrm{mg}$ ) were solubilized in $5\\mathrm{mL}$ of pyridine. Subsequently, the reaction took place at $100^{\\circ}\\mathrm{C}$ under continuous stirring for $4\\mathrm{h}$ in a nitrogen atmosphere. Following this, the solvent was evaporated via a nitrogen stream, and the resulting residue was dried in a vacuum oven at $80^{\\circ}\\mathrm{C}$ for two days. The selected 5,10,15,20-tetrakis-p-( $\\omega$ -methoxy-polyethylenedioxy phenyl)-metal porphyrin, where the metal replaces the two hydrogen atoms within the tetrapyrrolic core, was isolated through column chromatography, employing silica gel as the stationary phase and a $\\mathrm{CHCl}_3:\\mathrm{C}_2\\mathrm{H}_5\\mathrm{OH}:\\mathrm{N}(\\mathrm{C}_2\\mathrm{H}_5)_3$ (96.5:2.0: 1.5) as the eluent. The first colored band was collected and corresponded to the metal porphyrin derivative, resulting in a yield of $85\\%$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,546,591,561]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.3. Estimation of Singlet Oxygen Production ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,564,939,594]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To quantitatively investigate the production of singlet oxygen, the standard method based on the $p$ -nitroso- $\\mathrm{N}, \\mathrm{N}'$ -dimethylaniline (RNO) bleaching reaction was used [35]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,595,941,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Briefly, the potential sensitizer (Star3600_Me, $5\\mu \\mathrm{M}$ ), RNO ( $50~\\mu \\mathrm{M}$ ) and imidazole ( $10~\\mathrm{mM}$ ) were dissolved in water. As the standard reference, a solution of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS, $5\\mu \\mathrm{M}$ ) was used. Photoactivation of the sensitizers was performed by irradiating the solution with a green ( $50~\\mathrm{mW}$ , $\\lambda = 532~\\mathrm{nm}$ ) or red ( $100~\\mathrm{mW}$ , $\\lambda = 650~\\mathrm{nm}$ ) laser source. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[309,669,858,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The quantum yield of ${}^{1}\\mathrm{O}_{2}$ was calculated with the following relation [35]: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[450,694,761,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\Phi = \\Phi_ {\\mathrm {T P P S}} \\frac {\\mathrm {O D} ^ {\\mathrm {T P P S}}}{\\mathrm {O D} ^ {\\mathrm {S t a r 3 6 0 0} - \\mathrm {M e}}} \\times \\frac {\\Delta \\mathrm {A} ^ {\\mathrm {S t a r 3 6 0 0} - \\mathrm {M e}}}{\\Delta \\mathrm {A} ^ {\\mathrm {T P P S}}}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[272,738,941,799]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\Phi_{\\mathrm{TPPS}} = {}^{1}\\mathrm{O}_{2}$ quantum yield of TPPS @532 nm, using imidazole as the acceptor [36]; OD is the optical density considering the source irradiation wavelength; and $\\Delta A$ is the absorbance variation at $440~\\mathrm{nm}$ . OD and $\\Delta A$ are related to both the standard and molecular probe. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,810,519,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.4. Photodegradation Experiments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,829,941,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The photodegradation experiments were performed by using solid-state lasers (green, $\\lambda = 532\\mathrm{nm}$ ; red, $\\lambda = 650\\mathrm{nm}$ ) at a fixed distance from the quartz cuvette containing the appropriate solution target, which was kept under continuous stirring for the entire duration of the experiment. The photodegradation was monitored by acquiring UV-Vis, fluorescence and circular dichroism spectra of the solutions. The starting concentration was ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,941,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,102,939,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"always $5\\mu \\mathrm{M}$ for Star3600_Hg, and the used ratios were 1:100 for the experiments involving L-TRP and 1:1 for the ones with LSZ. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,143,393,156]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.5. Instruments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,162,941,355]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A Voyager DE (PerSeptive Biosystem, Waltham, MA, USA) equipped with a delay extraction device (operating at $25\\mathrm{kV}$ applied voltage after 2600 ns delay, potential gradient of $454\\mathrm{Vmm}^{-1}$ and a wire voltage of $25\\mathrm{V}$ ) was used to acquire MALDI-TOF mass spectra, detecting positive ions in linear mode. The MALDI-TOF spectra of samples containing lysozyme were acquired in linear mode without the use of the delay extraction device. The matrices for the sample preparation were trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene] malononitrile (DCTB) for Star3600_2H and Star3600_Me, and a sum of 2,5-di hydroxybenzoic acid and 2-hydroxy-5-methoxybenzoic acid (SuperDHB) in 1:2 acetonitrile/0.1% aqueous TFA [37]. The mass spectrometer was calibrated with a previously reported method [38]. Grams/386 software (Version 3.04, Galactic Industries Corp, Salem, NH, USA) has been used to determine the molecular weights [38]. The $m/z$ value is attributed to the molecular ion, considering the most abundant isotope of each element in the molecule. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,356,941,400]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"UV-Vis spectra were recorded with a Cary60 UV-Vis spectrophotometer (Agilent Technologies, Santa Clara, CA, USA), using quartz cuvettes (1 cm path length) and water as the solvent $(\\mathrm{T} = 25.0 \\pm 0.1^{\\circ}\\mathrm{C})$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,401,941,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fluorescence spectra were acquired with a FP-8200 spectrofluorimeter (Jasco Corporation, Tokyo, Japan), using a quartz cuvette (1 cm path length) and water as a solvent $(\\mathrm{T} = 25.0 \\pm 0.1^{\\circ}\\mathrm{C})$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,445,941,475]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Absorbance and fluorescence spectra were processed with Spectragryph optical spectroscopy software (version 1.2.11, Dr. F. Menges, Oberstdorf, Germany, 2019) [39]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,476,941,565]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The CD spectra were acquired using a JASCO J-815 spectropolarimeter (Jasco Corporation, Tokyo, Japan) with a 150 W Xenon lamp. The ellipticity, $\\theta \\propto \\varepsilon_{\\mathrm{L}} - \\varepsilon_{\\mathrm{R}}$ , was obtained by calibrating the instrument with a $0.06\\%$ aqueous solution of $[\\mathrm{D}_{10}]$ camphorsulfonate. The measurements were performed with a quartz cuvette (0.2 and $0.5\\mathrm{cm}$ path length) at constant temperature $(T = (20.0 \\pm 0.1^{\\circ}\\mathrm{C}))$ , using a Peltier thermostat device (JASCO PTC-423S/15, Jasco Corporation, Tokyo, Japan). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,577,473,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results and Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,593,860,607]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. Structural and Spectroscopic Characterization of Star3600_2H and Star3600_Me ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,611,939,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Star3600_2H has been synthesized through the etherification reaction between the phenyl groups of 5,10,15-tetrakis (p-hydroxyphenyl) porphyrin and the poly(ethylene glycol) methyl ether chloride $(\\mathrm{PEGMEC}_{750})$ . To ensure the full solubility of the porphyrin in aqueous media, we have chosen to use PEG branches with an average polymerization degree $(\\mathrm{Xn})$ of about 16. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,686,941,745]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The structure of the Star3600_2H was confirmed through MALDI-TOF mass spectrometry analysis (Figure 1). Specifically, the molar mass distribution, centered at $m/z = 3504$ , has shown peaks that are detected at $m/z$ values of $734 + \\mathrm{n}44$ , with n ranging from 43 to 79, attributable to $\\mathrm{MK^{+}}$ adducts species. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,746,941,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The metalated derivatives were produced through a reaction involving Star3600_2H and the acetate salt of the selected metal in pyridine solution at $100^{\\circ}\\mathrm{C}$ (see Scheme 1 and the experimental section). The confirmation of the metal insertion inside the porphyrin core was obtained via MALDI-TOF mass spectrometry and both UV-Vis and fluorescence spectroscopies. As an example, in Figure 1b the MALDI-TOF spectrum of Star3600_Hg is reported (mass spectra of each Star3600_Me derivative are not reported for brevity). It shows a series of peaks with a molecular mass distribution shifted to higher $m/z$ values (about 200 uma) than that of the free-base counterpart (Figure 1a). Moreover, the presence of a broadened peak distribution is noticeable between $m/z = 6000$ and 9000, which can be attributed to the $(\\mathrm{Star}3600 - \\mathrm{Hg})_{2}$ species having two Hg ions coordinated by two porphyrins [40]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,941,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[277,103,647,305]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0624/d2864310f0681e0854bc66643d5141923e66fb7914e8505c0b7d245de603c774.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[277,305,647,502]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. MALDI-TOF mass spectra of Star3600_2H (a) and Star3600_Hg (b). \"]","image_footnote":"[]","img_path":"images/0005/6cb43d89584f338f9a7bfa24852fc99236603cc8ecf0942c065d298d3baa2aab.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[115,543,887,775]","code_body":null,"code_caption":null,"image_caption":"[\"Scheme 1. Exemplificative scheme of the synthesis of Star3600_Me. \"]","image_footnote":"[]","img_path":"images/1012/d1efdbdf8d9923e13226da8cf4c5f44f181a37ed959b8e53ff25afa228120cc6.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,808,944,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The UV-vis spectrum of Star3600_2H shows a Soret band at $419~\\mathrm{nm}$ and four Q-bands at 520, 559, 595 and $652~\\mathrm{nm}$ , respectively. As expected for metal porphyrins, Star3600_Zn (Figure 2, green line) shows a bathocromic shift of the Soret band of about $8\\mathrm{nm}$ , which now appears at $428~\\mathrm{nm}$ , and the disappearance of two Q-bands, with the other two remaining at 563 and $603~\\mathrm{nm}$ (similar spectra are observed for all porphyrin-metal complexes, not reported for brevity). Typically, following Gouterman's four orbitals model and due to the $\\pi \\rightarrow \\pi^{*}$ transitions between the HOMO and LUMO, the number of Q-bands arises from ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,55,184,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,941,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[272,102,939,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the combination of different electronic transitions involving the central metal ion and the porphyrin ligands [31]. In particular, when a metal ion is located between the pyrrolic nitrogens, due to an increase in the symmetry of the porphyrin itself, a decrease in the number of Q-bands occurs [41]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,177,811,414]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. UV-Vis (continuous lines) and fluorescence (dashed lines) spectra of water solutions of Star3600_2H (red lines, $\\\\lambda_{\\\\mathrm{exc}} = 430~\\\\mathrm{nm}$ ), Star3600_Zn (green lines, $\\\\lambda_{\\\\mathrm{exc}} = 435~\\\\mathrm{nm}$ ) and Star3600_Hg (blue lines, $\\\\lambda_{\\\\mathrm{exc}} = 440~\\\\mathrm{nm}$ . Spectrum magnified $\\\\times 25$ ). \"]","image_footnote":"[]","img_path":"images/0192/dd39f48771f1570f9153fd1167726f65176aa6e84e3a5d6e3d05bfdd3152f9b1.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,479,939,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, the UV-vis spectrum of Star3600_Hg shows a Soret band at about $428\\mathrm{nm}$ overlapped with a band at $461\\mathrm{nm}$ , and four Q-bands (respectively, at 524, 561, 601 and $654\\mathrm{nm}$ ). The presence of the doubled Soret band and of the four Q-bands suggest the presence of both the Star3600_Hg (porphyrin-Hg 1:1 ratio) and the $(\\mathrm{Star3600 - Hg})_2$ systems (porphyrin-Hg 2:2 ratio), and it could be hypothesized that the Soret band at $428\\mathrm{nm}$ is due to the 1:1 complex, while the one at $461\\mathrm{nm}$ is attributable to the 2:2 complex. In this scenario, the observed UV-Vis spectrum derives from the overlapping of the spectra of both systems. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,599,941,689]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As concerns the fluorescence spectra (Figure 2, dashed lines), Star3600_2H exhibit a strong fluorescence at $655\\mathrm{nm}$ , while the mercury atom into the porphyrin core causes a strong fluorescence quenching, showing a weak signal at $652\\mathrm{nm}$ with a shoulder at $608\\mathrm{nm}$ (for a clearer representation, the Star3600_Hg fluorescence spectrum in Figure 2 is magnified $\\times 25$ ). Instead, Star3600_Zn shows a higher fluorescence intensity with respect to the Star3600_2H and Star3600_Hg systems. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,700,687,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Star3600_Me Estimation of Singlet Oxygen Production ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,719,941,824]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Porphyrins are widely used as photosensitizers thanks to their capability to generate reactive oxygen species when triggered by a suitable light source [42]. Indeed, once the photon is absorbed, determining an electron excitation from the ground state to the singlet state, the intersystem crossing process could generate an excited triplet state, in which energy might be transferred (in a non-radiative way) to the triplet ground state of the oxygen molecules (Figure 3a), generating singlet oxygen $\\left(^{1}\\mathrm{O}_{2}\\right)$ species [43]. Usually, this last phenomenon is exploited in photodynamic therapy treatment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,941,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[100,114,322,234]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0782/e386efc8d664077c75503e5ac845a046ae2a7d4a932eb3ba9d20a0f6f512fd20.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[361,137,919,219]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \",\"Figure 3. (a) Singlet oxygen production mechanism scheme and (b) RNO degradation mechanism mediated by the ${}^{1}\\\\mathrm{O}_{2}$ -imidazole system. \"]","image_footnote":"[]","img_path":"images/0459/2d16d4fe472298db5cc87384860e5c5e90a1fe3d93a1fffb8f826aa061a4b1df.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,286,941,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To estimate the quantum yield in singlet oxygen production of the investigated systems under light laser triggering, a standard colorimetric method based on the RNO bleaching phenomenon was used. In this approach, the ${}^{1}\\mathrm{O}_{2}$ species induce the RNO oxidation, exploiting the formation of a transient imidazole trans-annular peroxide intermediate (Figure 3b) [35]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,361,941,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Among the tested Star3600_Me systems (Me = nickel, zinc, tin, manganese, rhodium, copper, erbium, mercury, iron), only those containing Zn, Sn, Hg, Rh and Er ions can generate singlet oxygen species (the respective quantum yields are reported in Table 1). The inability of some metal to produce singlet oxygen (nickel, tin, manganese, copper, erbium, iron) porphyrins could be due to the static quenching phenomenon [30], hindering the attainment of the excited state [44]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,483,939,659]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0463/9a908aa77202fb45ba0bdc476a656363f1bda8e75623e8552826c89d7895c21c.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td>Photosensitizer</td><td>Quantum Yield</td></tr><tr><td>TPPS</td><td>0.62</td></tr><tr><td>Star3600_2H</td><td>0.34</td></tr><tr><td>Star3600_Zn</td><td>1.38</td></tr><tr><td>Star3600_Sn</td><td>0.94</td></tr><tr><td>Star3600_Hg</td><td>0.31</td></tr><tr><td>Star3600_Rh</td><td>0.31</td></tr><tr><td>Star3600_Er</td><td>0.25</td></tr></table>","table_caption":"[\"Table 1. Quantum yields of the singlet oxygen under green laser irradiation (532 nm). \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[273,674,668,689]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. Star3600_Me Sensing Properties toward Tryptophan ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,693,944,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to being used as photosensitizers for singlet oxygen production [45,46], some metal porphyrins are powerful macromolecular sensors for amino acids as well [47,48]. To verify the binding properties of the metal porphyrins (able to generate singlet oxygen) with respect to L-Trp, water solutions of Star3600_Me $(4.6\\times 10^{-6}\\mathrm{M})$ were mixed with L-Trp in a molar ratio of 1:100, and UV-Vis and circular dichroism spectra were acquired. As expected, because the Er, Rh, Sn and Zn porphyrins do not form a stable chiral complex with L-Trp, silent circular dichroism spectra were recorded (Figure 4, green, cyan, magenta, blue lines, respectively). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,941,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[282,103,907,420]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Upper: circular dichroism spectra of aqueous solutions of pristine Star3600_Hg (black line) and of Star3600_Er (green), Star3600_Rh (cyan), Star3600_Sn (magenta), Star3600_Zn (blue) and Star3600_Hg (red line) when mixed with L-Trp (molar ratio 1:100). Bottom: relative UV-Vis spectra in the Soret band region. \"]","image_footnote":"[]","img_path":"images/0016/19b817cb25780f8e8e21ed4f052ce20adcf98ce74de0fd4b9fcd1b1f9d08c65d.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[275,502,939,651]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, the mixture of Star3600_Hg and L-Trp (Figure 4, red line) shows complex induced circular dichroism (ICD) signals in correspondence with the porphyrin Soret bands [49], due to the formation of a static complex. In particular, the experimental data suggest the formation of multiple kinds of chiral supramolecular systems, mainly due to the overlapping of negative-positive (centered at about $429\\mathrm{nm}$ ) and positive (centered at about $456\\mathrm{nm}$ ) ICD signals, in which L-Trp is coordinated by the metal of Hg porphyrins. In general, the induced chirality generating a bisignate signal arises when identical (or nearly identical) chromophores with strong extinction coefficients are found closely positioned in space, so they are able to display an observable interaction that stems from the efficient coupling of their electric transition moments [50]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,652,939,800]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To have a further understanding of the behavior of Star3600_Hg when interacting with L-Trp, the absorption and fluorescence features were investigated. As reported in Figure 5, due to the stabilization phenomenon between the two systems, there is a time-dependent interaction between L-Trp and Star3600_Hg, showing a simultaneous increase in the band at $426\\mathrm{nm}$ and a decrease in the band at $461\\mathrm{nm}$ . Considering the circular dichroism experimental results, this behavior could be explained since probably both Star3600_Hg and $(\\mathrm{Star3600 - Hg})_2$ systems are able to create a stable complex with L-Trp [51]. Moreover, experimental data suggest that the $(\\mathrm{Star3600 - Hg})_2 / \\mathrm{L - Trp}$ complex transmutes itself in the Star3600_Hg-/L-Trp system, decreasing its concentration. Regarding the fluorescence emission spectrum, it shows a small increase in the emission intensity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[282,103,843,391]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. UV-vis (continuous lines) and fluorescence (dashed lines) spectra of aqueous solutions of Star3600_Hg (black line) and a mixture of Star3600_Hg and L-Trp in molar ratio 1:100 freshly prepared (red line) and after 10 and $120\\\\mathrm{min}$ (blue and green lines, respectively). \"]","image_footnote":"[]","img_path":"images/0166/295673bbe0f5ecba4790beaff9b6d2ee2bfed3ebcb208b68c3cbc48d66f1a22d.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,454,522,469]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.4. Tryptophan Photo-Degradation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,472,941,636]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Considering that Star3600_Hg acts as an efficient sensor towards L-Trp creating a stable complex, and that L-Trp is potentially able to be an intermediate in the photooxidation mechanism, the features of both Star3600_Hg and L-TRP were investigated to determine the degradation of polypeptides containing L-Trp. In the supposed degradation mechanism, Star3600_Hg acts as a singlet oxygen source, while L-Trp serves both as a molecular target and as the singlet oxygen receptor. This interaction generates a peroxide species analogous to the mechanism observed with imidazole [52], capable of oxidizing the RNO system (Figure 6). Similarly, with the same mechanism, the system could be used to oxidize/damage the Trp-containing polypeptide. To validate this hypothesis, singlet oxygen detection experiments were conducted using L-Trp as the singlet oxygen intermediate receptor in place of imidazole. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[94,650,905,816]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 6. RNO degradation mechanism mediated by the $^1\\\\mathrm{O}_2$ -L-Trp system. \"]","image_footnote":"[]","img_path":"images/0292/7deaf0bc7ba744a044e3556a173fdfad370fdceaebb3ab1e9cc38be3928c678e.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,848,941,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The experiments were performed using TPPS, Star3600_2H (used as references) and Star3600_Hg photosensitizers. Moreover, the ability to generate singlet oxygen using the above systems was also investigated using a red light laser as a trigger. This wavelength range was selected because of the higher safety of this wavelength with respect to the green ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,55,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,941,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,102,939,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"laser (less energetic), and because the light red region has a greater ability to penetrate the tissues. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,131,939,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For this purpose, a solution containing the sensitizer $(5\\mu \\mathrm{M})$ , RNO $(50~\\mu \\mathrm{M})$ and L-Trp $(10\\mathrm{mM})$ was freshly prepared and then subjected to laser irradiation. Since the quantum yield of TPPS depends on the employed acceptor (L-Trp), in this case, we used $\\Phi_{\\mathrm{TPPS - RED}} = 0.33$ $(^{1}\\mathrm{O}_{2}$ quantum yield of TPPS@630 nm) and $\\Phi_{\\mathrm{TPPS - GREEN}} = 0.50$ $(^{1}\\mathrm{O}_{2}$ quantum yield of TPPS@540 nm) values [53]. The results are summarized in Table 2 and show that Star3600_Hg singlet oxygen production properties are effective under green and red laser irradiation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,284,939,363]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0100/228483783736d21bd3db11c951bc5e159a8297f5710bdbbbc6c66067280bdf41.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":"<table><tr><td>Photosensitizer</td><td>ΦRed</td><td>ΦGreen</td></tr><tr><td>TPPS [53]</td><td>0.33</td><td>0.50</td></tr><tr><td>Star3600_2H</td><td>0.21</td><td>0.24</td></tr><tr><td>Star3600_Hg</td><td>0.22</td><td>0.60</td></tr></table>","table_caption":"[\"Table 2. Quantum yields of the singlet oxygen under red (650 nm) and green laser irradiation (532 nm). \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[275,380,941,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To shed light on the effect of Star3600_Hg acting as an artificial cleaving agent, L-Trp was used as a model since its residue can be found in many proteins. To verify that the formation of transannular species triggered by the porphyrinic photosensitizer induces the degradation of L-Trp, the disappearance of the peak at $\\lambda = 279\\mathrm{nm}$ was monitored. Briefly, a $5\\mu \\mathrm{M}$ aqueous solution of Star3600_Hg was combined with L-Trp (ratio $= 1:100$ and irradiated with green or red laser light for a duration of $80\\mathrm{min}$ . The change in its spectroscopic properties was observed by analyzing the same solution with absorbance spectroscopy (Figure 7), showing a strong decrease in the peak at $\\lambda = 279\\mathrm{nm}$ (belonging to L-Trp). Similar results were obtained under green laser triggering. The experimental results confirm that, by exploiting this phenomenon, L-Trp can be a degradation site when located in protein chains. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,560,660,771]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 7. UV-vis spectra of the mixture of $5\\\\mu \\\\mathrm{M}$ aqueous solution of Star3600_Hg and L-TRP (ratio 1:100) when exposed to a red laser $(650~\\\\mathrm{nm})$ irradiation. \"]","image_footnote":"[]","img_path":"images/0393/31e467d8135e13dd13baaa7535ddc9b2eddcc1080db3f664fd1372bb85310431.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[275,820,710,835]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.5. Lysozyme Recognition and Degradation with Star3600_Hg ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,838,939,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As a proof of concept of the feasibility of utilizing Star3600_Hg for the degradation of proteins containing L-Trp residues, the interaction of Star3600_Hg with lysozyme in aqueous solution $(5\\mu \\mathrm{M})$ was investigated. Lysozyme (LSZ) is a well-known protein, with an average molecular weight of about $14.6\\mathrm{kDa}$ , and six tryptophane residues on its structure [54]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[272,102,944,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Specifically, the formation of the complex between Star3600_Hg and LSZ was investigated by means of absorbance and fluorescence spectroscopies. As shown in Figure 8, the formation of the complex leads to a decrease in the shoulder $(\\lambda = 461~\\mathrm{nm})$ of the Star3600_Hg's Soret band. Conversely, fluorescence spectra show an intensity increase upon the complex formation. These occurrences were similar to the one observed in the experiment involving L-Trp complexation, indicating the formation of the protein-porphyrin complex. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,219,732,428]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 8. UV-Vis (continuous lines) and fluorescence (dashed lines) spectra $(\\\\lambda_{\\\\mathrm{exc}} = 440~\\\\mathrm{nm})$ of Star3600_Hg/LSZ complex. The black line is an aqueous solution $(5\\\\mu \\\\mathrm{M})$ of Star3600_Hg, and red and green lines are the aqueous solution mixture of Star3600_Hg with LSZ (molar ratio 1:1) freshly prepared and after 2 days, respectively. \"]","image_footnote":"[]","img_path":"images/0375/ee0d1dfdf6ba7522aa106ff49ebbad8795568e235f76a919caf0059c1ed8edd8.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,502,515,518]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.6. Light Irradiation Experiments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,521,941,611]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In both the green (Figure 9a) and red (Figure 9b) laser light irradiation experiments, performed with a mixture of Star3600_Hg as the photosensitizer and LSZ as the target, the fluorescence spectra of LSZ ( $\\lambda_{\\mathrm{exc}} = 290 \\mathrm{~nm}$ ) show an emission band at $338 \\mathrm{~nm}$ that decreases its intensity during the irradiation time, suggesting a denaturation/degradation phenomenon in the polypeptide. In the absence of Star3600_Hg, any significant change in the LSZ emission band is recorded. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,623,591,797]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0602/80851f2ff2a20bdc50be49bb8abdf75325b596b72b1d2fd66b90d52de3fe4a09.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[613,624,921,797]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 9. Fluorescence spectra $(\\\\lambda_{\\\\mathrm{exc}} = 290~\\\\mathrm{nm})$ of the aqueous solution of Star3600_Hg and LSZ mixture (both $5\\\\mu \\\\mathrm{M}$ ) under (a) green $(532\\\\mathrm{nm})$ and (b) red $(650\\\\mathrm{nm})$ laser irradiation. \"]","image_footnote":"[]","img_path":"images/0840/db3cbd4b67d0e7e352bbc877578a9ec7e14701e49abdc73ddd727b6ac3ad4d21.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,846,944,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Considering that far-UV CD spectra of proteins can give information about their secondary structure [55], specific circular dichroism experiments were performed before and after green laser irradiation (similar results were also obtained with red laser irradiation). The CD spectrum of native LSZ (Figure 10a, blue line) shows a positive band at $192\\mathrm{nm}$ (attributable to the $\\alpha$ -helical [56,57]) and two negative bands at $207\\mathrm{nm}$ ( $\\pi-\\pi^{*}$ transition) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[272,102,944,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and $220\\mathrm{nm}$ ( $\\mathfrak{n}-\\pi^{*}$ transitions of both random coil and $\\alpha$ -helical structures [58-60]). These bands overlap with those of the $\\beta$ -sheet structure, with a positive band at $195\\mathrm{nm}$ and a negative one at $218\\mathrm{nm}$ [57,61]. After irradiation with the green laser for $40\\mathrm{min}$ (Figure 10a, dashed green line) and $80\\mathrm{min}$ (Figure 10a, solid green line), a strong decrease in positive and negative bands and a modification in the CD shape were recorded. In particular, the CD spectrum of the solution irradiated for $80\\mathrm{min}$ showed huge shape modifications in the far-UV range attributable to the occurrence of random coil structure arrangements [61]. Finally, after laser irradiation, a small ICD signal appears in the metal porphyrin Soret region (400-490 nm, Figure 10b), suggesting that the cleavage of the protein is occurring, setting oligopeptide sequences in solution. These latter can interact with the free Star3600_Hg system, leading to the formation of oligopeptide-Star3600_Hg chiral complexes. Supporting this interpretation, a correlation between the irradiation time and the ICD signal intensity is observed. On the other hand, the UV-Vis spectrum of the irradiated complex (Figure 10c) shows a decrease in the intensity of the $(\\mathrm{Star3600 - Hg})_2$ system's band (461 nm), as previous observed in the interaction between $(\\mathrm{Star3600 - Hg})_2$ and L-Trp. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,343,875,627]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 10. (a) CD spectra of aqueous solutions of LSZ (blue line), Star3600_Hg and LSZ (both $5\\\\mu \\\\mathrm{M}$ ) mixture freshly prepared (black line), and after 40 (green dash dot line) and 80 (green solid line) minutes under green laser irradiation; (b) magnification of the range $400 - 490\\\\mathrm{nm}$ and (c) the related UV-vis spectra. \"]","image_footnote":"[]","img_path":"images/1018/d132e9f85b1c1bbdf2acb6532ac30a72d35d9f2b2e052e0b7baa751d0d37ced2.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,709,944,876]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, to have further confirmation of the scissor-like behavior of Star3600_Hg towards LSZ, the MALDI-TOF mass spectra of the pristine (Figure 11, black line) and $80\\mathrm{min}$ irradiated (Figure 11, magenta line) Star3600_Hg-lysozyme system were acquired. The MALDI-TOF spectrum of pristine lysozyme shows peaks due to the presence of the molecular species as single charge at about $m/z$ 14400 $(\\mathrm{LSZ}^{+})$ and double-charged species at about $m/z$ 7200 $(\\mathrm{LSZ}^{++})$ . Instead, the irradiated mixture spectrum shows several broadened peaks, belonging to the different species originating from the cleavage of the sites where there are L-Trp residues, as shown in Table 3 and in Figure 12 (L-Trp residues are indicated with the red letter \"W\"). Based on the experimental data, we suppose that the aminoacidic sequence can be cleaved in every position (or neighboring to AA residues) where there are L-Trp residues. Similar results were obtained for both excitation wavelengths. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,55,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[277,102,890,248]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0149/b642699472b37c6c69fafd5eabd28184df27970306b0d884247ec639d3a91139.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[278,253,890,413]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 11. MALDI-TOF mass spectra of pristine lysozyme (black line) and Star3600_Hg-LSZ solution after $80\\\\mathrm{min}$ of laser irradiation (magenta line). The symbols are explained in Table 3. \"]","image_footnote":"[]","img_path":"images/0587/113eefc2a57509ef055cdf45665362dd05cdfebea31cff018c8aabb4ffe2a0fd.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[275,485,941,799]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0228/f0176414c5cee15c12522ea1a362b0ae1e2cf2a624abca420dc515aa156fbddd.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":"<table><tr><td>Label</td><td>Molecular Mass Range</td><td>Residue</td><td>Residue Amount (%)</td></tr><tr><td>a</td><td>1655</td><td>R5 + 2W</td><td>>1</td></tr><tr><td>b</td><td>1840–2170 Da</td><td>R4R5 + 2W, R4R5 + 3W, R5R6 + W</td><td>1</td></tr><tr><td>c</td><td>2560–3850 Da</td><td>R4R5R6 + 2W, R4R5R6 + 3W, R1, R1 + W, R2, R2 + W</td><td>7</td></tr><tr><td>d</td><td>4870–5480 Da</td><td>R3 + 2W, R3R4 + 2W, R3 + 3W, R3R4 + 3W, R3R4 + 4W</td><td>2</td></tr><tr><td>e</td><td>6860–7650 Da</td><td>R1R2 + W, R3R4R5 + 5W, R1R2 + 2W, R3R4R5R6 + 3W, R1R2 + 3W, R3R4R5R6 + 4W, R3R4R5R6 + 5W.Pristine lysozyme (double charge)</td><td>7</td></tr><tr><td>f</td><td>10,650–11,740 Da</td><td>R2R3R4R5 + 5W, R2R3R4R5 + 6W, R2R3R4R5R6 + 6W.</td><td>3</td></tr><tr><td>g</td><td>11,740–12,350 Da</td><td>R1R2R3 + 3W, R1R2R3 + 4W, R1R2R3R4 + 4W, R1R2R3R4R5 + 5W</td><td>10</td></tr><tr><td>LSZ</td><td>14,400 Da</td><td>Pristine lysozyme</td><td>69</td></tr></table>","table_caption":"[\"Table 3. MALDI-TOF mass spectrum peaks attributions. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[278,816,771,898]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 12. Aminoacidic sequence of lysozyme. W indicates L-Trp residues. \"]","image_footnote":"[]","img_path":"images/0208/096a0163f82737ea6a181cd5dbd72e5fd49a7a545366b42b3759e0c6a5b00351.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[272,103,944,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lysozyme degradation can be explained by considering two pathways: (i) Protein denaturation, which occurs following the light-triggering of Star3600_Hg with the formation of singlet oxygen and the following radical species. The latter can react with the disulfide bonds of proteins, determining the partial denaturation of lysozyme [62,63]. (ii) Cleavage of the polypeptide chain, due to the peroxide intermediate on the L-Trp residue and the consequent formation of radicals [64,65] that determine the L-Trp degradation and/or the polypeptide scissoring mechanism [52,66] (Figure 13). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,222,766,416]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 13. Schematic representation of the Star 3600_Hg photo-induced proteolysis mechanism. \"]","image_footnote":"[]","img_path":"images/0700/2c4f1e84485c275815799a646c5e28a9c330046f5bfa8a839d44ef9523743d45.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,447,394,458]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,464,939,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this work, we investigated the ROS-generating ability of several polymer-based metal porphyrin derivatives, and the potential use of L-Trp as a sensor and, when triggered by either red or green laser light, as a photocleaving agent. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,508,941,569]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The presence of hydrophilic poly(ethylene glycol) chains directly linked to the porphyrinic core allowed the full water solubility of Star3600_2H and of its metal complexes. Among the studied metal porphyrins, it was determined that only the Zn-, Sn-, Hg-, Rh- and Er-coordinated derivatives can generate singlet oxygen species. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,569,941,627]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Furthermore, within the investigated metal porphyrins, the coordination of mercury in the center of the porphyrinic core gives the porphyrin the ability to also act as a molecular sensor, leading to a stable complex with L-Trp. The phenomenon is easily recognizable from the changes in the spectroscopic properties of the porphyrin itself. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,629,941,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Since L-Trp resulted to be suitable as an acceptor agent of ${}^{1}\\mathrm{O}_{2}$ species produced from the excitation of Star3600_Hg, and its residue can be found in several proteins, such as LSZ, the synergistic interaction of Star3600_Hg and L-Trp was exploited to selectively cleave the protein at sites where L-Trp residues are located. The fluorescence and circular dichroism spectroscopies and MALDI-TOF mass spectrometry investigations suggest the potential use of Star3600_Hg as a molecular scissor. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,731,944,816]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author Contributions: Conceptualization, P.G.M.; methodology, P.M.; validation, A.N., F.V. and P.M.; formal analysis, L.M., L.B., A.N. and F.V.; investigation, L.M. and L.B.; resources, A.N. and P.G.M.; data curation, L.M., L.B. and A.N.; writing—original draft preparation, L.M., A.N. and P.G.M.; writing—review and editing, L.M., L.B., A.N., F.V. and P.G.M.; visualization, L.M., A.N. and P.G.M.; supervision, A.N. and P.G.M.; project administration, P.G.M.; funding acquisition, P.G.M. All authors have read and agreed to the published version of the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,822,939,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding: This research was partially funded by the European Union (NextGeneration EU), through the MUR-PNRR project SAMOTHRACE (ECS00000022). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,857,650,872]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Institutional Review Board Statement: Not applicable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,879,724,892]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data Availability Statement: Data are contained within the article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,898,710,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflicts of Interest: The authors declare no conflicts of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,55,186,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[55,103,144,116]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[55,120,941,900]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. 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Porphyrin-loaded nanoparticles for cancer theranostics. Nanoscale 2016, 8, 12394-12405. [CrossRef] [PubMed] \",\"24. Dong, X.; Chen, H.; Qin, J.; Wei, C.; Liang, J.; Liu, T.; Kong, D.; Lv, F. Thermosensitive porphyrin-incorporated hydrogel with four-arm PEG-PCL copolymer (II): Doxorubicin loaded hydrogel as a dual fluorescent drug delivery system for simultaneous imaging tracking in vivo. Drug Deliv. 2017, 24, 641-650. [CrossRef] [PubMed] \",\"25. Vinodh, M.; Alipour, F.H.; Mohamod, A.A.; Al-Azemi, T.F. Molecular Assemblies of Porphyrins and Macrocyclic Receptors: Recent Developments in Their Synthesis and Applications. *Molecules* 2012, 17, 11763-11799. [CrossRef] \",\"26. Gelfuso, G.M.; Figueiredo, F.V.; Gratieri, T.; Lopez, R.F.V. The Effects of pH and Ionic Strength on Topical Delivery of a Negatively Charged Porphyrin (TPPS4). J. Pharm. Sci. 2008, 97, 4249-4257. [CrossRef] [PubMed] \"]","page_idx":"14","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[53,102,942,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"27. 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[CrossRef] \"]","page_idx":"15","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,941,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 of 17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[53,102,941,418]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"55. Sreerama, N.; Venyaminov, S.Y.; Woody, R.W. 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[CrossRef] \",\"60. Li, Y.; Koopal, L.K.; Chen, Y.; Shen, A.; Tan, W. Conformational modifications of lysozyme caused by interaction with humic acid studied with spectroscopy. Sci. Total Environ. 2021, 768, 144858. [CrossRef] \",\"61. Greenfield, N.J.; Fasman, G.D. Computed circular dichroism spectra for the evaluation of protein conformation. Biochemistry 2002, 8, 4108-4116. [CrossRef] \",\"62. Clennan, E.L.; Wang, D.; Clifton, C.; Chen, M.F. Geometry-Dependent Quenching of Singlet Oxygen by Dialkyl Disulfides. J. Am. Chem. Soc. 1997, 119, 9081–9082. [CrossRef] \",\"63. Jiang, S.; Carroll, L.; Rasmussen, L.M.; Davies, M.J. Oxidation of protein disulfide bonds by singlet oxygen gives rise to glutathionylated proteins. Redox Biol. 2021, 38, 101822. [CrossRef] [PubMed] \",\"64. Lushchak, V.I. Free radical oxidation of proteins and its relationship with functional state of organisms. Biochemistry 2007, 72, 809-827. [CrossRef] [PubMed] \",\"65. Stadtman, E.R.; Levine, R.L. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. *Amino Acids* 2003, 25, 207-218. [CrossRef] \",\"66. Bellmaine, S.; Schnellbaecher, A.; Zimmer, A. Reactivity and degradation products of tryptophan in solution and proteins. Free Radic. Biol. Med. 2020, 160, 696-718. [CrossRef] \"]","page_idx":"16","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[53,435,941,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,184,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Polymers 2024, 16, 301 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"17 of 17 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[53,122,107,136]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[53,137,843,185]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Water-Soluble Star Polymer as a Potential Photoactivated Nanotool for Lysozyme Degradation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[53,197,915,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lidia Mezzina $^{1}$ , Angelo Nicosia $^{1, *}$ , Laura Barone $^{1}$ , Fabiana Vento $^{1}$ and Placido Giuseppe Mineo $^{1,2,3, *}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,237,937,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"$^{1}$ Department of Chemical Sciences and INSTM UdR of Catania, University of Catania, V.le A. Doria 6, I-95125 Catania, Italy; lidia.mezzina@phd.unict.it (L.M.); barone.laura@studium.unict.it (L.B.); fabianav2@libero.it (F.V.) \\\",\\\"$^{2}$ Institute for Chemical and Physical Processes, National Research Council (IPCF-CNR), Viale F. Stagno d'Alcomtres 37, I-98158 Messina, Italy \\\",\\\"3 Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Via P. Gaifami 18, I-95126 Catania, Italy \\\",\\\"* Correspondence: angelo.nicosia@unict.it (A.N.); placido.mineo@unict.it (P.G.M.) \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[272,357,941,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: The development of nanotools for chemical sensing and macromolecular modifications is a new challenge in the biomedical field, with emphasis on artificial peptidases designed to cleave peptide bonds at specific sites. In this landscape, metal porphyrins are attractive due to their ability to form stable complexes with amino acids and to generate reactive oxygen species when irradiated by light of appropriate wavelengths. The issues of hydrophobic behavior and aggregation in aqueous environments of porphyrins can be solved by using its PEGylated derivatives. This work proposes the design of an artificial photo-protease agent based on a PEGylated mercury porphyrin, able to form a stable complex with L-Tryptophan, an amino acid present also in the lysozyme structure (a well-known protein model). The sensing and photodegradation features of PEGylated mercury porphyrin were exploited to detect and degrade both L-Trp and lysozyme using ROS, generated under green $(532\\\\mathrm{nm})$ and red $(650\\\\mathrm{nm})$ light lasers. The obtained system (Star3600_Hg) and its behavior as a photo-protease agent were studied by means of several spectroscopies (UV-Vis, fluorescence and circular dichroism), and MALDI-TOF mass spectrometry, showing the cleavage of lysozyme and the appearance of several short-chain residues. The approach of this study paves the way for potential applications in theranostics and targeted bio-medical therapies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,554,146,576]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0477/f34aaa69525ee764b35ec806a4845a91656d6cae8111cd25c0a3afc71713576b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[53,581,263,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Citation: Mezzina, L.; Nicosia, A.; \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,595,226,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Barone, L.; Vento, F.; Mineo, P.G.\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,609,226,621]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Water-Soluble Star Polymer as a \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,624,255,636]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Potential Photoactivated Nanotool for \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,638,231,650]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lysozyme Degradation. Polymers \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,652,221,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2024, 16, 301. https://doi.org/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,665,184,678]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3390/polym16020301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,688,245,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Academic Editor: Helena Felgueiras \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,709,206,722]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 23 December 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,724,189,736]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Revised: 18 January 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,738,196,750]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted: 19 January 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,753,200,764]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published: 22 January 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,777,154,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0716/d6ab8c3515a8d6def96967babc610cdebea2976e7dd6195055d8c928f61bebb2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[53,808,257,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,602,870,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: porphyrin; protein degradation; photo-degradation; lysozyme; L-tryptophan \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,663,394,675]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,680,939,725]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the challenges in the biomedical field is to study new systems that act as nano-tools for chemical sensing or modifications at molecular levels, minimizing immune response or biodegradation problems [1]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,726,941,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"More focus has been placed on the creation of site-specific protein-cleaving agents, which is a remarkable challenge due to the exceptional stability of peptide bonds [2]. One of the advances in the use of artificial peptidases lies in the possibility of mapping and discerning binding sites on proteins and in the possibility of using them as molecular scissors to generate smaller fragments suitable for protein sequencing studies [3], the design of new DNA-targeted drugs [4] or even for the production of new biomaterials [5]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,816,941,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A commonly used approach is to design specific chemicals capable of binding to proteins at specific sites and cleaving their backbone when exposed to light irradiation [6]. This purpose could be pursued by using specific classes of chromophores that, in the presence of specific molecules, form complexes and modify their physicochemical properties as a result of structural modifications or binding processes [6]. Among these systems, porphyrins draw great attention because of the possibility of coordinating a metal in the center of the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,115,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[121,65,275,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"polymers \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,64,939,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MDPI \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[55,963,438,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301. https://doi.org/10.3390/polym16020301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[675,963,939,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://www.mdpi.com/journal/polymers \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[278,102,939,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"tetra pyrrolic core, which can then interact with several kinds of biologically interesting molecules such as amino acids [7,8]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,131,939,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In recent years, porphyrins have been widely used in sensing in solid state [9,10], in solution [11,12], and in theranostics (a field of medicine that combines therapy and diagnostics) due to their unique properties and versatility [13-15]. In particular, porphyrins are among the best candidates for non-invasive diagnostics (such as imaging) since they can be used as contrast agents in techniques like magnetic resonance imaging (MRI), positron emission tomography (PET) and fluorescence imaging [16-18]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,222,941,355]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Furthermore, porphyrins are particularly suitable to be employed in targeted therapies, such as photodynamic therapy (PDT) [19]. This exploits the synergistic effect of a photosensitizer that, when irradiated with a proper light source, can react with oxygen in its fundamental state to initiate a well-known photochemical process that leads to the generation of reactive oxygen species (ROS) such as singlet oxygen, ${}^{1}\\\\mathrm{O}_{2}$ [20], a cytotoxic agent [15]. However, in PDT, the appropriate wavelength of the excitation source is important. In fact, a light range between 500 and $900\\\\mathrm{nm}$ is needed, since this is the light range where tissues are more optically transparent. Moreover, the use of high-energy ultraviolet (UV) and near-UV wavelengths can lead to DNA and cellular damage [21]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,356,939,594]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Even if porphyrins are excellent candidates for PDT, they suffer from hydrophobic behavior due to their highly conjugated structure and hence the tendency to aggregate in aqueous media, such as the cell environment [22]. To overcome this issue, a variety of approaches can be used [17], such as the loading of porphyrin onto nanoparticles [23], their incorporation into hydrogels [24] or coupling with cyclodextrins [25]. In this context, the use of ionic porphyrins (e.g., the meso-tetrakis(p-sulfonatophenyl)porphyrin) has many drawbacks, such as sensitivity to environmental conditions including the pH and ionic strength of a solution [26-28]. Moreover, the presence of charges in the porphyrin structure could determine the denaturation of proteins and/or hinder the penetration of the porphyrin itself inside cells, aside from the non-specific binding that can lead the porphyrin to be bound to proteins or biomolecules with complementary charges rather than the target protein [29]. An alternative viable option is the use of PEGylated porphyrins [30], where the presence of PEG chains in peripheral positions with an appropriate polymerization degree [30,31] renders the porphyrin suitable for biomedical applications (avoiding the aggregation phenomena), guaranteeing excellent water solubility, stealth behaviors towards the immune system and biocompatibility [30]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,595,939,668]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lysozyme is one of the most studied proteins, since it has several valuable properties and is widespread [32]. Moreover, it shows bacteriostatic and bactericidal properties [33] and could be used as a food preservative to prevent the growth of food spoilage microorganisms, carrying out its antibacterial activity by acting as a catalyst for the hydrolysis of specific polysaccharides contained in bacteria's cell walls [34]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,669,939,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this work, we designed an artificial photo-protease agent able to form a complex with L-Tryptophan (L-Trp) residue that, when irradiated by light with a suitable wavelength, determines the amino acid/protein degradation. In particular, several metal porphyrin derivatives were investigated as L-Trp sensors and photosensitizers. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,728,941,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Taking into account the sensing and the photochemical features of a PEGylated porphyrin with a mercury atom complexed into the tetrapyrrolic core (Star3600_Hg), and the capability of L-Trp to act as an intermediate in the photo-oxidation mechanism involving the production of singlet oxygen, the above features were exploited to determine the selective degradation of lysozyme polypeptide. The synthesized systems and photodegradation features were investigated by means of MALDI-TOF mass spectrometry and UV-Vis, fluorescence and circular dichroism spectroscopies. To the best of our knowledge, this is the first case reported about a water-soluble mercury porphyrin suitable to be used as an artificial protease. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[273,102,475,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Materials and Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,120,939,151]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Metal acetates, chloroform, ethanol, triethylamine, LC-MS-grade water and pyridine were purchased from Sigma Aldrich (Merck Group, Milan, Italy). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,162,801,189]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1. Synthesis of 5,10,15,20-Tetrakis- $p$ -(ω-methoxy-poly-oxyethylene phenyl) Porphyrin (Star3600_2H) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,193,941,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Briefly, a solution of $1.57\\\\mathrm{g}$ of PEGMEC $(2.15\\\\mathrm{mmol})$ solubilized in $9\\\\mathrm{mL}$ of $\\\\mathrm{H}_2\\\\mathrm{O}$ :THF solution (1:1) was added to $0.18\\\\mathrm{g}$ of P4OH $(0.27\\\\mathrm{mmol})$ previously solubilized in $2.2\\\\mathrm{mL}$ of an aqueous solution of NaOH $0.5\\\\mathrm{M}$ , and stirred for $24\\\\mathrm{h}$ . Then, a further $2.2\\\\mathrm{mL}$ of NaOH $0.5\\\\mathrm{M}$ and $2\\\\mathrm{mL}$ of THF were added to the mixture and allowed to react for $24\\\\mathrm{h}$ more. The reaction product was acidified and dried under a nitrogen stream and then in a vacuum oven $(80^{\\\\circ}\\\\mathrm{C}$ for $48\\\\mathrm{h}$ ). The residue was solubilized in $\\\\mathrm{CHCl}_3$ and purified via chromatography using silica gel as the stationary phase and the mixture $\\\\mathrm{CHCl}_3:\\\\mathrm{EtOH}:\\\\mathrm{N}(\\\\mathrm{C}_2\\\\mathrm{H}_5)_3$ (96.5:2.0:1.5) as the eluent, resulting in a yield of $30\\\\%$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,324,828,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2. Synthesis of the 5,10,15,20-Tetrakis- $p$ -(ω-methoxy-poly-oxyethylene phenyl) Metal-Porphyrins (Star3600_Me) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,355,941,533]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The synthesis of metal porphyrins involved the reaction between Star3600_2H and the acetate of the chosen metal. Briefly, $100\\\\mu \\\\mathrm{mol}$ of the desired metal salt (acetate of nickel, zinc, tin, manganese, rhodium, copper, erbium, mercury, iron) and $10\\\\mu \\\\mathrm{mol}$ of Star3600_2H (about $36\\\\mathrm{mg}$ ) were solubilized in $5\\\\mathrm{mL}$ of pyridine. Subsequently, the reaction took place at $100^{\\\\circ}\\\\mathrm{C}$ under continuous stirring for $4\\\\mathrm{h}$ in a nitrogen atmosphere. Following this, the solvent was evaporated via a nitrogen stream, and the resulting residue was dried in a vacuum oven at $80^{\\\\circ}\\\\mathrm{C}$ for two days. The selected 5,10,15,20-tetrakis-p-( $\\\\omega$ -methoxy-polyethylenedioxy phenyl)-metal porphyrin, where the metal replaces the two hydrogen atoms within the tetrapyrrolic core, was isolated through column chromatography, employing silica gel as the stationary phase and a $\\\\mathrm{CHCl}_3:\\\\mathrm{C}_2\\\\mathrm{H}_5\\\\mathrm{OH}:\\\\mathrm{N}(\\\\mathrm{C}_2\\\\mathrm{H}_5)_3$ (96.5:2.0: 1.5) as the eluent. The first colored band was collected and corresponded to the metal porphyrin derivative, resulting in a yield of $85\\\\%$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,546,591,561]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.3. Estimation of Singlet Oxygen Production \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,564,939,594]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To quantitatively investigate the production of singlet oxygen, the standard method based on the $p$ -nitroso- $\\\\mathrm{N}, \\\\mathrm{N}'$ -dimethylaniline (RNO) bleaching reaction was used [35]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,595,941,668]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Briefly, the potential sensitizer (Star3600_Me, $5\\\\mu \\\\mathrm{M}$ ), RNO ( $50~\\\\mu \\\\mathrm{M}$ ) and imidazole ( $10~\\\\mathrm{mM}$ ) were dissolved in water. As the standard reference, a solution of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS, $5\\\\mu \\\\mathrm{M}$ ) was used. Photoactivation of the sensitizers was performed by irradiating the solution with a green ( $50~\\\\mathrm{mW}$ , $\\\\lambda = 532~\\\\mathrm{nm}$ ) or red ( $100~\\\\mathrm{mW}$ , $\\\\lambda = 650~\\\\mathrm{nm}$ ) laser source. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[309,669,858,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The quantum yield of ${}^{1}\\\\mathrm{O}_{2}$ was calculated with the following relation [35]: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[450,694,761,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\Phi = \\\\Phi_ {\\\\mathrm {T P P S}} \\\\frac {\\\\mathrm {O D} ^ {\\\\mathrm {T P P S}}}{\\\\mathrm {O D} ^ {\\\\mathrm {S t a r 3 6 0 0} - \\\\mathrm {M e}}} \\\\times \\\\frac {\\\\Delta \\\\mathrm {A} ^ {\\\\mathrm {S t a r 3 6 0 0} - \\\\mathrm {M e}}}{\\\\Delta \\\\mathrm {A} ^ {\\\\mathrm {T P P S}}}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[272,738,941,799]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\Phi_{\\\\mathrm{TPPS}} = {}^{1}\\\\mathrm{O}_{2}$ quantum yield of TPPS @532 nm, using imidazole as the acceptor [36]; OD is the optical density considering the source irradiation wavelength; and $\\\\Delta A$ is the absorbance variation at $440~\\\\mathrm{nm}$ . OD and $\\\\Delta A$ are related to both the standard and molecular probe. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,810,519,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.4. Photodegradation Experiments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,829,941,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The photodegradation experiments were performed by using solid-state lasers (green, $\\\\lambda = 532\\\\mathrm{nm}$ ; red, $\\\\lambda = 650\\\\mathrm{nm}$ ) at a fixed distance from the quartz cuvette containing the appropriate solution target, which was kept under continuous stirring for the entire duration of the experiment. The photodegradation was monitored by acquiring UV-Vis, fluorescence and circular dichroism spectra of the solutions. The starting concentration was \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,941,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,102,939,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"always $5\\\\mu \\\\mathrm{M}$ for Star3600_Hg, and the used ratios were 1:100 for the experiments involving L-TRP and 1:1 for the ones with LSZ. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,143,393,156]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.5. Instruments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,162,941,355]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A Voyager DE (PerSeptive Biosystem, Waltham, MA, USA) equipped with a delay extraction device (operating at $25\\\\mathrm{kV}$ applied voltage after 2600 ns delay, potential gradient of $454\\\\mathrm{Vmm}^{-1}$ and a wire voltage of $25\\\\mathrm{V}$ ) was used to acquire MALDI-TOF mass spectra, detecting positive ions in linear mode. The MALDI-TOF spectra of samples containing lysozyme were acquired in linear mode without the use of the delay extraction device. The matrices for the sample preparation were trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene] malononitrile (DCTB) for Star3600_2H and Star3600_Me, and a sum of 2,5-di hydroxybenzoic acid and 2-hydroxy-5-methoxybenzoic acid (SuperDHB) in 1:2 acetonitrile/0.1% aqueous TFA [37]. The mass spectrometer was calibrated with a previously reported method [38]. Grams/386 software (Version 3.04, Galactic Industries Corp, Salem, NH, USA) has been used to determine the molecular weights [38]. The $m/z$ value is attributed to the molecular ion, considering the most abundant isotope of each element in the molecule. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,356,941,400]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"UV-Vis spectra were recorded with a Cary60 UV-Vis spectrophotometer (Agilent Technologies, Santa Clara, CA, USA), using quartz cuvettes (1 cm path length) and water as the solvent $(\\\\mathrm{T} = 25.0 \\\\pm 0.1^{\\\\circ}\\\\mathrm{C})$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,401,941,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fluorescence spectra were acquired with a FP-8200 spectrofluorimeter (Jasco Corporation, Tokyo, Japan), using a quartz cuvette (1 cm path length) and water as a solvent $(\\\\mathrm{T} = 25.0 \\\\pm 0.1^{\\\\circ}\\\\mathrm{C})$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,445,941,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Absorbance and fluorescence spectra were processed with Spectragryph optical spectroscopy software (version 1.2.11, Dr. F. Menges, Oberstdorf, Germany, 2019) [39]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,476,941,565]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The CD spectra were acquired using a JASCO J-815 spectropolarimeter (Jasco Corporation, Tokyo, Japan) with a 150 W Xenon lamp. The ellipticity, $\\\\theta \\\\propto \\\\varepsilon_{\\\\mathrm{L}} - \\\\varepsilon_{\\\\mathrm{R}}$ , was obtained by calibrating the instrument with a $0.06\\\\%$ aqueous solution of $[\\\\mathrm{D}_{10}]$ camphorsulfonate. The measurements were performed with a quartz cuvette (0.2 and $0.5\\\\mathrm{cm}$ path length) at constant temperature $(T = (20.0 \\\\pm 0.1^{\\\\circ}\\\\mathrm{C}))$ , using a Peltier thermostat device (JASCO PTC-423S/15, Jasco Corporation, Tokyo, Japan). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,577,473,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results and Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,593,860,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. Structural and Spectroscopic Characterization of Star3600_2H and Star3600_Me \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,611,939,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Star3600_2H has been synthesized through the etherification reaction between the phenyl groups of 5,10,15-tetrakis (p-hydroxyphenyl) porphyrin and the poly(ethylene glycol) methyl ether chloride $(\\\\mathrm{PEGMEC}_{750})$ . To ensure the full solubility of the porphyrin in aqueous media, we have chosen to use PEG branches with an average polymerization degree $(\\\\mathrm{Xn})$ of about 16. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,686,941,745]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The structure of the Star3600_2H was confirmed through MALDI-TOF mass spectrometry analysis (Figure 1). Specifically, the molar mass distribution, centered at $m/z = 3504$ , has shown peaks that are detected at $m/z$ values of $734 + \\\\mathrm{n}44$ , with n ranging from 43 to 79, attributable to $\\\\mathrm{MK^{+}}$ adducts species. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,746,941,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The metalated derivatives were produced through a reaction involving Star3600_2H and the acetate salt of the selected metal in pyridine solution at $100^{\\\\circ}\\\\mathrm{C}$ (see Scheme 1 and the experimental section). The confirmation of the metal insertion inside the porphyrin core was obtained via MALDI-TOF mass spectrometry and both UV-Vis and fluorescence spectroscopies. As an example, in Figure 1b the MALDI-TOF spectrum of Star3600_Hg is reported (mass spectra of each Star3600_Me derivative are not reported for brevity). It shows a series of peaks with a molecular mass distribution shifted to higher $m/z$ values (about 200 uma) than that of the free-base counterpart (Figure 1a). Moreover, the presence of a broadened peak distribution is noticeable between $m/z = 6000$ and 9000, which can be attributed to the $(\\\\mathrm{Star}3600 - \\\\mathrm{Hg})_{2}$ species having two Hg ions coordinated by two porphyrins [40]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,941,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[277,103,647,305]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0624/d2864310f0681e0854bc66643d5141923e66fb7914e8505c0b7d245de603c774.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[277,305,647,502]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. MALDI-TOF mass spectra of Star3600_2H (a) and Star3600_Hg (b). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0005/6cb43d89584f338f9a7bfa24852fc99236603cc8ecf0942c065d298d3baa2aab.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[115,543,887,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Scheme 1. Exemplificative scheme of the synthesis of Star3600_Me. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1012/d1efdbdf8d9923e13226da8cf4c5f44f181a37ed959b8e53ff25afa228120cc6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,808,944,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The UV-vis spectrum of Star3600_2H shows a Soret band at $419~\\\\mathrm{nm}$ and four Q-bands at 520, 559, 595 and $652~\\\\mathrm{nm}$ , respectively. As expected for metal porphyrins, Star3600_Zn (Figure 2, green line) shows a bathocromic shift of the Soret band of about $8\\\\mathrm{nm}$ , which now appears at $428~\\\\mathrm{nm}$ , and the disappearance of two Q-bands, with the other two remaining at 563 and $603~\\\\mathrm{nm}$ (similar spectra are observed for all porphyrin-metal complexes, not reported for brevity). Typically, following Gouterman's four orbitals model and due to the $\\\\pi \\\\rightarrow \\\\pi^{*}$ transitions between the HOMO and LUMO, the number of Q-bands arises from \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,55,184,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,941,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[272,102,939,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the combination of different electronic transitions involving the central metal ion and the porphyrin ligands [31]. In particular, when a metal ion is located between the pyrrolic nitrogens, due to an increase in the symmetry of the porphyrin itself, a decrease in the number of Q-bands occurs [41]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,177,811,414]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. UV-Vis (continuous lines) and fluorescence (dashed lines) spectra of water solutions of Star3600_2H (red lines, $\\\\\\\\lambda_{\\\\\\\\mathrm{exc}} = 430~\\\\\\\\mathrm{nm}$ ), Star3600_Zn (green lines, $\\\\\\\\lambda_{\\\\\\\\mathrm{exc}} = 435~\\\\\\\\mathrm{nm}$ ) and Star3600_Hg (blue lines, $\\\\\\\\lambda_{\\\\\\\\mathrm{exc}} = 440~\\\\\\\\mathrm{nm}$ . Spectrum magnified $\\\\\\\\times 25$ ). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0192/dd39f48771f1570f9153fd1167726f65176aa6e84e3a5d6e3d05bfdd3152f9b1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,479,939,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, the UV-vis spectrum of Star3600_Hg shows a Soret band at about $428\\\\mathrm{nm}$ overlapped with a band at $461\\\\mathrm{nm}$ , and four Q-bands (respectively, at 524, 561, 601 and $654\\\\mathrm{nm}$ ). The presence of the doubled Soret band and of the four Q-bands suggest the presence of both the Star3600_Hg (porphyrin-Hg 1:1 ratio) and the $(\\\\mathrm{Star3600 - Hg})_2$ systems (porphyrin-Hg 2:2 ratio), and it could be hypothesized that the Soret band at $428\\\\mathrm{nm}$ is due to the 1:1 complex, while the one at $461\\\\mathrm{nm}$ is attributable to the 2:2 complex. In this scenario, the observed UV-Vis spectrum derives from the overlapping of the spectra of both systems. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,599,941,689]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As concerns the fluorescence spectra (Figure 2, dashed lines), Star3600_2H exhibit a strong fluorescence at $655\\\\mathrm{nm}$ , while the mercury atom into the porphyrin core causes a strong fluorescence quenching, showing a weak signal at $652\\\\mathrm{nm}$ with a shoulder at $608\\\\mathrm{nm}$ (for a clearer representation, the Star3600_Hg fluorescence spectrum in Figure 2 is magnified $\\\\times 25$ ). Instead, Star3600_Zn shows a higher fluorescence intensity with respect to the Star3600_2H and Star3600_Hg systems. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,700,687,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Star3600_Me Estimation of Singlet Oxygen Production \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,719,941,824]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Porphyrins are widely used as photosensitizers thanks to their capability to generate reactive oxygen species when triggered by a suitable light source [42]. Indeed, once the photon is absorbed, determining an electron excitation from the ground state to the singlet state, the intersystem crossing process could generate an excited triplet state, in which energy might be transferred (in a non-radiative way) to the triplet ground state of the oxygen molecules (Figure 3a), generating singlet oxygen $\\\\left(^{1}\\\\mathrm{O}_{2}\\\\right)$ species [43]. Usually, this last phenomenon is exploited in photodynamic therapy treatment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,941,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[100,114,322,234]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0782/e386efc8d664077c75503e5ac845a046ae2a7d4a932eb3ba9d20a0f6f512fd20.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[361,137,919,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\",\\\"Figure 3. (a) Singlet oxygen production mechanism scheme and (b) RNO degradation mechanism mediated by the ${}^{1}\\\\\\\\mathrm{O}_{2}$ -imidazole system. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0459/2d16d4fe472298db5cc87384860e5c5e90a1fe3d93a1fffb8f826aa061a4b1df.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,286,941,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To estimate the quantum yield in singlet oxygen production of the investigated systems under light laser triggering, a standard colorimetric method based on the RNO bleaching phenomenon was used. In this approach, the ${}^{1}\\\\mathrm{O}_{2}$ species induce the RNO oxidation, exploiting the formation of a transient imidazole trans-annular peroxide intermediate (Figure 3b) [35]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,361,941,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Among the tested Star3600_Me systems (Me = nickel, zinc, tin, manganese, rhodium, copper, erbium, mercury, iron), only those containing Zn, Sn, Hg, Rh and Er ions can generate singlet oxygen species (the respective quantum yields are reported in Table 1). The inability of some metal to produce singlet oxygen (nickel, tin, manganese, copper, erbium, iron) porphyrins could be due to the static quenching phenomenon [30], hindering the attainment of the excited state [44]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,483,939,659]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0463/9a908aa77202fb45ba0bdc476a656363f1bda8e75623e8552826c89d7895c21c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Photosensitizer</td><td>Quantum Yield</td></tr><tr><td>TPPS</td><td>0.62</td></tr><tr><td>Star3600_2H</td><td>0.34</td></tr><tr><td>Star3600_Zn</td><td>1.38</td></tr><tr><td>Star3600_Sn</td><td>0.94</td></tr><tr><td>Star3600_Hg</td><td>0.31</td></tr><tr><td>Star3600_Rh</td><td>0.31</td></tr><tr><td>Star3600_Er</td><td>0.25</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Quantum yields of the singlet oxygen under green laser irradiation (532 nm). \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[273,674,668,689]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. Star3600_Me Sensing Properties toward Tryptophan \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,693,944,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to being used as photosensitizers for singlet oxygen production [45,46], some metal porphyrins are powerful macromolecular sensors for amino acids as well [47,48]. To verify the binding properties of the metal porphyrins (able to generate singlet oxygen) with respect to L-Trp, water solutions of Star3600_Me $(4.6\\\\times 10^{-6}\\\\mathrm{M})$ were mixed with L-Trp in a molar ratio of 1:100, and UV-Vis and circular dichroism spectra were acquired. As expected, because the Er, Rh, Sn and Zn porphyrins do not form a stable chiral complex with L-Trp, silent circular dichroism spectra were recorded (Figure 4, green, cyan, magenta, blue lines, respectively). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,941,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[282,103,907,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Upper: circular dichroism spectra of aqueous solutions of pristine Star3600_Hg (black line) and of Star3600_Er (green), Star3600_Rh (cyan), Star3600_Sn (magenta), Star3600_Zn (blue) and Star3600_Hg (red line) when mixed with L-Trp (molar ratio 1:100). Bottom: relative UV-Vis spectra in the Soret band region. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0016/19b817cb25780f8e8e21ed4f052ce20adcf98ce74de0fd4b9fcd1b1f9d08c65d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[275,502,939,651]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, the mixture of Star3600_Hg and L-Trp (Figure 4, red line) shows complex induced circular dichroism (ICD) signals in correspondence with the porphyrin Soret bands [49], due to the formation of a static complex. In particular, the experimental data suggest the formation of multiple kinds of chiral supramolecular systems, mainly due to the overlapping of negative-positive (centered at about $429\\\\mathrm{nm}$ ) and positive (centered at about $456\\\\mathrm{nm}$ ) ICD signals, in which L-Trp is coordinated by the metal of Hg porphyrins. In general, the induced chirality generating a bisignate signal arises when identical (or nearly identical) chromophores with strong extinction coefficients are found closely positioned in space, so they are able to display an observable interaction that stems from the efficient coupling of their electric transition moments [50]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,652,939,800]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To have a further understanding of the behavior of Star3600_Hg when interacting with L-Trp, the absorption and fluorescence features were investigated. As reported in Figure 5, due to the stabilization phenomenon between the two systems, there is a time-dependent interaction between L-Trp and Star3600_Hg, showing a simultaneous increase in the band at $426\\\\mathrm{nm}$ and a decrease in the band at $461\\\\mathrm{nm}$ . Considering the circular dichroism experimental results, this behavior could be explained since probably both Star3600_Hg and $(\\\\mathrm{Star3600 - Hg})_2$ systems are able to create a stable complex with L-Trp [51]. Moreover, experimental data suggest that the $(\\\\mathrm{Star3600 - Hg})_2 / \\\\mathrm{L - Trp}$ complex transmutes itself in the Star3600_Hg-/L-Trp system, decreasing its concentration. Regarding the fluorescence emission spectrum, it shows a small increase in the emission intensity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[282,103,843,391]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. UV-vis (continuous lines) and fluorescence (dashed lines) spectra of aqueous solutions of Star3600_Hg (black line) and a mixture of Star3600_Hg and L-Trp in molar ratio 1:100 freshly prepared (red line) and after 10 and $120\\\\\\\\mathrm{min}$ (blue and green lines, respectively). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0166/295673bbe0f5ecba4790beaff9b6d2ee2bfed3ebcb208b68c3cbc48d66f1a22d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,454,522,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.4. Tryptophan Photo-Degradation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,472,941,636]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Considering that Star3600_Hg acts as an efficient sensor towards L-Trp creating a stable complex, and that L-Trp is potentially able to be an intermediate in the photooxidation mechanism, the features of both Star3600_Hg and L-TRP were investigated to determine the degradation of polypeptides containing L-Trp. In the supposed degradation mechanism, Star3600_Hg acts as a singlet oxygen source, while L-Trp serves both as a molecular target and as the singlet oxygen receptor. This interaction generates a peroxide species analogous to the mechanism observed with imidazole [52], capable of oxidizing the RNO system (Figure 6). Similarly, with the same mechanism, the system could be used to oxidize/damage the Trp-containing polypeptide. To validate this hypothesis, singlet oxygen detection experiments were conducted using L-Trp as the singlet oxygen intermediate receptor in place of imidazole. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[94,650,905,816]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 6. RNO degradation mechanism mediated by the $^1\\\\\\\\mathrm{O}_2$ -L-Trp system. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0292/7deaf0bc7ba744a044e3556a173fdfad370fdceaebb3ab1e9cc38be3928c678e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,848,941,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The experiments were performed using TPPS, Star3600_2H (used as references) and Star3600_Hg photosensitizers. Moreover, the ability to generate singlet oxygen using the above systems was also investigated using a red light laser as a trigger. This wavelength range was selected because of the higher safety of this wavelength with respect to the green \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,55,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,941,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,102,939,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"laser (less energetic), and because the light red region has a greater ability to penetrate the tissues. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,131,939,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For this purpose, a solution containing the sensitizer $(5\\\\mu \\\\mathrm{M})$ , RNO $(50~\\\\mu \\\\mathrm{M})$ and L-Trp $(10\\\\mathrm{mM})$ was freshly prepared and then subjected to laser irradiation. Since the quantum yield of TPPS depends on the employed acceptor (L-Trp), in this case, we used $\\\\Phi_{\\\\mathrm{TPPS - RED}} = 0.33$ $(^{1}\\\\mathrm{O}_{2}$ quantum yield of TPPS@630 nm) and $\\\\Phi_{\\\\mathrm{TPPS - GREEN}} = 0.50$ $(^{1}\\\\mathrm{O}_{2}$ quantum yield of TPPS@540 nm) values [53]. The results are summarized in Table 2 and show that Star3600_Hg singlet oxygen production properties are effective under green and red laser irradiation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,284,939,363]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0100/228483783736d21bd3db11c951bc5e159a8297f5710bdbbbc6c66067280bdf41.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Photosensitizer</td><td>ΦRed</td><td>ΦGreen</td></tr><tr><td>TPPS [53]</td><td>0.33</td><td>0.50</td></tr><tr><td>Star3600_2H</td><td>0.21</td><td>0.24</td></tr><tr><td>Star3600_Hg</td><td>0.22</td><td>0.60</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Quantum yields of the singlet oxygen under red (650 nm) and green laser irradiation (532 nm). \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[275,380,941,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To shed light on the effect of Star3600_Hg acting as an artificial cleaving agent, L-Trp was used as a model since its residue can be found in many proteins. To verify that the formation of transannular species triggered by the porphyrinic photosensitizer induces the degradation of L-Trp, the disappearance of the peak at $\\\\lambda = 279\\\\mathrm{nm}$ was monitored. Briefly, a $5\\\\mu \\\\mathrm{M}$ aqueous solution of Star3600_Hg was combined with L-Trp (ratio $= 1:100$ and irradiated with green or red laser light for a duration of $80\\\\mathrm{min}$ . The change in its spectroscopic properties was observed by analyzing the same solution with absorbance spectroscopy (Figure 7), showing a strong decrease in the peak at $\\\\lambda = 279\\\\mathrm{nm}$ (belonging to L-Trp). Similar results were obtained under green laser triggering. The experimental results confirm that, by exploiting this phenomenon, L-Trp can be a degradation site when located in protein chains. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,560,660,771]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 7. UV-vis spectra of the mixture of $5\\\\\\\\mu \\\\\\\\mathrm{M}$ aqueous solution of Star3600_Hg and L-TRP (ratio 1:100) when exposed to a red laser $(650~\\\\\\\\mathrm{nm})$ irradiation. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0393/31e467d8135e13dd13baaa7535ddc9b2eddcc1080db3f664fd1372bb85310431.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[275,820,710,835]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.5. Lysozyme Recognition and Degradation with Star3600_Hg \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,838,939,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As a proof of concept of the feasibility of utilizing Star3600_Hg for the degradation of proteins containing L-Trp residues, the interaction of Star3600_Hg with lysozyme in aqueous solution $(5\\\\mu \\\\mathrm{M})$ was investigated. Lysozyme (LSZ) is a well-known protein, with an average molecular weight of about $14.6\\\\mathrm{kDa}$ , and six tryptophane residues on its structure [54]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[272,102,944,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Specifically, the formation of the complex between Star3600_Hg and LSZ was investigated by means of absorbance and fluorescence spectroscopies. As shown in Figure 8, the formation of the complex leads to a decrease in the shoulder $(\\\\lambda = 461~\\\\mathrm{nm})$ of the Star3600_Hg's Soret band. Conversely, fluorescence spectra show an intensity increase upon the complex formation. These occurrences were similar to the one observed in the experiment involving L-Trp complexation, indicating the formation of the protein-porphyrin complex. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,219,732,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 8. UV-Vis (continuous lines) and fluorescence (dashed lines) spectra $(\\\\\\\\lambda_{\\\\\\\\mathrm{exc}} = 440~\\\\\\\\mathrm{nm})$ of Star3600_Hg/LSZ complex. The black line is an aqueous solution $(5\\\\\\\\mu \\\\\\\\mathrm{M})$ of Star3600_Hg, and red and green lines are the aqueous solution mixture of Star3600_Hg with LSZ (molar ratio 1:1) freshly prepared and after 2 days, respectively. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0375/ee0d1dfdf6ba7522aa106ff49ebbad8795568e235f76a919caf0059c1ed8edd8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,502,515,518]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.6. Light Irradiation Experiments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,521,941,611]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In both the green (Figure 9a) and red (Figure 9b) laser light irradiation experiments, performed with a mixture of Star3600_Hg as the photosensitizer and LSZ as the target, the fluorescence spectra of LSZ ( $\\\\lambda_{\\\\mathrm{exc}} = 290 \\\\mathrm{~nm}$ ) show an emission band at $338 \\\\mathrm{~nm}$ that decreases its intensity during the irradiation time, suggesting a denaturation/degradation phenomenon in the polypeptide. In the absence of Star3600_Hg, any significant change in the LSZ emission band is recorded. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,623,591,797]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0602/80851f2ff2a20bdc50be49bb8abdf75325b596b72b1d2fd66b90d52de3fe4a09.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[613,624,921,797]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 9. Fluorescence spectra $(\\\\\\\\lambda_{\\\\\\\\mathrm{exc}} = 290~\\\\\\\\mathrm{nm})$ of the aqueous solution of Star3600_Hg and LSZ mixture (both $5\\\\\\\\mu \\\\\\\\mathrm{M}$ ) under (a) green $(532\\\\\\\\mathrm{nm})$ and (b) red $(650\\\\\\\\mathrm{nm})$ laser irradiation. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0840/db3cbd4b67d0e7e352bbc877578a9ec7e14701e49abdc73ddd727b6ac3ad4d21.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,846,944,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Considering that far-UV CD spectra of proteins can give information about their secondary structure [55], specific circular dichroism experiments were performed before and after green laser irradiation (similar results were also obtained with red laser irradiation). The CD spectrum of native LSZ (Figure 10a, blue line) shows a positive band at $192\\\\mathrm{nm}$ (attributable to the $\\\\alpha$ -helical [56,57]) and two negative bands at $207\\\\mathrm{nm}$ ( $\\\\pi-\\\\pi^{*}$ transition) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[272,102,944,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and $220\\\\mathrm{nm}$ ( $\\\\mathfrak{n}-\\\\pi^{*}$ transitions of both random coil and $\\\\alpha$ -helical structures [58-60]). These bands overlap with those of the $\\\\beta$ -sheet structure, with a positive band at $195\\\\mathrm{nm}$ and a negative one at $218\\\\mathrm{nm}$ [57,61]. After irradiation with the green laser for $40\\\\mathrm{min}$ (Figure 10a, dashed green line) and $80\\\\mathrm{min}$ (Figure 10a, solid green line), a strong decrease in positive and negative bands and a modification in the CD shape were recorded. In particular, the CD spectrum of the solution irradiated for $80\\\\mathrm{min}$ showed huge shape modifications in the far-UV range attributable to the occurrence of random coil structure arrangements [61]. Finally, after laser irradiation, a small ICD signal appears in the metal porphyrin Soret region (400-490 nm, Figure 10b), suggesting that the cleavage of the protein is occurring, setting oligopeptide sequences in solution. These latter can interact with the free Star3600_Hg system, leading to the formation of oligopeptide-Star3600_Hg chiral complexes. Supporting this interpretation, a correlation between the irradiation time and the ICD signal intensity is observed. On the other hand, the UV-Vis spectrum of the irradiated complex (Figure 10c) shows a decrease in the intensity of the $(\\\\mathrm{Star3600 - Hg})_2$ system's band (461 nm), as previous observed in the interaction between $(\\\\mathrm{Star3600 - Hg})_2$ and L-Trp. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,343,875,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 10. (a) CD spectra of aqueous solutions of LSZ (blue line), Star3600_Hg and LSZ (both $5\\\\\\\\mu \\\\\\\\mathrm{M}$ ) mixture freshly prepared (black line), and after 40 (green dash dot line) and 80 (green solid line) minutes under green laser irradiation; (b) magnification of the range $400 - 490\\\\\\\\mathrm{nm}$ and (c) the related UV-vis spectra. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/1018/d132e9f85b1c1bbdf2acb6532ac30a72d35d9f2b2e052e0b7baa751d0d37ced2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,709,944,876]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, to have further confirmation of the scissor-like behavior of Star3600_Hg towards LSZ, the MALDI-TOF mass spectra of the pristine (Figure 11, black line) and $80\\\\mathrm{min}$ irradiated (Figure 11, magenta line) Star3600_Hg-lysozyme system were acquired. The MALDI-TOF spectrum of pristine lysozyme shows peaks due to the presence of the molecular species as single charge at about $m/z$ 14400 $(\\\\mathrm{LSZ}^{+})$ and double-charged species at about $m/z$ 7200 $(\\\\mathrm{LSZ}^{++})$ . Instead, the irradiated mixture spectrum shows several broadened peaks, belonging to the different species originating from the cleavage of the sites where there are L-Trp residues, as shown in Table 3 and in Figure 12 (L-Trp residues are indicated with the red letter \\\"W\\\"). Based on the experimental data, we suppose that the aminoacidic sequence can be cleaved in every position (or neighboring to AA residues) where there are L-Trp residues. Similar results were obtained for both excitation wavelengths. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,55,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[277,102,890,248]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0149/b642699472b37c6c69fafd5eabd28184df27970306b0d884247ec639d3a91139.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[278,253,890,413]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 11. MALDI-TOF mass spectra of pristine lysozyme (black line) and Star3600_Hg-LSZ solution after $80\\\\\\\\mathrm{min}$ of laser irradiation (magenta line). The symbols are explained in Table 3. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0587/113eefc2a57509ef055cdf45665362dd05cdfebea31cff018c8aabb4ffe2a0fd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[275,485,941,799]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0228/f0176414c5cee15c12522ea1a362b0ae1e2cf2a624abca420dc515aa156fbddd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Label</td><td>Molecular Mass Range</td><td>Residue</td><td>Residue Amount (%)</td></tr><tr><td>a</td><td>1655</td><td>R5 + 2W</td><td>>1</td></tr><tr><td>b</td><td>1840–2170 Da</td><td>R4R5 + 2W, R4R5 + 3W, R5R6 + W</td><td>1</td></tr><tr><td>c</td><td>2560–3850 Da</td><td>R4R5R6 + 2W, R4R5R6 + 3W, R1, R1 + W, R2, R2 + W</td><td>7</td></tr><tr><td>d</td><td>4870–5480 Da</td><td>R3 + 2W, R3R4 + 2W, R3 + 3W, R3R4 + 3W, R3R4 + 4W</td><td>2</td></tr><tr><td>e</td><td>6860–7650 Da</td><td>R1R2 + W, R3R4R5 + 5W, R1R2 + 2W, R3R4R5R6 + 3W, R1R2 + 3W, R3R4R5R6 + 4W, R3R4R5R6 + 5W.Pristine lysozyme (double charge)</td><td>7</td></tr><tr><td>f</td><td>10,650–11,740 Da</td><td>R2R3R4R5 + 5W, R2R3R4R5 + 6W, R2R3R4R5R6 + 6W.</td><td>3</td></tr><tr><td>g</td><td>11,740–12,350 Da</td><td>R1R2R3 + 3W, R1R2R3 + 4W, R1R2R3R4 + 4W, R1R2R3R4R5 + 5W</td><td>10</td></tr><tr><td>LSZ</td><td>14,400 Da</td><td>Pristine lysozyme</td><td>69</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3. MALDI-TOF mass spectrum peaks attributions. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[278,816,771,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 12. Aminoacidic sequence of lysozyme. W indicates L-Trp residues. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0208/096a0163f82737ea6a181cd5dbd72e5fd49a7a545366b42b3759e0c6a5b00351.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[55,57,184,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[272,103,944,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lysozyme degradation can be explained by considering two pathways: (i) Protein denaturation, which occurs following the light-triggering of Star3600_Hg with the formation of singlet oxygen and the following radical species. The latter can react with the disulfide bonds of proteins, determining the partial denaturation of lysozyme [62,63]. (ii) Cleavage of the polypeptide chain, due to the peroxide intermediate on the L-Trp residue and the consequent formation of radicals [64,65] that determine the L-Trp degradation and/or the polypeptide scissoring mechanism [52,66] (Figure 13). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,222,766,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 13. Schematic representation of the Star 3600_Hg photo-induced proteolysis mechanism. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0700/2c4f1e84485c275815799a646c5e28a9c330046f5bfa8a839d44ef9523743d45.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,447,394,458]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,464,939,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this work, we investigated the ROS-generating ability of several polymer-based metal porphyrin derivatives, and the potential use of L-Trp as a sensor and, when triggered by either red or green laser light, as a photocleaving agent. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,508,941,569]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The presence of hydrophilic poly(ethylene glycol) chains directly linked to the porphyrinic core allowed the full water solubility of Star3600_2H and of its metal complexes. Among the studied metal porphyrins, it was determined that only the Zn-, Sn-, Hg-, Rh- and Er-coordinated derivatives can generate singlet oxygen species. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,569,941,627]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Furthermore, within the investigated metal porphyrins, the coordination of mercury in the center of the porphyrinic core gives the porphyrin the ability to also act as a molecular sensor, leading to a stable complex with L-Trp. The phenomenon is easily recognizable from the changes in the spectroscopic properties of the porphyrin itself. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,629,941,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Since L-Trp resulted to be suitable as an acceptor agent of ${}^{1}\\\\mathrm{O}_{2}$ species produced from the excitation of Star3600_Hg, and its residue can be found in several proteins, such as LSZ, the synergistic interaction of Star3600_Hg and L-Trp was exploited to selectively cleave the protein at sites where L-Trp residues are located. The fluorescence and circular dichroism spectroscopies and MALDI-TOF mass spectrometry investigations suggest the potential use of Star3600_Hg as a molecular scissor. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,731,944,816]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author Contributions: Conceptualization, P.G.M.; methodology, P.M.; validation, A.N., F.V. and P.M.; formal analysis, L.M., L.B., A.N. and F.V.; investigation, L.M. and L.B.; resources, A.N. and P.G.M.; data curation, L.M., L.B. and A.N.; writing—original draft preparation, L.M., A.N. and P.G.M.; writing—review and editing, L.M., L.B., A.N., F.V. and P.G.M.; visualization, L.M., A.N. and P.G.M.; supervision, A.N. and P.G.M.; project administration, P.G.M.; funding acquisition, P.G.M. All authors have read and agreed to the published version of the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,822,939,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding: This research was partially funded by the European Union (NextGeneration EU), through the MUR-PNRR project SAMOTHRACE (ECS00000022). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,857,650,872]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Institutional Review Board Statement: Not applicable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,879,724,892]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data Availability Statement: Data are contained within the article. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,898,710,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflicts of Interest: The authors declare no conflicts of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,55,186,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Polymers 2024, 16, 301 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 of 17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[55,103,144,116]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,120,941,900]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Free radical oxidation of proteins and its relationship with functional state of organisms. Biochemistry 2007, 72, 809-827. [CrossRef] [PubMed] \\\",\\\"65. Stadtman, E.R.; Levine, R.L. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. *Amino Acids* 2003, 25, 207-218. [CrossRef] \\\",\\\"66. Bellmaine, S.; Schnellbaecher, A.; Zimmer, A. Reactivity and degradation products of tryptophan in solution and proteins. Free Radic. Biol. Med. 2020, 160, 696-718. 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Renewable Sustainable Energy 12, 033304 (2020); https://doi.org/10.1063/5.0004393 \nSubmitted: 12 February 2020. Accepted: 31 May 2020. 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[37,76,130,475]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energ ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[49,846,120,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AIP Publishing ","text_format":null,"text_level":null,"type":"aside_text"},{"bbox":"[197,915,746,929]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. 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","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[81,117,883,175]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data-driven modeling of the wake behind a wind turbine array EP ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,202,683,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cite as: J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \nSubmitted: 12 February 2020 · Accepted: 31 May 2020 \nPublished Online: 26 June 2020 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[732,205,774,245]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0544/d837ad12c299687529c2117219593ece18aa43cab583b8171be0e68b0f1094de.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[797,206,851,245]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0264/d989bd1d48f6c24935b7c9c178ce261f83ec9a29b74c69ccef7fb56bc8e2fae8.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[872,206,911,245]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0698/82907044da6d750aafa1e17cf2f0737c406158cf34de1072578b0d715fe44154.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,263,372,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Naseem Ali $①$ and Raúl Bayoán Cala) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,291,189,304]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AFFILIATIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[81,310,776,323]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Department of Mechanical and Materials Engineering, Portland State University, Portland, Oregon 97201, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,334,544,349]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{a)}$ Author to whom correspondence should be addressed: rcal@pdx.edu ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,370,168,383]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ABSTRACT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,389,916,482]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The wake flow in a wind turbine array boundary layer is described using the Koopman operator. Dynamics of the flow are decomposed into the linear and forcing terms, and the low-energy delay coordinates are revealed. The rare events show the non-Gaussian long tails that capture the switching and bursting phenomena. The near-wake region shows the incoherent phase space region, where the dynamics are strongly nonlinear. The far-wake region is marked with the small non-Gaussian forcing term, and the dynamics are largely governed by linear dynamics. The data-driven predictive model is built based on the Hankel-based dynamic mode decomposition and treats the nonlinear state of forcing term as external actuation. The model forecasts the evolution of the flow field for short-term timescales. The mean relative errors between the predictive and test fluctuating velocities are approximately $15\\%$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,487,537,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing. https://doi.org/10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,538,217,552]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,557,486,660]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Modeling the turbine response to non-Gaussian conditions can help explain the signature in the aerodynamic forces, fatigue loads, and development of alternative control schemes. $^{1,2,32}$ The variations in the mean statistics of the wind turbine wake flow highlight the nature of the flow response to the external forcing of the wind turbine. $^{2-5,33-35}$ Because turbulence exists on different temporal and spatial scales in a wind farm, the behavior of the non-Gaussian conditions is dependent on the physical location downstream the rotor. $^{2,6}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,660,486,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Systems like wind plants have a large number of degrees of freedom that cause a considerable amount of uncertainty in parameters when modeling. For wind farm controller analysis, high fidelity models are required for exploring the optimal possibilities of wind farm control. Due to the computational cost of these models, they are not convenient for pursuing a dynamical system and control model. Therefore, new generations of models are required to solve this deficiency. Reduced-order models can provide coherent features of wake dynamics and solve part of the computational complexity although these models are only suitable for specific conditions and are not proven for real cases. Linking between reduced-order model and parameter-varying control can provide a new generation of the optimized wind farm control. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,828,486,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Developing a flow model from statistics based on the ensemble of observations, which can represent a solution to the dynamical system itself, is of central importance. The data-driven model includes ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,538,916,671]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"reducing the degrees of freedom and presenting a dynamical model that links the evolution of the most dominant features and the trajectories in the high-fidelity phase space. The wake of the turbine is a nonlinear system with intermittent energy that transfers between flow scales in the energy cascade. $^{7,8}$ Therefore, predicting and identifying the coordinate transformations that highlight the time response to the strongly nonlinear forces are potentially important for the wind farm design. Time evolution of interacting quantities in engineering applications such as wind energy can be described using a dynamical system approach. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,671,916,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data-driven techniques have recently received more attention as alternative approaches for directing wind farm analysis or control. These approaches rely on specific operating conditions; hence, they provide linear models for a specific operating point. Because the operation of the wind turbines is time dependent, data-driven approaches can describe the wake in more detail regarding the flow conditions, such as thermal stability and turbulent intensity, as well as provide systems the ability to automatically learn and improve performance and stability. Following the Takens embedding theorem, which translates high-dimensional datasets into a relatively low-dimensional space, applied to a sequence of observations of the state, data-driven dynamical systems can detect the full dynamics by reconstructing a set of states and preserve the structural aspect of the states. The intermittent forces are strange phase spaces of a dynamical system characterized by chaotic trajectories, and are responsible for divergent behavior ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,866,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,264,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-1 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[78,119,485,212]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"with time and cause uncertainty to the prediction. Consequently, isolating the deterministic structure from the randomness of the chaotic dynamics is potentially useful for control strategies. Koopman operator theory is an efficient approach to decompose the chaotic system into the linear evolution and nonlinear forcing, where the time history of the measurements can estimate the full-state of the system and provide a foundation for its linear dynamics. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[83,212,486,538]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In nonlinear dynamics, the dynamical system can be represented in the linear representations through the Koopman analysis. A Koopman operator has the ability to analyze and tackle the nonlinear system in an infinite-dimensional linear approach. In data-driven models, for example, Giannakis and Majda and Giannakis projected the delay-embedded data onto the basis function of Laplace-Beltrami and Koopman operator respectively, to present a model reduction with the aim of forecasting the time series for ergodic dynamical systems. Arbabi and Mezic linked the Hankel based dynamic mode decomposition (DMD) to the Koopman operator, demonstrating that applying DMD to Hankel observation matrices yields the true Koopman eigenvalues and eigenfunctions. Korda and Mezic identified linear predictors for nonlinear controlled dynamical systems using the Koopman operator framework. The nonlinear dynamics are projected to a higher dimensional space that displays the evolution is approximately linear. Giannakis et al. employed a Koopman eigenfunction analysis to study the long-time evolution of the three-dimensional flow. Their findings showed that the behavior of the large-scale circulation is recovered from the eigenfunctions of a data-driven Koopman operator. Brunton et al. provided a Hankel alternative view of Koopman to understand the disorder in chaos quantitatively by treating examples such as measles outbreaks and magnetic fields. Recently, Khodkar et al. introduced the Koopman-based framework for forecasting the spatiotemporal evolution of high-dimensional chaotic dynamics and turbulence. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,540,486,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data-driven approaches have been used to study wind turbine wakes. For example, Gebraad et al. $^{18}$ presented a novel data-driven model to optimize the yaw settings of wind turbines in a wind plant for improved energy production of the wind plant. Iungo et al. $^{19}$ proposed a data-driven RANS approach to optimize power plant control and prevent detrimental wake interactions. Iungo et al. $^{20}$ proposed a new data-driven reduced order model for prediction of wind turbine wakes. The model captured the main physical processes and dynamics of wind turbine wakes. Park et al. $^{21}$ used a data-driven optimization method to find the optimum control actions. Gocmen and Giebel $^{22}$ presented a data-driven wake model for short-term power estimation. Ti and Yang $^{23}$ used the machine learning and computational fluid dynamics simulation to develop new wake velocity and turbulence models to improve the turbine wake predictions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,723,486,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data-driven analysis based on the Koopman operator is used here to build a linear model in the leading delay coordinates to forecast the future state of stochastic fluctuating velocity. The model will be built after isolating the linear modes from a low energy delay coordinate that triggers intermittent bursting and switching events. The nonlinear term is used as an input parameter to train the model. The aim is also to connect the nonlinear mode distribution, which causes the linear model to diverge, with intermittency, and quantify the activity of the intermittent force with respect to time. The manuscript is organized as follows: Sec. II outlines the Koopman theory; Sec. III presents in detail experimental setup; Sec. IV provides a discussion of the finding and the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,119,913,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"relevance in the field; Sec. V presents the forecasting for the spatial and temporal evolution. Conclusions are presented in Sec. VI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,153,594,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"II. THEORY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,170,913,223]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The perspective of the Koopman operator relies on mapping the measurement dataset to different coordinates that make the dynamics appear linear. Here, the Koopman operator is built based on the Hankel matrix, $H$ , as<sup>10</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[563,231,911,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array}{l} H = \\left[ \\begin{array}{c c c c} u (t _ {1}) & u (t _ {2}) & \\dots & u (t _ {p}) \\\\ u (t _ {2}) & u (t _ {3}) & \\dots & u (t _ {p + 1}) \\\\ \\vdots & \\vdots & \\ddots & \\vdots \\\\ u (t _ {q}) & u (t _ {q + 1}) & \\dots & u (t _ {m}) \\end{array} \\right] \\\\ = \\left[ \\begin{array}{c c c c} u (t _ {1}) & \\mathcal {K} u (t _ {1}) & \\dots & \\mathcal {K} ^ {p - 1} u (t _ {1}) \\\\ \\mathcal {K} u (t _ {1}) & \\mathcal {K} ^ {2} u (t _ {1}) & \\dots & \\mathcal {K} ^ {p} u (t _ {1}) \\\\ \\vdots & \\vdots & \\ddots & \\vdots \\\\ \\mathcal {K} ^ {q - 1} u (t _ {1}) & \\mathcal {K} ^ {q} u (t _ {1}) & \\dots & \\mathcal {K} ^ {m - 1} u (t _ {1}) \\end{array} \\right], \\tag {1} \\\\ \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,377,913,457]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\mathcal{K}$ is the Koopman operator, $u$ is a vector-valued observation of fluctuating velocity, and $t$ is the time. Singular value decomposition (SVD) of the Hankel matrix can estimate the embedding dimension for time-delay coordinates that provide the conditions under which a chaotic dynamical system is reconstructed from a set of observations of the state of a dynamical system as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[671,464,913,480]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nH = \\Psi \\Sigma V ^ {T}, \\tag {2}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,485,913,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where the columns of $\\Psi$ and $V$ present the right- and left-singular vectors, respectively; they are a set of orthonormal eigenvectors. The chaotic dynamics is decomposed using the Hankel alternative view of Koopman into a linear model and the forcing term. The eigentime-delay vector, $V = [v_{1}, v_{2}, \\ldots, v_{R - 1}]^{T}$ , is used to define the forced term $\\nu_{R}$ from the nonlinear dynamics. Following the Hankel alternative view of Koopman approach introduced in the work of Brunton et al. $^{10}$ and Khodkar et al. $^{17}$ adding a forcing term to the linear model is considered to approximate the nonlinear dynamics more accurately. A future vector-valued observable that is not a part of the training data can be predicted as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[656,639,913,653]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nu ^ {t + 1} = A u ^ {t} + B F, \\tag {3}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,660,913,754]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $F$ is the form of external forcing, where it takes the quadratic form based on the Reynolds stress terms. The $B$ is the control matrix related to the forcing term. The $A$ and $B$ are the input parameters to create state-space model and simulate the time response of dynamic system, respectively. The Hankel based dynamic mode decomposition with control (H-DMDc) is used to estimate the $A$ and $B$ matrices using the minimization approach introduced in the work of Proctor et al.,[24] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[642,761,913,777]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nA = \\Psi^ {T} \\Pi V \\Sigma^ {- 1} \\Psi_ {1} ^ {T} \\Psi , \\tag {4}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[650,779,913,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nB = \\Psi^ {T} \\Pi V \\Sigma^ {- 1} \\Psi_ {2} ^ {T}, \\tag {5}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,802,913,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where these matrices are calculated in a reduced-dimension subspace. Here, $\\Psi_{1}$ and $\\Psi_{2}$ are constructed from the first $qm$ and the remaining rows of $\\Psi$ . Figure 1 summarizes the main steps of the current approach. The training data that are obtained from any velocity or power sensor can be fed into DMDc algorithm to estimate the model ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[75,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-2 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[83,119,485,281]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 1. Schematic of data-driven method. \"]","image_footnote":"[]","img_path":"images/0081/002681ee3d33dfe9dff9bfbcef12c533b1bbf152348bf3d2cb041309c5b9072a.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,334,486,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"operators. The forecasting step starts after as shown in Eq. (3). The advantage of forecasting step can be fed into a controller to change the turbine condition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,379,277,391]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"III. EXPERIMENTAL SETUP ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,396,488,672]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An experiment with an array of horizontal axis wind turbines was conducted at the closed-loop Corrsin wind tunnel at Johns Hopkins University. The entrance of the tunnel was furnished with an active grid to generate turbulence. The inlet mean velocity shear profile was generated using nine strakes. A 24-grit aluminum oxide sand paper was provided along the test section in the ground to roughen the boundary shape, see Fig. 2. A three-bladed rotor of $12\\mathrm{cm}$ diameter, $D$ , was used as a wind turbine model. Nine wind turbines models were distributed as a $3\\times 3$ array with space of 7D in the streamwise and 3D in the spanwise directions. The measurements considered here were taken behind the center of the third row of the wind farm. The data were gathered at a frequency of $40\\mathrm{kHz}$ to sample $4\\times 10^{6}$ data points. The measurements were conducted at the streamwise-wall-normal plane $(x - y)$ and the spanwise-wall-normal plane $(z - y)$ . For the $x - y$ plane, the measurements were collected at nine locations in the streamwise direction starting from $x = 0.5D$ to $x = 8D$ . For the $z - y$ plane, the measurements were taken at nine locations in the spanwise direction starting from $z = -4D / 6$ to $z = 4D / 6$ with an increment of $D / 6$ . For each plane, the measurements are taken for 21 locations in the wall-normal direction starting at $0.5\\mathrm{cm}$ above the ground and move vertically with an increment of $1\\mathrm{cm}$ . More details about the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,119,916,145]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"experimental setup and measurements can be found in the work of Cal et al.[25] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,153,604,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IV. RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,170,916,394]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Statistical quantities are shown here to provide an important distinction between the flow regions downstream the rotor. Figure 3 presents the normalized streamwise mean velocity $(U / U_{\\infty})$ , and the ratio between the integral length scale $(L_{in})$ , and Taylor microscale $(\\lambda)$ . The integral length scale is calculated based on auto-correlation between two different times. The impact of the rotor is substantial on the near-wake region, specifically behind the nacelle and tower, where the minimum values of the streamwise mean velocity, integral length scales, and Taylor microscale are observed. These parameters monotonically increase toward the outside of the rotor. The same trend is shown in the comparison between the near- and far-wake regions. The tower adds more perturbations to the flow and translates to the wake region. In the spanwise direction, the wake expansion is shown below the top tip (TT), where velocities are low. The reduced size of the $L_{in}$ is due to the amplification of enstrophy and flow separation. The flow outside the swept area is marked with relatively constant $L_{in}$ and $\\lambda$ , specifically above the top tip. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,394,916,671]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 4 presents the principal components of the SVD with the linear model that is built based on the regression model for the hub height (HH) and top tip locations at the center of the rotor. The figure shows the main principle of the Koopman analysis using a SVD in a finite-dimensional nonlinear system by testing the quality of the reconstruction of the eigentime series. These locations are shown for generality as they present the most sensitive locations that carry chaotic changes in the wake. The regression model is presented for the linear variables in right-singular vectors $V$ . Then, the regression coefficients for linear and forcing terms are used to train and simulate the time response of the dynamical system. The Hankel decomposition can analyze complex time series and reveal the characteristic features of strongly nonlinear dynamics (rare events). For both cases, the linear model fits and captures the main features in the transition coordinate. The simulated trajectory using the fit model matches that of the original system, indicating the well conditioning. The variance of the distributions at the peaks indicates the small errors in the estimation of the eigenvectors. The dynamics of the linear model can predict the spatial-temporal evolution after training the model. The model use the forcing term as an input to run the on-line model and provide an accurate reconstruction of the new attractor corresponding to the test data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[101,686,897,847]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 2. Experimental setup. Reproduced with permission from Cal et al., J. Renewable Sustainable Energy 2(1), 013106 (2010). © Copyright 2010 AlP Publishing. \"]","image_footnote":"[]","img_path":"images/0842/b3efbe7f523f21a4f53ae5541a8bd9f6191fab386c914813cd303bcb21163797.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-3 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[156,135,839,249]","code_body":null,"code_caption":null,"image_caption":"[\"(a) $U / U_{\\\\infty}$ \"]","image_footnote":"[]","img_path":"images/0309/60dfa508377bfe7b63cf78ce1e9fb9d68c3f7df2c088e3ac4c4fc1723118e4a3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[156,286,839,400]","code_body":null,"code_caption":null,"image_caption":"[\"(b) $L_{in} / \\\\lambda$ \",\"FIG. 3. Flow characteristics: (a) normalized mean velocity $(U / U_{\\\\infty})$ , (b) the ratio between the integral length scale $(L_{in})$ and Taylor microscale $(\\\\lambda)$ . The black circle indicates the rotor area. \"]","image_footnote":"[]","img_path":"images/0167/3e6c65b99cdb10c3e663dd96fc132ceeaa75b87b3b768f97b227e71006e163d9.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,451,486,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The statistics of the forcing term $\\nu_{R}$ are a non-Gaussian distribution with long tails as shown in Fig. 5. The most active place regarding the forcing term is noticed at the hub height. In contrast, the far-wake region shows a small departure from Gaussianity. Thus, the $\\nu_{R}$ carries the signature of high-frequency bursts and it is important to find the timing of this forcing to characterize the switching dynamics. Characterizing the times of the nonlinear force is required to uniquely determine the future system states and isolate the impact of the external forces with respect to ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,451,913,555]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"a background flow. Linear system identification is applied in the literature in many applications such as in climate time series analysis.[26,27] The instability and intermittent phenomena generate a variable dynamic loading and fatigue as well as have a major impact on the stability of the grid. In physical space, the intermittent events correspond to the rotor swept region that introduces most perturbations to the energy cascade. The transition of these events through the velocity signal and the advection on the nonlinear force downstream the rotor are still unknown. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[156,592,839,708]","code_body":null,"code_caption":null,"image_caption":"[\"(a) HH \"]","image_footnote":"[]","img_path":"images/0676/45306d367bd37b58c09afefd9b798945508be94b911eaef7e909c9bc270f004e.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[156,728,839,845]","code_body":null,"code_caption":null,"image_caption":"[\"(b) TT \",\"FIG. 4. The eigentime-delay series (gray) with the linear model of the flow at the hub height (HH) and top tip (TT) locations of $z = 0$ . \"]","image_footnote":"[]","img_path":"images/0004/3be6a6f167406cf9e2605e46ebfc301d429aca33298e269d8a500d1001e94f00.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[75,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-4 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[124,119,501,353]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0062/8fd297df03a7755c588bcf264aeba9bb74bf4ba6c5c5a4776f24b0e8765964fb.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[504,119,870,352]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 5. Probability density function (PDF) of the rare forcing events at the bottom tip (BT), hub height (HH), and top tip (TT) of $z / D = 0$ location. \"]","image_footnote":"[]","img_path":"images/0919/db445da74ce6b1f9afd77ad5a3307bc7e16d461b1020f3b167c3267d1b53bd0f.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,407,486,841]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 6 presents the principal components of the SVD for the hub height location including the linear term, $\\nu_{1}$ , and the nonlinear forcing term, $\\nu_{R}$ . To uncover the locations at which the nonlinear forcing term is active, the $\\nu_{R}$ is isolated above a certain threshold. The locations that show inactive force are marked with black color. The eigentime-delay vectors gradually develop structures and spectral content. Forcing term $\\nu_{R}$ is the nonlinear geometrical structure of time series data and presents the existence of intermittent patterns in the considered locations. During the intermittent bursts, the nonlinear modes display the activated fine spatial structure and show the departure from Gaussianity. Note that the dynamics of the trajectories are governed by the linear term when the forcing term is small. The hub height location at the rotor center shows relatively large fluctuations in the nonlinear term in comparison with that at $z / D = 4 / 6$ . The center of the rotor presents the nonlinearity as an on-off intermittent force. Switching between chaotic bursts static behavior can describe the nonlinearity of the system. Platt et al.[28] highlighted that on-off chaos can be detected at the suitably chosen coordinates. Using the Hankel matrix analysis provides the opportunity to classify the flow signal and highlights these coordinates that show the alternating in the chaosity. The locations downstream the rotor have unstable invariant manifolds and attractors that produce on-off intermittency. Outside the swept area, the nonlinearity displays less switching with the time and the activity of the force is balanced by inactivity periods, indicating that linearity suppresses the forcing terms and the flow becomes less chaotic. The statistics of the forcing term activity at the hub height show that at the center of the rotor the activity presents about $68\\%$ of the total time duration, whereas outside the swept region the activity presents about $78\\%$ . Although the ratio activity of the forcing term outside the swept area is larger than inside, the strength of the nonlinearity is much small outside the rotor area, indicating that the large forcing term induces the flow to react against the nonlinear forces and makes a balance to null the nonlinearity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,841,486,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 7 presents the principal components of the SVD for the top tip location including the linear and the nonlinear forcing terms. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,407,915,709]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The physical location shows less impact on the flow at the top tip and above, where the inside and outside the swept area show the same trend in the nonlinearity distribution through the forcing term. As pointed in Ali and Cal,[29] the top tip location is less intermittent and independent of the physical location. Here, the same trend is shown regarding location independence. However, the flow at these locations carries a nonlinear force as shown in Fig. 7. The justification for this observation is that the nonlinearity of the forcing term can take different shapes; one of them is the intermittency. Thus, the nonlinearity can be imposed by a different mechanism that is active at these locations, for example, the tip vortices, momentum entrainment, and the interaction between the wake and the flow above. This is the extension for all approaches that are used to detect the intermittency in the energy cascade of turbulence. The statistics of the forcing term activity at the top tip display that at the center of the rotor the activity presents about $75\\%$ of the total time duration, whereas the activity at the outside of the swept region is about $79\\%$ , indicating that the chaos induced by the wind turbines is dependent on the parameter variations and the external disturbances change percentage of nonlinearity to a certain degree. A small variation in the activity is presented in the top tip and above regions. Also, in comparison with the hub height, the activity is substantial at the top tip but the amplitude of the force is low. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,710,915,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 8 presents the principal components of the SVD for the hub height position at two locations downstream the rotor, including $x / D = 1$ and 8. This figure is introduced to check the transition and the activity of the nonlinear forcing term downstream the rotor. The shape of the nonlinear term reveals the signature of the burst events. The on-off forcing is dominant in the near-wake region and distributed at a certain frequency with a high level of nonlinearity. Moreover, the activity of the forcing term is pronounced when the linear term is negative, indicating that the intermittent events are starker at low-speed flow. Also, the trajectories of the nonlinear forcing term reveal that the flow dynamic at the near-wake region follows different trajectories, where they never exactly are repeated. Moving from $1D$ to $8D$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,261,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-5 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[156,119,844,218]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0972/948f8f402dfddf451c177168732f9ec4e5315e41be719039396aa272e115e8b0.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[153,244,841,359]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0129/ab7d8fc09e0b74d65f84a19de0211c1c6f979e35f007f1ba1df017c73f59ef43.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[153,365,841,461]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0390/accd9e00ee3e632b06c811495fac698ffb374fcddb31b31017cc9ec8eaece1a2.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[153,491,841,604]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 6. The eigentime-delay series and forcing term of the velocity signal at the hub height location of $z - y$ plane. \"]","image_footnote":"[]","img_path":"images/0991/14c90b376cb97887e880ed3af36da388b0525002407cff59f1c18702ac3c6fd4.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,644,486,763]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"reduces the frequency of the burst events and also shrinks the amplitude of the nonlinearity. Thereafter, the flow at the far-wake region $x = 8D$ shows a major reduction in the burst event and the nonlinearity is uniformly distributed along with the linear term. The statistics of the forcing term activity reveal that at the near-wake region the activity presents about $75\\%$ of the total time duration, whereas outside the swept region the activity presents about $78\\%$ . It is interesting to observe that the ratio at the far-wake region is the same ratio of the forcing terms outside the swept area at the $z - y$ plane. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,763,486,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The statistics of the principal components describe the velocity fluctuation distribution based on the physical location within the turbine canopy and show the greatest amounts of variability. In general, the near-wake region displays more nonlinear behavior due to the tip vortex shedding associated with that location. The swept area of the rotor is imprinted with different sizes of coherent structures caused by the nacelle, tower, and rotor tips that consequently alter the inertial subrange of the energy cascade via the shedding frequency. Vortex ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,644,913,726]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"shedding changes the flow structure and imposes highly anisotropy near the rotor. The anisotropy is also influenced by the turbulence kinetic energy production and the entrainment from above the canopy, thus increasing the interaction between the scales and introducing the on-off intermittent events. $^{30,31}$ On the other hand, the far-wake region is marked with small amplitude intermittent forces. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,730,883,742]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"V. FORECASTING SPATIAL-TEMPORAL EVOLUTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[506,747,913,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The main goal of approximating the Koopman operator is to delineate all of the behavior of the nonlinear system in the stability region of the dynamical systems and linearize the nonlinear dynamics. The required training and testing sets are reconstructed from the time signal of the measurement points described in Sec. III. The prediction is achieved for thousands of time steps. Each time step presents an average of $0.03\\mathrm{s}$ (1200 time increments), which is approximately the order of the integral length scale. Treating the flow as a linear model with the explicit interpretation of the nonlinearity as an external force ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[156,119,844,218]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0722/f7d78dd4b927b70cbf241d7789bc1177aa7974c894b71454b3c8e58f93c0201f.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[153,244,841,359]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0770/65265d38a0dcf75cac22275884ad91e818db6141f3d9641ef3a75be79a50ca49.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[153,365,841,461]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0150/e95cde713995296ca46a999b3cce13b7767d2241e8910fcbd66375b5e1f57bc9.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[153,491,841,604]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 7. The eigentime-delay series and forcing term of the velocity signal at the top tip location of $z - y$ plane. \"]","image_footnote":"[]","img_path":"images/0622/cfebce74fbe2727d33094dc2a18dcd4d8d426fa0a8835729b3659fe48b713567.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,658,488,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"helps in presenting a promising model for prediction of the underlying nonlinear processes. Figures 9 and 10 show the prediction of the fluctuating velocity signals of 21 wall-normal locations at different places downstream the rotor. The prediction matches the test data in a short time and starts diverging from the testing data relatively short times, meaning the underlying dynamics for detecting the nonlinearities are discovered through the data-driven approach. However, the divergence shown after a short time is due to that the delay-embedding of the measurements are not provided any information about the order of nonlinearity. The mean relative error is defined as $E(t) = ||u_f^{P_r} - u_f^{test}||_2 / ||u_f^{test}||_2$ , where $u_{f}^{P_{r}}$ is the fluctuating velocity that is predicted from the model, and $u_{f}^{test}$ is the actual fluctuating velocity measured via the hot-wire anemometer. The mean relative errors are approximately $15\\%$ , where less accurate prediction is shown with increasing advective timescales, where the growth becomes exponentially unbound. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,658,916,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The proposed tool for the prediction can be part of the wind farm control system to predict the wind and control the turbines such as changing the yaw angle of the wind turbine or the blade pitch to keep optimal operating conditions for all turbines in the array, and that will ensure the increase in the power output. The predicted model is a critical key for model predictive control, where the switching control between a number of actuation (for example, yawed and non-yawed) can be achieved to track a reference operation in an unsteady flow within wind farm.[18] The turbine sensors used in the field such as sensors that measure power or LIDAR signals can be used as an input to achieve the wind farm control.[9] The Koopman operator can be used as a systems model to process noise and measurement noise via two steps: first, the prediction step that utilizes a previously estimated state of the linear model to predict the value of the next state and estimate the state covariance. The second step is the updated step, where the state estimation will be corrected based on the current ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-7 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[156,119,841,215]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0014/959d1689701dbadc3ac5e37313df2d36db309a9771b74b5040d4c4537ffae1c9.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[155,248,839,358]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0276/3e59b3dc66e40bb3513fef0daabdb87b3a2e8ac9cbd51d6f00fae681a09be422.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[155,365,839,461]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0678/e37cfa7ffe06feac94df98ff741403a4c26d2c2ab3222196d9e6ecd831a4c661.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[155,491,839,603]","code_body":null,"code_caption":null,"image_caption":"[\"FIG. 8. The eigentime-delay series and forcing term of the velocity signal at the hub height location of $x - y$ plane. \"]","image_footnote":"[]","img_path":"images/0641/04d30dbd37665105e61a3ed3c385bf0ed1c72dea9536e66a12ecf62780fa1f77.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,658,486,739]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"measurements and the statistical properties of the model. The evolution of the error covariance can be predicted with the full state forward model, where the actual observations will be used as an input into mathematical and computational models to create a unified, complete description. Also, this method can be used to model the dynamic stability of the grid in response to disturbances. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[81,744,210,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"VI. CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,761,486,867]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The chaos of the wake flow behind a wind turbine is presented using the Koopman operator. The goals of the current work are to connect the chaos force, which causes the linear model to diverge, with intermittency, demonstrate, and quantify the activity of the intermittent force with respect to time; and more importantly, evaluate the proficiency of the data-driven model to predict the future state of the system, where the stochastic fluctuating velocity is based on trained data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,658,916,870]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Linear representations show the potential ability to distinguish flow events downstream the rotor. The major variations in the nonlinear forcing term are found at the center of the rotor, where the hub height shows the large transients and intermittent events. Less nonlinearity is shown at the top tip location. Outside the swept area, the locations share the same nonlinearity events. Also, the signature of the nonlinear forces sustains outside the rotor area. The robustness of the nonlinear forcing term is shown outside the swept area and at the far-wake regions. This model physically describes the chaotic transitions between the center of the rotor and the atmospheric stream flow, caused by wake advection and vortex shedding in the spanwise direction. The current approach also successfully predicts the flow field for short term timescales. The mean errors between the predictive and test fluctuating velocities are approximately $15\\%$ . The proposed method needs further investigations to obtain a full description of the nonlinear term. Achieving this goal will help in forecasting the variability of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,681,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[81,137,362,242]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0828/0176721e91c83859325197ba905242b23ccc5d6799faa3871a1773facb91cfa4.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[411,137,665,242]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0693/8e6b6dfe28301995c0e6a876ed3de6ade51ac7163f6b6c266f1d6127de155d8c.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,274,361,396]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0783/79b40fe4a38e1558a62b524ea34019f4a1010b6d7018a8a4ec70a69f345f90f7.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[411,274,665,396]","code_body":null,"code_caption":null,"image_caption":"[\"(d) \"]","image_footnote":"[]","img_path":"images/0521/8f1b644e83507a171420c263786180c58458051e77a5b1f0cc6ab6f11c390625.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,447,361,551]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0811/5309352b4499513eaf7f164836937f6cbfa8fedd99be7e26e28d1af1a8c9de1f.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[411,447,665,551]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0714/0f9050fb6ec36be0fc6dfea411b7d9f8bd2911f2b987753b835f25eb04ae880c.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,584,361,705]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0326/a54d39ddfede431b0284d6035e0625f97f94108729ec73385a52414bd904f719.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[411,584,665,705]","code_body":null,"code_caption":null,"image_caption":"[\"(d) \",\"FIG. 9. Predication fluctuating velocities at $x / D = 1$ at (a) 75, (b) 150, (c) 450, and (d) 800 time units. The blue and orange lines present the measured and predicted velocities, respectively. \",\"FIG. 10. Predication fluctuating velocities at $x / D = 6$ . \"]","image_footnote":"[]","img_path":"images/0675/605aa293ca5b9687204853b9188696b9090ef3d0c1411b4513fff7d4d285615c.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[80,724,486,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the wind to protect the system in high winds, capture more energy in low winds, and reduce the uncertainty of the output by supporting real-time operations. Forecasting the variability of the wind will allow anticipating wind generation levels to adjust the power system accordingly. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,789,486,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The current model is a part of system identification and uses the measurements from the wind plant to estimate the relevant properties of the system. The simple structure and fast computation of the data-driven model are well-suited for real-time control. The measurements of the real-world wind plant can be fed into the model structure to identify the model parameters and then adjust the internal model ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[506,724,915,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"based on the predicted future state and test a few sets such as yawed angles to reach the optimized control points. Based on the evaluation of predicted turbine power outputs, the updated yaw settings are stored as a baseline if improvement is shown. Another advantage of the current model is that it can display the effect of inflow conditions and tested parameters on the relevant structural loads on the turbine by analyzing the nonlinear forces. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,824,661,836]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DATA AVAILABILITY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,841,915,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The data that support the findings of this study are available from the corresponding author upon reasonable request. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,679,66]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[856,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-9 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[83,119,186,133]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[83,137,485,688]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"<sup>1</sup>J. 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Calaf, \\\"Compounded energy gains in collocated wind plants: Energy balance quantification and wake morphology description,\\\" Renewable Energy 150, 868-877 (2020). \",\"$^{6}$ R. Calif and F. G. Schmitt, \\\"Multiscaling and joint multiscaling description of the atmospheric wind speed and the aggregate power output from a wind farm,\\\" Nonlinear Processes Geophys. 21(2), 379-392 (2014). \",\"$^{7}$ N. Ali, A. S. Aseyev, and R. B. Cal, \\\"Structure functions, scaling exponents and intermittency in the wake of a wind turbine array,\\\" J. Renewable Sustainable Energy 8(1), 013304 (2016). \",\"$^{8}$ H. Kadum, S. Rockel, M. Hölling, J. Peinke, and R. B. Cal, \\\"Wind turbine wake intermittency dependence on turbulence intensity and pitch motion,\\\" J. Renewable Sustainable Energy 11(5), 053302 (2019). \",\"S. Boersma, B. M. Doekemeijer, P. M. O. Gebraad, P. A. Fleming, J. Annoni, A. K. Scholbrock, J. A. Frederik, and J.-W. van Wingerden, \\\"A tutorial on control-oriented modeling and control of wind farms,\\\" in 2017 American Control Conference (ACC) (IEEE, 2017), pp. 1-18. \",\"10S. L. Brunton, B. W. Brunton, J. L. Proctor, E. Kaiser, and J. N. Kutz, \\\"Chaos as an intermittently forced linear system,\\\" Nat. Commun. 8(1), 19 (2017). \",\"$\\\\mathfrak{H}_{\\\\mathrm{I}}$ Mezić, \\\"Spectral properties of dynamical systems, model reduction and decompositions,\\\" Nonlinear Dyn. 41(1-3), 309-325 (2005). \",\"$^{12}$ D. Giannakis and A. J. Majda, \\\"Nonlinear Laplacian spectral analysis for time series with intermittency and low-frequency variability,\\\" Proc. Nat. Acad. Sci. 109(7), 2222-2227 (2012). \",\"13D. Giannakis, \\\"Data-driven spectral decomposition and forecasting of ergodic dynamical systems,\\\" Appl. Comput. Harmonic Anal. 47, 338 (2019). \",\"$^{14}$ H. Arbabi and I. Mezic, \\\"Ergodic theory, dynamic mode decomposition, and computation of spectral properties of the Koopman operator,\\\" SIAM J. Appl. Dyn. Syst. 16(4), 2096-2126 (2017). \",\"15 M. Korda and I. Mezić, \\\"Linear predictors for nonlinear dynamical systems: Koopman operator meets model predictive control,\\\" Automatica 93, 149-160 (2018). \",\"16D. Giannakis, A. Kolchinskaya, D. Krasnov, and J. Schumacher, \\\"Koopman analysis of the long-term evolution in a turbulent convection cell,\\\" J. Fluid Mech. 847, 735-767 (2018). \",\"17M. A. Khodkar, P. Hassanzadeh, and A. Antoulas, \\\"A Koopman-based framework for forecasting the spatiotemporal evolution of chaotic dynamics with nonlinearities modeled as exogenous forcings,\\\" arXiv:1909.00076 (2019). \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[509,119,913,688]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"18P. M. O. Gebraad, F. W. Teeuwisse, J.-W. van Wingerden, P. A. Fleming, S. D. Ruben, J. R. Marden, and L. Y. Pao, \\\"A data-driven model for wind plant power optimization by yaw control,\\\" in 2014 American Control Conference (IEEE, 2014), pp. 3128-3134. \",\"19G. V. Iungo, F. Viola, U. Ciri, M. A. Rotea, and S. Leonardi, \\\"Data-driven RANS for simulations of large wind farms,\\\" J. Phys. 625, 012025 (2015). \",\"20G. V. Iungo, C. Santoni-Ortiz, M. Abkar, F. Porté-Agel, M. A. Rotea, and S. 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Pappa, \\\"An eigensystem realization algorithm for modal parameter identification and model reduction,\\\" J. Guid., Control, Dyn. 8(5), 620-627 (1985). \",\"27D. S. Broomhead, R. Jones, M. Fleischmann, D. J. Tildesley, and R. C. Ball, \\\"Time-series analysis,\\\" Proc. R. Soc. London, Ser. A 423(1864), 103-121 (1989). \",\"28N. Platt, E. Spiegel, and C. Tresser, \\\"On-off intermittency: A mechanism for bursting,\\\" Phys. Rev. Lett. 70(3), 279 (1993). \",\"29N. Ali and R. B. Cal, \\\"Scale evolution, intermittency and fluctuation relations in the near-wake of a wind turbine array,\\\" Chaos, Solitons Fractals 119, 215-229 (2019). \",\"30N. Ali, A. S. Aseyev, M. S. Melius, M. Tutkun, and R. B. Cal, \\\"Evaluation of higher order moments and isotropy in the wake of a wind turbine array,\\\" Whither Turbulence and Big Data in the 21st Century? (Springer, 2017), pp. 273-292. \",\"31N. Ali, N. Hamilton, G. Cortina, M. Calaf, and R. B. Cal, \\\"Anisotropy stress invariants of thermally stratified wind turbine array boundary layers using large eddy simulations,\\\" J. Renewable Sustainable Energy 10(1), 013301 (2018). \",\"$^{32}$ N. Ali, H. F. Kadum, and R. B. Cal, “Focused-based multifractal analysis of the wake in a wind turbine array utilizing proper orthogonal decomposition,” J. Renewable Sustainable Energy 8(6), 063306 (2016). \",\"33S. Rockel, J. Peinke, M. Holling, and R. B. Cal, \\\"Wake to wake interaction of floating wind turbine models in free pitch motion: An eddy viscosity and mixing length approach,\\\" Renewable Energy 85, 666-676 (2016). \",\"34S. Rockel, E. Camp, J. Schmidt, J. Peinke, R. B. Cal, and M. Hølling, \\\"Experimental study on influence of pitch motion on the wake of a floating wind turbine model,\\\" Energies 7(4), 1954-1985 (2014). \",\"35S. Rockel, J. Peinke, M. Holling, and R. B. Cal, \\\"Dynamic wake development of a floating wind turbine in free pitch motion subjected to turbulent inflow generated with an active grid,\\\" Renewable Energy 112, 1-16 (2017). \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[73,45,305,77]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Renewable and Sustainable Energy ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[622,53,679,66]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[723,53,864,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scitation.org/journal/rse ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,913,429,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,929,263,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under license by AIP Publishing ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[851,913,921,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12,033304-10 ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[191,69,947,127]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data-driven modeling of the wake behind a wind turbine array EP \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[189,149,906,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cite as: J. Renewable Sustainable Energy 12, 033304 (2020); https://doi.org/10.1063/5.0004393 \\nSubmitted: 12 February 2020. Accepted: 31 May 2020. Published Online: 26 June 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,192,483,211]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Naseem Ali $①$ , and Raúl Bayoán Cal $①$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,223,307,236]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COLLECTIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[192,260,511,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"EP This paper was selected as an Editor's Pick \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[741,297,784,326]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"View Online \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0068/cc5cc0cbfe5f8308b594d2e6decde684398a70d982eb86ee224ccb5af7dd6ef7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[830,297,875,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Export Citation \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0900/896809abcc8eb10690a999b651194a3d79a16a3e72de1db8e1a3ee3f510b3af9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[919,295,965,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"CrossMark \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0615/fd7138aefd1ec4074336d453fb83e9211a7fc09ef488095a08867083ab35b938.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[191,375,529,390]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLES YOU MAY BE INTERESTED IN \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[189,407,815,441]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Real-time modeling technique optimizes power output from wind turbines \\nScilight 2020, 26111 (2020); https://doi.org/10.1063/10.0001528 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,456,447,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Multirotor wind turbine wakes \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,473,767,490]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Physics of Fluids 31, 085106 (2019); https://doi.org/10.1063/1.5097285 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[246,788,310,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0880/a9a9d57bad68226774eaf0656f539d003d2c91922f18bcb95d998ae12bbf1e00.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[352,786,691,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"NEW: TOPIC ALERTS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[352,817,921,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Explore the latest discoveries in your field of research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[808,855,944,871]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SIGN UP TODAY! \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[37,76,130,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[49,846,120,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"aside_text\"\n },\n {\n \"bbox\": \"[197,915,746,929]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); https://doi.org/10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[908,917,977,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[199,936,312,950]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2020 Author(s). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[81,117,883,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data-driven modeling of the wake behind a wind turbine array EP \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,202,683,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cite as: J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \\nSubmitted: 12 February 2020 · Accepted: 31 May 2020 \\nPublished Online: 26 June 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[732,205,774,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0544/d837ad12c299687529c2117219593ece18aa43cab583b8171be0e68b0f1094de.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[797,206,851,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0264/d989bd1d48f6c24935b7c9c178ce261f83ec9a29b74c69ccef7fb56bc8e2fae8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[872,206,911,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0698/82907044da6d750aafa1e17cf2f0737c406158cf34de1072578b0d715fe44154.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,263,372,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Naseem Ali $①$ and Raúl Bayoán Cala) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,291,189,304]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AFFILIATIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,310,776,323]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Department of Mechanical and Materials Engineering, Portland State University, Portland, Oregon 97201, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,334,544,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{a)}$ Author to whom correspondence should be addressed: rcal@pdx.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,370,168,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ABSTRACT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,389,916,482]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The wake flow in a wind turbine array boundary layer is described using the Koopman operator. Dynamics of the flow are decomposed into the linear and forcing terms, and the low-energy delay coordinates are revealed. The rare events show the non-Gaussian long tails that capture the switching and bursting phenomena. The near-wake region shows the incoherent phase space region, where the dynamics are strongly nonlinear. The far-wake region is marked with the small non-Gaussian forcing term, and the dynamics are largely governed by linear dynamics. The data-driven predictive model is built based on the Hankel-based dynamic mode decomposition and treats the nonlinear state of forcing term as external actuation. The model forecasts the evolution of the flow field for short-term timescales. The mean relative errors between the predictive and test fluctuating velocities are approximately $15\\\\%$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,487,537,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing. https://doi.org/10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,538,217,552]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,557,486,660]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Modeling the turbine response to non-Gaussian conditions can help explain the signature in the aerodynamic forces, fatigue loads, and development of alternative control schemes. $^{1,2,32}$ The variations in the mean statistics of the wind turbine wake flow highlight the nature of the flow response to the external forcing of the wind turbine. $^{2-5,33-35}$ Because turbulence exists on different temporal and spatial scales in a wind farm, the behavior of the non-Gaussian conditions is dependent on the physical location downstream the rotor. $^{2,6}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,660,486,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Systems like wind plants have a large number of degrees of freedom that cause a considerable amount of uncertainty in parameters when modeling. For wind farm controller analysis, high fidelity models are required for exploring the optimal possibilities of wind farm control. Due to the computational cost of these models, they are not convenient for pursuing a dynamical system and control model. Therefore, new generations of models are required to solve this deficiency. Reduced-order models can provide coherent features of wake dynamics and solve part of the computational complexity although these models are only suitable for specific conditions and are not proven for real cases. Linking between reduced-order model and parameter-varying control can provide a new generation of the optimized wind farm control. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,828,486,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Developing a flow model from statistics based on the ensemble of observations, which can represent a solution to the dynamical system itself, is of central importance. The data-driven model includes \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,538,916,671]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"reducing the degrees of freedom and presenting a dynamical model that links the evolution of the most dominant features and the trajectories in the high-fidelity phase space. The wake of the turbine is a nonlinear system with intermittent energy that transfers between flow scales in the energy cascade. $^{7,8}$ Therefore, predicting and identifying the coordinate transformations that highlight the time response to the strongly nonlinear forces are potentially important for the wind farm design. Time evolution of interacting quantities in engineering applications such as wind energy can be described using a dynamical system approach. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,671,916,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data-driven techniques have recently received more attention as alternative approaches for directing wind farm analysis or control. These approaches rely on specific operating conditions; hence, they provide linear models for a specific operating point. Because the operation of the wind turbines is time dependent, data-driven approaches can describe the wake in more detail regarding the flow conditions, such as thermal stability and turbulent intensity, as well as provide systems the ability to automatically learn and improve performance and stability. Following the Takens embedding theorem, which translates high-dimensional datasets into a relatively low-dimensional space, applied to a sequence of observations of the state, data-driven dynamical systems can detect the full dynamics by reconstructing a set of states and preserve the structural aspect of the states. The intermittent forces are strange phase spaces of a dynamical system characterized by chaotic trajectories, and are responsible for divergent behavior \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,866,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,264,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[78,119,485,212]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"with time and cause uncertainty to the prediction. Consequently, isolating the deterministic structure from the randomness of the chaotic dynamics is potentially useful for control strategies. Koopman operator theory is an efficient approach to decompose the chaotic system into the linear evolution and nonlinear forcing, where the time history of the measurements can estimate the full-state of the system and provide a foundation for its linear dynamics. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[83,212,486,538]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In nonlinear dynamics, the dynamical system can be represented in the linear representations through the Koopman analysis. A Koopman operator has the ability to analyze and tackle the nonlinear system in an infinite-dimensional linear approach. In data-driven models, for example, Giannakis and Majda and Giannakis projected the delay-embedded data onto the basis function of Laplace-Beltrami and Koopman operator respectively, to present a model reduction with the aim of forecasting the time series for ergodic dynamical systems. Arbabi and Mezic linked the Hankel based dynamic mode decomposition (DMD) to the Koopman operator, demonstrating that applying DMD to Hankel observation matrices yields the true Koopman eigenvalues and eigenfunctions. Korda and Mezic identified linear predictors for nonlinear controlled dynamical systems using the Koopman operator framework. The nonlinear dynamics are projected to a higher dimensional space that displays the evolution is approximately linear. Giannakis et al. employed a Koopman eigenfunction analysis to study the long-time evolution of the three-dimensional flow. Their findings showed that the behavior of the large-scale circulation is recovered from the eigenfunctions of a data-driven Koopman operator. Brunton et al. provided a Hankel alternative view of Koopman to understand the disorder in chaos quantitatively by treating examples such as measles outbreaks and magnetic fields. Recently, Khodkar et al. introduced the Koopman-based framework for forecasting the spatiotemporal evolution of high-dimensional chaotic dynamics and turbulence. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,540,486,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data-driven approaches have been used to study wind turbine wakes. For example, Gebraad et al. $^{18}$ presented a novel data-driven model to optimize the yaw settings of wind turbines in a wind plant for improved energy production of the wind plant. Iungo et al. $^{19}$ proposed a data-driven RANS approach to optimize power plant control and prevent detrimental wake interactions. Iungo et al. $^{20}$ proposed a new data-driven reduced order model for prediction of wind turbine wakes. The model captured the main physical processes and dynamics of wind turbine wakes. Park et al. $^{21}$ used a data-driven optimization method to find the optimum control actions. Gocmen and Giebel $^{22}$ presented a data-driven wake model for short-term power estimation. Ti and Yang $^{23}$ used the machine learning and computational fluid dynamics simulation to develop new wake velocity and turbulence models to improve the turbine wake predictions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,723,486,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data-driven analysis based on the Koopman operator is used here to build a linear model in the leading delay coordinates to forecast the future state of stochastic fluctuating velocity. The model will be built after isolating the linear modes from a low energy delay coordinate that triggers intermittent bursting and switching events. The nonlinear term is used as an input parameter to train the model. The aim is also to connect the nonlinear mode distribution, which causes the linear model to diverge, with intermittency, and quantify the activity of the intermittent force with respect to time. The manuscript is organized as follows: Sec. II outlines the Koopman theory; Sec. III presents in detail experimental setup; Sec. IV provides a discussion of the finding and the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,119,913,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"relevance in the field; Sec. V presents the forecasting for the spatial and temporal evolution. Conclusions are presented in Sec. VI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,153,594,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"II. THEORY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,170,913,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The perspective of the Koopman operator relies on mapping the measurement dataset to different coordinates that make the dynamics appear linear. Here, the Koopman operator is built based on the Hankel matrix, $H$ , as<sup>10</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[563,231,911,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} H = \\\\left[ \\\\begin{array}{c c c c} u (t _ {1}) & u (t _ {2}) & \\\\dots & u (t _ {p}) \\\\\\\\ u (t _ {2}) & u (t _ {3}) & \\\\dots & u (t _ {p + 1}) \\\\\\\\ \\\\vdots & \\\\vdots & \\\\ddots & \\\\vdots \\\\\\\\ u (t _ {q}) & u (t _ {q + 1}) & \\\\dots & u (t _ {m}) \\\\end{array} \\\\right] \\\\\\\\ = \\\\left[ \\\\begin{array}{c c c c} u (t _ {1}) & \\\\mathcal {K} u (t _ {1}) & \\\\dots & \\\\mathcal {K} ^ {p - 1} u (t _ {1}) \\\\\\\\ \\\\mathcal {K} u (t _ {1}) & \\\\mathcal {K} ^ {2} u (t _ {1}) & \\\\dots & \\\\mathcal {K} ^ {p} u (t _ {1}) \\\\\\\\ \\\\vdots & \\\\vdots & \\\\ddots & \\\\vdots \\\\\\\\ \\\\mathcal {K} ^ {q - 1} u (t _ {1}) & \\\\mathcal {K} ^ {q} u (t _ {1}) & \\\\dots & \\\\mathcal {K} ^ {m - 1} u (t _ {1}) \\\\end{array} \\\\right], \\\\tag {1} \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,377,913,457]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\mathcal{K}$ is the Koopman operator, $u$ is a vector-valued observation of fluctuating velocity, and $t$ is the time. Singular value decomposition (SVD) of the Hankel matrix can estimate the embedding dimension for time-delay coordinates that provide the conditions under which a chaotic dynamical system is reconstructed from a set of observations of the state of a dynamical system as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[671,464,913,480]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nH = \\\\Psi \\\\Sigma V ^ {T}, \\\\tag {2}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,485,913,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where the columns of $\\\\Psi$ and $V$ present the right- and left-singular vectors, respectively; they are a set of orthonormal eigenvectors. The chaotic dynamics is decomposed using the Hankel alternative view of Koopman into a linear model and the forcing term. The eigentime-delay vector, $V = [v_{1}, v_{2}, \\\\ldots, v_{R - 1}]^{T}$ , is used to define the forced term $\\\\nu_{R}$ from the nonlinear dynamics. Following the Hankel alternative view of Koopman approach introduced in the work of Brunton et al. $^{10}$ and Khodkar et al. $^{17}$ adding a forcing term to the linear model is considered to approximate the nonlinear dynamics more accurately. A future vector-valued observable that is not a part of the training data can be predicted as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[656,639,913,653]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nu ^ {t + 1} = A u ^ {t} + B F, \\\\tag {3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,660,913,754]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $F$ is the form of external forcing, where it takes the quadratic form based on the Reynolds stress terms. The $B$ is the control matrix related to the forcing term. The $A$ and $B$ are the input parameters to create state-space model and simulate the time response of dynamic system, respectively. The Hankel based dynamic mode decomposition with control (H-DMDc) is used to estimate the $A$ and $B$ matrices using the minimization approach introduced in the work of Proctor et al.,[24] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[642,761,913,777]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nA = \\\\Psi^ {T} \\\\Pi V \\\\Sigma^ {- 1} \\\\Psi_ {1} ^ {T} \\\\Psi , \\\\tag {4}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[650,779,913,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nB = \\\\Psi^ {T} \\\\Pi V \\\\Sigma^ {- 1} \\\\Psi_ {2} ^ {T}, \\\\tag {5}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,802,913,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where these matrices are calculated in a reduced-dimension subspace. Here, $\\\\Psi_{1}$ and $\\\\Psi_{2}$ are constructed from the first $qm$ and the remaining rows of $\\\\Psi$ . Figure 1 summarizes the main steps of the current approach. The training data that are obtained from any velocity or power sensor can be fed into DMDc algorithm to estimate the model \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[75,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[83,119,485,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 1. Schematic of data-driven method. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0081/002681ee3d33dfe9dff9bfbcef12c533b1bbf152348bf3d2cb041309c5b9072a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,334,486,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"operators. The forecasting step starts after as shown in Eq. (3). The advantage of forecasting step can be fed into a controller to change the turbine condition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,379,277,391]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"III. EXPERIMENTAL SETUP \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,396,488,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An experiment with an array of horizontal axis wind turbines was conducted at the closed-loop Corrsin wind tunnel at Johns Hopkins University. The entrance of the tunnel was furnished with an active grid to generate turbulence. The inlet mean velocity shear profile was generated using nine strakes. A 24-grit aluminum oxide sand paper was provided along the test section in the ground to roughen the boundary shape, see Fig. 2. A three-bladed rotor of $12\\\\mathrm{cm}$ diameter, $D$ , was used as a wind turbine model. Nine wind turbines models were distributed as a $3\\\\times 3$ array with space of 7D in the streamwise and 3D in the spanwise directions. The measurements considered here were taken behind the center of the third row of the wind farm. The data were gathered at a frequency of $40\\\\mathrm{kHz}$ to sample $4\\\\times 10^{6}$ data points. The measurements were conducted at the streamwise-wall-normal plane $(x - y)$ and the spanwise-wall-normal plane $(z - y)$ . For the $x - y$ plane, the measurements were collected at nine locations in the streamwise direction starting from $x = 0.5D$ to $x = 8D$ . For the $z - y$ plane, the measurements were taken at nine locations in the spanwise direction starting from $z = -4D / 6$ to $z = 4D / 6$ with an increment of $D / 6$ . For each plane, the measurements are taken for 21 locations in the wall-normal direction starting at $0.5\\\\mathrm{cm}$ above the ground and move vertically with an increment of $1\\\\mathrm{cm}$ . More details about the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,119,916,145]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"experimental setup and measurements can be found in the work of Cal et al.[25] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,153,604,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IV. RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,170,916,394]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Statistical quantities are shown here to provide an important distinction between the flow regions downstream the rotor. Figure 3 presents the normalized streamwise mean velocity $(U / U_{\\\\infty})$ , and the ratio between the integral length scale $(L_{in})$ , and Taylor microscale $(\\\\lambda)$ . The integral length scale is calculated based on auto-correlation between two different times. The impact of the rotor is substantial on the near-wake region, specifically behind the nacelle and tower, where the minimum values of the streamwise mean velocity, integral length scales, and Taylor microscale are observed. These parameters monotonically increase toward the outside of the rotor. The same trend is shown in the comparison between the near- and far-wake regions. The tower adds more perturbations to the flow and translates to the wake region. In the spanwise direction, the wake expansion is shown below the top tip (TT), where velocities are low. The reduced size of the $L_{in}$ is due to the amplification of enstrophy and flow separation. The flow outside the swept area is marked with relatively constant $L_{in}$ and $\\\\lambda$ , specifically above the top tip. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,394,916,671]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 4 presents the principal components of the SVD with the linear model that is built based on the regression model for the hub height (HH) and top tip locations at the center of the rotor. The figure shows the main principle of the Koopman analysis using a SVD in a finite-dimensional nonlinear system by testing the quality of the reconstruction of the eigentime series. These locations are shown for generality as they present the most sensitive locations that carry chaotic changes in the wake. The regression model is presented for the linear variables in right-singular vectors $V$ . Then, the regression coefficients for linear and forcing terms are used to train and simulate the time response of the dynamical system. The Hankel decomposition can analyze complex time series and reveal the characteristic features of strongly nonlinear dynamics (rare events). For both cases, the linear model fits and captures the main features in the transition coordinate. The simulated trajectory using the fit model matches that of the original system, indicating the well conditioning. The variance of the distributions at the peaks indicates the small errors in the estimation of the eigenvectors. The dynamics of the linear model can predict the spatial-temporal evolution after training the model. The model use the forcing term as an input to run the on-line model and provide an accurate reconstruction of the new attractor corresponding to the test data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[101,686,897,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 2. Experimental setup. Reproduced with permission from Cal et al., J. Renewable Sustainable Energy 2(1), 013106 (2010). © Copyright 2010 AlP Publishing. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0842/b3efbe7f523f21a4f53ae5541a8bd9f6191fab386c914813cd303bcb21163797.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[156,135,839,249]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) $U / U_{\\\\\\\\infty}$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0309/60dfa508377bfe7b63cf78ce1e9fb9d68c3f7df2c088e3ac4c4fc1723118e4a3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[156,286,839,400]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) $L_{in} / \\\\\\\\lambda$ \\\",\\\"FIG. 3. Flow characteristics: (a) normalized mean velocity $(U / U_{\\\\\\\\infty})$ , (b) the ratio between the integral length scale $(L_{in})$ and Taylor microscale $(\\\\\\\\lambda)$ . The black circle indicates the rotor area. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0167/3e6c65b99cdb10c3e663dd96fc132ceeaa75b87b3b768f97b227e71006e163d9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,451,486,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The statistics of the forcing term $\\\\nu_{R}$ are a non-Gaussian distribution with long tails as shown in Fig. 5. The most active place regarding the forcing term is noticed at the hub height. In contrast, the far-wake region shows a small departure from Gaussianity. Thus, the $\\\\nu_{R}$ carries the signature of high-frequency bursts and it is important to find the timing of this forcing to characterize the switching dynamics. Characterizing the times of the nonlinear force is required to uniquely determine the future system states and isolate the impact of the external forces with respect to \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,451,913,555]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"a background flow. Linear system identification is applied in the literature in many applications such as in climate time series analysis.[26,27] The instability and intermittent phenomena generate a variable dynamic loading and fatigue as well as have a major impact on the stability of the grid. In physical space, the intermittent events correspond to the rotor swept region that introduces most perturbations to the energy cascade. The transition of these events through the velocity signal and the advection on the nonlinear force downstream the rotor are still unknown. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[156,592,839,708]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) HH \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0676/45306d367bd37b58c09afefd9b798945508be94b911eaef7e909c9bc270f004e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[156,728,839,845]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) TT \\\",\\\"FIG. 4. The eigentime-delay series (gray) with the linear model of the flow at the hub height (HH) and top tip (TT) locations of $z = 0$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0004/3be6a6f167406cf9e2605e46ebfc301d429aca33298e269d8a500d1001e94f00.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[75,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[124,119,501,353]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0062/8fd297df03a7755c588bcf264aeba9bb74bf4ba6c5c5a4776f24b0e8765964fb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[504,119,870,352]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 5. Probability density function (PDF) of the rare forcing events at the bottom tip (BT), hub height (HH), and top tip (TT) of $z / D = 0$ location. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0919/db445da74ce6b1f9afd77ad5a3307bc7e16d461b1020f3b167c3267d1b53bd0f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,407,486,841]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 6 presents the principal components of the SVD for the hub height location including the linear term, $\\\\nu_{1}$ , and the nonlinear forcing term, $\\\\nu_{R}$ . To uncover the locations at which the nonlinear forcing term is active, the $\\\\nu_{R}$ is isolated above a certain threshold. The locations that show inactive force are marked with black color. The eigentime-delay vectors gradually develop structures and spectral content. Forcing term $\\\\nu_{R}$ is the nonlinear geometrical structure of time series data and presents the existence of intermittent patterns in the considered locations. During the intermittent bursts, the nonlinear modes display the activated fine spatial structure and show the departure from Gaussianity. Note that the dynamics of the trajectories are governed by the linear term when the forcing term is small. The hub height location at the rotor center shows relatively large fluctuations in the nonlinear term in comparison with that at $z / D = 4 / 6$ . The center of the rotor presents the nonlinearity as an on-off intermittent force. Switching between chaotic bursts static behavior can describe the nonlinearity of the system. Platt et al.[28] highlighted that on-off chaos can be detected at the suitably chosen coordinates. Using the Hankel matrix analysis provides the opportunity to classify the flow signal and highlights these coordinates that show the alternating in the chaosity. The locations downstream the rotor have unstable invariant manifolds and attractors that produce on-off intermittency. Outside the swept area, the nonlinearity displays less switching with the time and the activity of the force is balanced by inactivity periods, indicating that linearity suppresses the forcing terms and the flow becomes less chaotic. The statistics of the forcing term activity at the hub height show that at the center of the rotor the activity presents about $68\\\\%$ of the total time duration, whereas outside the swept region the activity presents about $78\\\\%$ . Although the ratio activity of the forcing term outside the swept area is larger than inside, the strength of the nonlinearity is much small outside the rotor area, indicating that the large forcing term induces the flow to react against the nonlinear forces and makes a balance to null the nonlinearity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,841,486,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 7 presents the principal components of the SVD for the top tip location including the linear and the nonlinear forcing terms. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,407,915,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The physical location shows less impact on the flow at the top tip and above, where the inside and outside the swept area show the same trend in the nonlinearity distribution through the forcing term. As pointed in Ali and Cal,[29] the top tip location is less intermittent and independent of the physical location. Here, the same trend is shown regarding location independence. However, the flow at these locations carries a nonlinear force as shown in Fig. 7. The justification for this observation is that the nonlinearity of the forcing term can take different shapes; one of them is the intermittency. Thus, the nonlinearity can be imposed by a different mechanism that is active at these locations, for example, the tip vortices, momentum entrainment, and the interaction between the wake and the flow above. This is the extension for all approaches that are used to detect the intermittency in the energy cascade of turbulence. The statistics of the forcing term activity at the top tip display that at the center of the rotor the activity presents about $75\\\\%$ of the total time duration, whereas the activity at the outside of the swept region is about $79\\\\%$ , indicating that the chaos induced by the wind turbines is dependent on the parameter variations and the external disturbances change percentage of nonlinearity to a certain degree. A small variation in the activity is presented in the top tip and above regions. Also, in comparison with the hub height, the activity is substantial at the top tip but the amplitude of the force is low. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,710,915,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 8 presents the principal components of the SVD for the hub height position at two locations downstream the rotor, including $x / D = 1$ and 8. This figure is introduced to check the transition and the activity of the nonlinear forcing term downstream the rotor. The shape of the nonlinear term reveals the signature of the burst events. The on-off forcing is dominant in the near-wake region and distributed at a certain frequency with a high level of nonlinearity. Moreover, the activity of the forcing term is pronounced when the linear term is negative, indicating that the intermittent events are starker at low-speed flow. Also, the trajectories of the nonlinear forcing term reveal that the flow dynamic at the near-wake region follows different trajectories, where they never exactly are repeated. Moving from $1D$ to $8D$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,261,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[156,119,844,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0972/948f8f402dfddf451c177168732f9ec4e5315e41be719039396aa272e115e8b0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[153,244,841,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0129/ab7d8fc09e0b74d65f84a19de0211c1c6f979e35f007f1ba1df017c73f59ef43.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[153,365,841,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0390/accd9e00ee3e632b06c811495fac698ffb374fcddb31b31017cc9ec8eaece1a2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[153,491,841,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 6. The eigentime-delay series and forcing term of the velocity signal at the hub height location of $z - y$ plane. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0991/14c90b376cb97887e880ed3af36da388b0525002407cff59f1c18702ac3c6fd4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,644,486,763]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"reduces the frequency of the burst events and also shrinks the amplitude of the nonlinearity. Thereafter, the flow at the far-wake region $x = 8D$ shows a major reduction in the burst event and the nonlinearity is uniformly distributed along with the linear term. The statistics of the forcing term activity reveal that at the near-wake region the activity presents about $75\\\\%$ of the total time duration, whereas outside the swept region the activity presents about $78\\\\%$ . It is interesting to observe that the ratio at the far-wake region is the same ratio of the forcing terms outside the swept area at the $z - y$ plane. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,763,486,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The statistics of the principal components describe the velocity fluctuation distribution based on the physical location within the turbine canopy and show the greatest amounts of variability. In general, the near-wake region displays more nonlinear behavior due to the tip vortex shedding associated with that location. The swept area of the rotor is imprinted with different sizes of coherent structures caused by the nacelle, tower, and rotor tips that consequently alter the inertial subrange of the energy cascade via the shedding frequency. Vortex \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,644,913,726]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"shedding changes the flow structure and imposes highly anisotropy near the rotor. The anisotropy is also influenced by the turbulence kinetic energy production and the entrainment from above the canopy, thus increasing the interaction between the scales and introducing the on-off intermittent events. $^{30,31}$ On the other hand, the far-wake region is marked with small amplitude intermittent forces. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,730,883,742]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"V. FORECASTING SPATIAL-TEMPORAL EVOLUTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,747,913,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The main goal of approximating the Koopman operator is to delineate all of the behavior of the nonlinear system in the stability region of the dynamical systems and linearize the nonlinear dynamics. The required training and testing sets are reconstructed from the time signal of the measurement points described in Sec. III. The prediction is achieved for thousands of time steps. Each time step presents an average of $0.03\\\\mathrm{s}$ (1200 time increments), which is approximately the order of the integral length scale. Treating the flow as a linear model with the explicit interpretation of the nonlinearity as an external force \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[156,119,844,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0722/f7d78dd4b927b70cbf241d7789bc1177aa7974c894b71454b3c8e58f93c0201f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[153,244,841,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0770/65265d38a0dcf75cac22275884ad91e818db6141f3d9641ef3a75be79a50ca49.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[153,365,841,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0150/e95cde713995296ca46a999b3cce13b7767d2241e8910fcbd66375b5e1f57bc9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[153,491,841,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 7. The eigentime-delay series and forcing term of the velocity signal at the top tip location of $z - y$ plane. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0622/cfebce74fbe2727d33094dc2a18dcd4d8d426fa0a8835729b3659fe48b713567.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,658,488,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"helps in presenting a promising model for prediction of the underlying nonlinear processes. Figures 9 and 10 show the prediction of the fluctuating velocity signals of 21 wall-normal locations at different places downstream the rotor. The prediction matches the test data in a short time and starts diverging from the testing data relatively short times, meaning the underlying dynamics for detecting the nonlinearities are discovered through the data-driven approach. However, the divergence shown after a short time is due to that the delay-embedding of the measurements are not provided any information about the order of nonlinearity. The mean relative error is defined as $E(t) = ||u_f^{P_r} - u_f^{test}||_2 / ||u_f^{test}||_2$ , where $u_{f}^{P_{r}}$ is the fluctuating velocity that is predicted from the model, and $u_{f}^{test}$ is the actual fluctuating velocity measured via the hot-wire anemometer. The mean relative errors are approximately $15\\\\%$ , where less accurate prediction is shown with increasing advective timescales, where the growth becomes exponentially unbound. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,658,916,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The proposed tool for the prediction can be part of the wind farm control system to predict the wind and control the turbines such as changing the yaw angle of the wind turbine or the blade pitch to keep optimal operating conditions for all turbines in the array, and that will ensure the increase in the power output. The predicted model is a critical key for model predictive control, where the switching control between a number of actuation (for example, yawed and non-yawed) can be achieved to track a reference operation in an unsteady flow within wind farm.[18] The turbine sensors used in the field such as sensors that measure power or LIDAR signals can be used as an input to achieve the wind farm control.[9] The Koopman operator can be used as a systems model to process noise and measurement noise via two steps: first, the prediction step that utilizes a previously estimated state of the linear model to predict the value of the next state and estimate the state covariance. The second step is the updated step, where the state estimation will be corrected based on the current \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[156,119,841,215]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0014/959d1689701dbadc3ac5e37313df2d36db309a9771b74b5040d4c4537ffae1c9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[155,248,839,358]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0276/3e59b3dc66e40bb3513fef0daabdb87b3a2e8ac9cbd51d6f00fae681a09be422.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[155,365,839,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0678/e37cfa7ffe06feac94df98ff741403a4c26d2c2ab3222196d9e6ecd831a4c661.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[155,491,839,603]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIG. 8. The eigentime-delay series and forcing term of the velocity signal at the hub height location of $x - y$ plane. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0641/04d30dbd37665105e61a3ed3c385bf0ed1c72dea9536e66a12ecf62780fa1f77.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,658,486,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"measurements and the statistical properties of the model. The evolution of the error covariance can be predicted with the full state forward model, where the actual observations will be used as an input into mathematical and computational models to create a unified, complete description. Also, this method can be used to model the dynamic stability of the grid in response to disturbances. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[81,744,210,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"VI. CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,761,486,867]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The chaos of the wake flow behind a wind turbine is presented using the Koopman operator. The goals of the current work are to connect the chaos force, which causes the linear model to diverge, with intermittency, demonstrate, and quantify the activity of the intermittent force with respect to time; and more importantly, evaluate the proficiency of the data-driven model to predict the future state of the system, where the stochastic fluctuating velocity is based on trained data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,658,916,870]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Linear representations show the potential ability to distinguish flow events downstream the rotor. The major variations in the nonlinear forcing term are found at the center of the rotor, where the hub height shows the large transients and intermittent events. Less nonlinearity is shown at the top tip location. Outside the swept area, the locations share the same nonlinearity events. Also, the signature of the nonlinear forces sustains outside the rotor area. The robustness of the nonlinear forcing term is shown outside the swept area and at the far-wake regions. This model physically describes the chaotic transitions between the center of the rotor and the atmospheric stream flow, caused by wake advection and vortex shedding in the spanwise direction. The current approach also successfully predicts the flow field for short term timescales. The mean errors between the predictive and test fluctuating velocities are approximately $15\\\\%$ . The proposed method needs further investigations to obtain a full description of the nonlinear term. Achieving this goal will help in forecasting the variability of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,681,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[81,137,362,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0828/0176721e91c83859325197ba905242b23ccc5d6799faa3871a1773facb91cfa4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[411,137,665,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0693/8e6b6dfe28301995c0e6a876ed3de6ade51ac7163f6b6c266f1d6127de155d8c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,274,361,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0783/79b40fe4a38e1558a62b524ea34019f4a1010b6d7018a8a4ec70a69f345f90f7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[411,274,665,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0521/8f1b644e83507a171420c263786180c58458051e77a5b1f0cc6ab6f11c390625.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,447,361,551]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0811/5309352b4499513eaf7f164836937f6cbfa8fedd99be7e26e28d1af1a8c9de1f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[411,447,665,551]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0714/0f9050fb6ec36be0fc6dfea411b7d9f8bd2911f2b987753b835f25eb04ae880c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,584,361,705]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0326/a54d39ddfede431b0284d6035e0625f97f94108729ec73385a52414bd904f719.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[411,584,665,705]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(d) \\\",\\\"FIG. 9. Predication fluctuating velocities at $x / D = 1$ at (a) 75, (b) 150, (c) 450, and (d) 800 time units. The blue and orange lines present the measured and predicted velocities, respectively. \\\",\\\"FIG. 10. Predication fluctuating velocities at $x / D = 6$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0675/605aa293ca5b9687204853b9188696b9090ef3d0c1411b4513fff7d4d285615c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[80,724,486,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the wind to protect the system in high winds, capture more energy in low winds, and reduce the uncertainty of the output by supporting real-time operations. Forecasting the variability of the wind will allow anticipating wind generation levels to adjust the power system accordingly. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,789,486,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The current model is a part of system identification and uses the measurements from the wind plant to estimate the relevant properties of the system. The simple structure and fast computation of the data-driven model are well-suited for real-time control. The measurements of the real-world wind plant can be fed into the model structure to identify the model parameters and then adjust the internal model \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[506,724,915,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"based on the predicted future state and test a few sets such as yawed angles to reach the optimized control points. Based on the evaluation of predicted turbine power outputs, the updated yaw settings are stored as a baseline if improvement is shown. Another advantage of the current model is that it can display the effect of inflow conditions and tested parameters on the relevant structural loads on the turbine by analyzing the nonlinear forces. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,824,661,836]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DATA AVAILABILITY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,841,915,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The data that support the findings of this study are available from the corresponding author upon reasonable request. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,679,66]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[856,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[83,119,186,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[83,137,485,688]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"<sup>1</sup>J. 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Tutkun, and R. B. Cal, \\\\\\\"Evaluation of higher order moments and isotropy in the wake of a wind turbine array,\\\\\\\" Whither Turbulence and Big Data in the 21st Century? (Springer, 2017), pp. 273-292. \\\",\\\"31N. Ali, N. Hamilton, G. Cortina, M. Calaf, and R. B. Cal, \\\\\\\"Anisotropy stress invariants of thermally stratified wind turbine array boundary layers using large eddy simulations,\\\\\\\" J. Renewable Sustainable Energy 10(1), 013301 (2018). \\\",\\\"$^{32}$ N. Ali, H. F. Kadum, and R. B. Cal, “Focused-based multifractal analysis of the wake in a wind turbine array utilizing proper orthogonal decomposition,” J. Renewable Sustainable Energy 8(6), 063306 (2016). \\\",\\\"33S. Rockel, J. Peinke, M. Holling, and R. B. Cal, \\\\\\\"Wake to wake interaction of floating wind turbine models in free pitch motion: An eddy viscosity and mixing length approach,\\\\\\\" Renewable Energy 85, 666-676 (2016). \\\",\\\"34S. Rockel, E. Camp, J. Schmidt, J. Peinke, R. B. Cal, and M. Hølling, \\\\\\\"Experimental study on influence of pitch motion on the wake of a floating wind turbine model,\\\\\\\" Energies 7(4), 1954-1985 (2014). \\\",\\\"35S. Rockel, J. Peinke, M. Holling, and R. B. Cal, \\\\\\\"Dynamic wake development of a floating wind turbine in free pitch motion subjected to turbulent inflow generated with an active grid,\\\\\\\" Renewable Energy 112, 1-16 (2017). \\\"]\",\n \"page_idx\": \"10\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[73,45,305,77]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Renewable and Sustainable Energy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[622,53,679,66]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[723,53,864,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scitation.org/journal/rse \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,913,429,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"J. Renewable Sustainable Energy 12, 033304 (2020); doi: 10.1063/5.0004393 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,929,263,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under license by AIP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[851,913,921,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12,033304-10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1063/5.0004393"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Physics"},"sha256":{"kind":"string","value":"45bcfb0c2cef7a65ab93c642e72c55331cf19550cc1f47c2dd72178e99ce3d68"},"title":{"kind":"string","value":"Data-driven modeling of the wake behind a wind turbine array"}}},{"rowIdx":171,"cells":{"abstract":{"kind":"string","value":"\n \nIn this paper, a classical deflation process raised by Dayton, Li and Zeng is realized for the Brent equations, which provides new bounds for local dimensions of the solution set. Originally, this deflation process focuses on isolated solutions. We generalize it to the case of irreducible components and a related conjecture is given. We analysis its realization and apply it to the Brent equations. The decrease of the nullities is easily observed. So the deflation process can be served as a useful tool for determining the local dimensions. In addition, our result implies that along with the decrease of the tensor rank, the singular solutions will become more and more.\n "},"author":{"kind":"string","value":"Liping Zhang|Xin Li|Yifen Ke"},"content_list":{"kind":"list like","value":[{"bbox":"[238,185,758,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[382,243,616,256]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"XIN LI, LIPING ZHANG, AND YIFEN KE ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[263,279,735,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract. In this paper, a classical deflation process raised by Dayton, Li and Zeng is realized for the Brent equations, which provides new bounds for local dimensions of the solution set. Originally, this deflation process focuses on isolated solutions. We generalize it to the case of irreducible components and a related conjecture is given. We analysis its realization and apply it to the Brent equations. The decrease of the nullities is easily observed. So the deflation process can be served as a useful tool for determining the local dimensions. In addition, our result implies that along with the decrease of the tensor rank, the singular solutions will become more and more. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[446,422,552,438]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,445,792,489]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In [18, Sect. 8], Heule et al. raised the question: what is the dimension of the solution set of Brent equations? Following our last paper [28], using the deflation process raised in [7, 8], we continue discussing the local dimensions of solutions of Brent equations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,491,792,551]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $F ( \\mathbf { x } ) : \\mathbb { C } ^ { n } \\to \\mathbb { C } ^ { m }$ be a polynomial system with solution set $\\mathbf { V } ( F )$ . Let $J ( \\mathbf { x } ) \\in \\mathbb { C } ^ { m \\times n }$ be the Jacobian of $F ( \\mathbf { x } )$ . Given a solution $\\hat { \\mathbf { x } } \\in \\mathbf { V } ( F )$ and let $\\dim _ { \\hat { \\mathbf { x } } } \\mathbf { V } ( F )$ denote its local dimension. The Jacobian criterion of [11, Theorem 4.1.12] tells us that the nullity of $J ( \\hat { \\mathbf { x } } )$ is an upper bound of $\\dim _ { \\hat { \\mathbf { x } } } \\mathbf { V } ( F )$ : ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[398,556,598,571]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0096/e123a326fdf2c8d3709317f606e259c75718059fdae874f3e768cf2450f8146d.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\dim _ { \\hat { \\mathbf { x } } } \\mathbf { V } ( F ) \\leq n - \\operatorname { r a n k } \\left( J ( { \\hat { \\mathbf { x } } } ) \\right) .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,578,500,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Usually, (1.1) may be not an equality, that is, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[398,597,598,613]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0290/40045791fd9820ba5bba6493445648dc91781166921dcba98aaddaac92977b6c.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathrm { d i m } _ { \\hat { \\mathbf { x } } } \\mathbf { V } ( F ) < n - \\mathrm { r a n k } \\left( J ( \\hat { \\mathbf { x } } ) \\right) .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,617,794,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When (1.2) happens, in numerical algebraic geometry, the solution $\\hat { \\mathbf { x } }$ is said to be singular (or ultrasingular) [3, 32, 37]. It is well-known that the locally quadratical convergence of Newton’s method is only guaranteed when (1.1) is an equality (see e.g. [37]). Near the neighbourhood of singular solutions, Newton’s method often loses its locally quadratical convergence. In order to recover Newton’s method and turn (1.1) into an equality, the “deflation” technique is introduced, which is also a useful tool for the estimation of local dimensions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,724,794,844]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The deflation technique was firstly introduced by Ojika [30, 31] for the isolated solution. After that many improvements and generalizations were given [7, 8, 16, 26]. Given a polynomial system and a solution. A deflation process produces a new expanded polynomial system and a new expanded solution. For a generic (smooth) point, the nullity of Jacobian of the new expanded solution can be much closer to its local dimension. For isolated singular solutions, it was shown in [7, 8, 26] that the nullity will decrease to zero after a finite number of steps. For a positive dimensional irreducible component, Hauenstein and Wampler introduced a new form of deflation called strong deflation [16], and they refer to the deflation process raised in [7, 8, 26] as weak deflation. Through strong deflation process, Hauenstein and Wampler proved that their deflation sequence will decrease to the local dimension of the generic (smooth) points of the irreducible component [16, Lemma 4.7]. For the other (singular) points, the stabilized number of the (strong) deflation sequence will be no greater than their local dimension [16, Sect.5.3]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[220,858,705,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2020 Mathematics Subject Classification. Primary 14Q15; Secondary 65H10. Key words and phrases. Deflation, Singularity, Brent equations, Local dimension, Jacobian. ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[22,218,62,696]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[493,888,503,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,146,794,222]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,222,794,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the (weak) deflation raised in [7, 8, 26], it focuses on the isolated solutions. However, it is not hard to see that it is also suitable to the positive dimensional solutions. In [37, Sect. 9], in order to recover the quadratic convergence rate of Newton’s iteration at ultrasingular zeroes, Zeng conjectured that for generic (smooth) points, the weak deflation process will also terminate at the local dimension of positive dimensional solutions after a finite number of steps. That is, similar properties of strong deflation in [16] also hold for the weak deflation process raised in [7, 8] under the positive dimensional generalization. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,329,794,463]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"By Lemma 4.7 of [16], the strong deflation can turn (1.1) into an equality. However, it will introduce much more new variables and polynomials than the weak deflation. So the implementation of strong deflation is not so practical for large polynomial systems, such as the Brent equations. In addition, the local dimension determination methods raised in [1, 25, 36] are also not suitable to large polynomial systems, too. Let $\\langle m , n , p \\rangle$ denote the matrix multiplication tensor. We find that it is convenient to calculate the first 4 numbers of the weak deflation sequences for $m n p \\leq 1 2 5$ . So our results imply that the weak deflation is a useful tool for determining the local dimensions for polynomial systems arising in the field of bilinear complexity [24]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,479,794,660]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Organization and main results. Firstly, after some preliminaries, more details of the conjecture in [37] are given, see Section 2 and Conjecture 1 in Section 3. Some elementary results are discussed, which are similar to those in [16]. Secondly, the constructions of the Jacobians in the first three steps of the deflation process in [7, 8] are analysed, which are also suitable for other steps, see Section 4. Thirdly, numerical experiments are given for the solutions of the Brent equations, see Section 5. The first 4 numbers of the deflation sequences of many known solutions (see e.g. [14, 17]) are calculated, which provide bounds for their local dimensions. Some interesting results are found. For example, the local dimension of Strassen’s classical solution should be 23, see Section 5.1. For the solutions provided in [17], after the first deflation step, we find that most solutions are singular. This provides a new numerical evidence that finding the tensor decomposition of low rank is hard [12, 19]. Some remarks and open problems are given in Section 6. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,661,794,720]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our numerical results are obtained by Matlab2022a. Some codes and data can be found on [29]. The numerical experiments are taken on the server of ZJUT with the configuration: Intel(R) Xeon(R) Silver 4210R CPU running at 2.40GHz plus $2 . 3 9 \\mathrm { G H z }$ and 256 GB memory. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[442,744,553,758]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Preliminaries ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,766,794,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Throughout this paper, $\\mathbb { C }$ is the complex field. The vector space of $m \\times n$ complex matrices is denoted by $\\mathbb { C } ^ { m \\times n }$ . Let $\\mathbb { C } ^ { n }$ (or $\\mathbb { C } ^ { n \\times 1 }$ ) denote the $n$ -dimensional column vector space over $\\mathbb { C }$ . Given a matrix $A \\in \\mathbb { C } ^ { m \\times n }$ . Let rank $( A )$ denote the rank of $A$ . The nullity of $A$ is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[455,832,540,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0155/002270b871ed02c907b436a1653f36b6047095c752cd6405f71b4ac2b81f2dc2.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn - \\operatorname { r a n k } ( A ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[199,853,795,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which is the dimension of the null space of $A$ and denoted by $\\Im ( A )$ . In the following, the deflation process always refers to the deflation process raised in [7, 8] or its generalization. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[444,121,552,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,121,214,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,146,794,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $F : \\mathbb { C } ^ { n } \\to \\mathbb { C } ^ { m }$ be a polynomial system. So there exist $m$ polynomials $f _ { i } : \\mathbb { C } ^ { n } \\to \\mathbb { C }$ $( i = 1 , 2 , . . . m )$ such that $F = [ f _ { 1 } , f _ { 2 } , . . . f _ { m } ] ^ { \\mathbf { T } }$ . The solution set of $F$ over $\\mathbb { C }$ is called an algebraic set and denoted by $\\mathbf { V } ( F )$ , that is, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[336,198,660,213]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0990/341cbbdc8f69933b3267aa23c1bff2f9b8ed6a1e874af392279b38533a26981b.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf { V } ( F ) = \\{ \\mathbf { x } \\in \\mathbb { C } ^ { n } | f _ { 1 } ( \\mathbf { x } ) = f _ { 2 } ( \\mathbf { x } ) = \\cdots = f _ { m } ( \\mathbf { x } ) = 0 \\} .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,218,794,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $J ( \\mathbf { x } )$ denote the Jacobian matrix of $F ( \\mathbf { x } )$ . So $J ( \\mathbf { x } ) \\in \\mathbb { C } ^ { m \\times n }$ . An algebraic set $\\mathbf { V }$ is reducible if there exist nonempty algebraic sets $V _ { 1 } , V _ { 2 } \\subsetneq \\mathbf { V }$ such that $\\mathbf { V } = V _ { 1 } \\cup V _ { 2 }$ . $\\mathbf { V }$ is irreducible if no such decomposition exists. Each algebraic set $\\mathbf { V }$ can be decomposed into a unique finite union of irreducible algebraic subsets: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[419,285,578,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0106/08debd2d5ced935a3557cdc5c00798969a592291c165821ba44bc348be714089.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf { V } = V _ { 1 } \\cup V _ { 2 } \\cup \\cdots \\cup V _ { r } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,305,794,426]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $V _ { i }$ is called the irreducible component of $\\mathbf { V }$ . For an irreducible component $V$ , the set of manifold points in $V$ is connected and its dimension as a complex manifold is defined to be the dimension of $V$ , denoted dim $V$ [4, 32]. If $\\dim V \\ = \\ k$ , $V$ is said to be a $k$ - dimensional irreducible component. The local dimension of a point $\\mathbf { x } \\in \\mathbf { V }$ is the maximal dimension of the irreducible components of $\\mathbf { V }$ that contain $\\mathbf { X }$ , which is denoted by $\\dim _ { \\mathbf { X } } \\mathbf { V }$ . For an irreducible component $V$ , a property $P$ holds generically on $V$ if there is a nonempty Zariski open set $U \\subseteq V$ such that $P$ holds on $V$ . Each point of $U$ is called a generic point of $V$ with respect to $P$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[200,426,792,458]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Considering $\\mathbf { V } ( F )$ as a geometric object in $\\mathbb { C } ^ { n }$ , we have the following definition which makes a slight change of [15, Def. 2.1]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[200,464,794,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Definition 2.1. A point $\\mathbf { x } _ { 0 } \\in \\mathbf { V } ( F )$ is called geometric smooth, if there exists a unique irreducible component $V \\subseteq \\mathbf { V } ( F )$ containing $\\mathbf { X } _ { 0 }$ such that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[431,501,566,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0408/8e5a33f781f775328b474d785c120475b0f94a40f8ab071a823de0228db5449d.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\dim T _ { \\mathbf { x } _ { 0 } } ( V ) = \\dim V\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[207,522,794,553]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $T _ { \\mathbf { x } _ { 0 } } ( V )$ is the tangent space of $V$ at $\\mathbf { X } _ { 0 }$ . Otherwise, $\\mathbf { X } _ { 0 }$ is called a geometric singular point of $\\mathbf { V } ( F )$ . The set of all geometric singular points of $\\mathbf { V } ( F )$ is denoted by $\\mathrm { S i n g } _ { G } ( \\mathbf { V } ( F ) )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[207,560,792,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is well-known that geometric smooth points are generic on an irreducible component. On the other hand, we have the following definition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,598,794,643]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Definition 2.2. Let $F ( \\mathbf { x } )$ be a polynomial system whose solution set and Jacobian are $\\mathbf { V } ( F )$ and $J ( \\mathbf { x } )$ , respectively. A point $\\mathbf { x } _ { 0 } \\in \\mathbf { V } ( F )$ is called numerical smooth, if there exists a unique irreducible component $V \\subseteq \\mathbf { V } ( F )$ containing $\\mathbf { X } _ { 0 }$ such that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[437,648,560,665]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0580/531c8e085a258b7c8fbe605640a94cc483be999d501c83156994d60df6091913.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathcal { N } ( J ( \\mathbf { x } _ { 0 } ) ) = \\dim V .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,670,795,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Otherwise, $\\mathbf { X } _ { 0 }$ is called a numerical singular point of $\\mathbf { V } ( F )$ . The set of all numerical singular points of $\\mathbf { V } ( F )$ is denoted by $\\mathrm { S i n g } _ { N } ( { \\bf V } ( F ) )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,708,602,723]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Remark 2.3. It is well-known that if $\\mathbf { x } _ { 0 } \\in \\mathrm { S i n g } _ { N } ( \\mathbf { V } ( F ) )$ , then ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[418,728,578,746]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0927/70a4bd5516ef01aa34310b65a332e43431d54d0c7b755fe5d4fb58c6444ed6ca.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { \\mathcal { N } ( J ( \\mathbf { x } _ { 0 } ) ) > \\mathrm { d i m } _ { \\mathbf { x } _ { 0 } } \\mathbf { V } ( F ) . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,751,795,795]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Comparing Definition 2.1 and 2.2, we know that numerical smooth points are geometric smooth. However, numerical singular points may contain geometric smooth points. For example, the irreducible components with multiplicity greater than one [3, Example 8.10]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[223,796,555,811]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the polynomial system $F = [ f _ { 1 } , f _ { 2 } , . . . , f _ { m } ] ^ { \\mathrm { T } }$ , let ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,816,604,833]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0310/6c51f3f55b8eee1f4c9e0c4269cf6920ba1c3f8a99402355b0e791d4b4bca9a9.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\langle f _ { 1 } , f _ { 2 } , . . . , f _ { m } \\rangle \\subseteq \\mathbb { C } [ x _ { 1 } , x _ { 2 } , . . . , x _ { n } ]\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,838,792,867]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"denote the ideal generated by $f _ { i }$ . On the other hand, let $\\mathbf { I } ( \\mathbf { V } ( F ) )$ denote the vanishing ideal on $\\mathbf { V } ( F )$ : ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[308,868,687,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0550/dad4b5a12ed7b0d9ed54fbc28740af19b84febd2ab24e87b165711ff0ca80ca1.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf { I } ( \\mathbf { V } ( F ) ) = \\{ f \\in \\mathbb { C } [ x _ { 1 } , x _ { 2 } , . . . , x _ { n } ] | f ( \\mathbf { x } ) = 0 { \\mathrm { ~ f o r ~ a l l ~ } } \\mathbf { x } \\in \\mathbf { V } ( F ) \\} .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[297,119,702,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[784,121,794,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,146,794,175]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"By Proposition 2 of [6, Sect.6 Chapter 9] and Corollary 9 of [6, Sect.7 Chapter 9], we know that if ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[415,176,581,193]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0956/74c3a6d5fe7acf803b188ac767d69215e5ed961192cf0112b84facd468634217.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\langle f _ { 1 } , f _ { 2 } , . . . , f _ { m } \\rangle = \\mathbf { I } ( \\mathbf { V } ( F ) ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,195,794,241]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"then Definition 2.1 and 2.2 are equivalent, that is, the geometric smooth (resp. singular) points and numerical smooth (resp. singular) points are the same. However, for any polynomial system $F = [ f _ { 1 } , f _ { 2 } , . . . , f _ { m } ] ^ { \\mathrm { T } }$ , it is well-known that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[415,246,581,262]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0175/d7b403e1e22af4b690f45a66f2df4fbc8f78f282e3a908e9a09c1dd299b93229.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\langle f _ { 1 } , f _ { 2 } , . . . , f _ { m } \\rangle \\subseteq \\mathbf { I } ( \\mathbf { V } ( F ) ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[200,266,794,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and deciding if they are equal is usually hard. So, for those polynomial systems we are interested, the geometric smooth points may be numerical singular. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,304,794,349]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The definition of semiregularity and ultrasingularity of [37] are formalised to irreducible components as follows. For the definition of intersection multiplicity of an irreducible component, we refer to [3, Sec. 11.3]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,356,794,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Definition 2.4. For a polynomial system $F$ , given a $k$ -dimensional irreducible component $V \\subseteq \\mathbf { V } ( F )$ . If all geometric smooth points are numerical smooth, then we call $V$ is a $k$ - dimensional semiregular irreducible component. That is, there is a nonempty Zariski open set $U \\subseteq V$ such that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[387,417,607,433]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0586/95569077def9de3842409ab00cb9616722073537c2dfa8150293b8ddcae755bd.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nk = \\dim _ { \\mathbf { x } } \\mathbf { V } ( F ) = T _ { \\mathbf { x } } V = \\mathcal { N } ( J ( \\mathbf { x } ) ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[207,435,709,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $\\mathbf { x } \\in U$ . Each point in $U$ is called a $k$ -dimensional semiregular solution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,450,794,510]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, if all geometric smooth points are numerical singular and have the same intersection multiplicity, then we call $V$ is a $k$ -dimensional ultrasingular irreducible component. That is, there is a nonempty Zariski open set $U \\subseteq V$ and a constant positive number $n _ { 0 }$ such that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[369,511,625,526]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0437/8d00fc33a6d413fd39b6ba5d7851bd8c061343de7d8af444da9d5f0cf5bb8ae5.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nk = \\dim _ { \\mathbf { x } } { \\mathbf V } ( F ) = T _ { \\mathbf { x } } V < \\Re ( J ( \\mathbf { x } ) ) = n _ { 0 } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,529,715,545]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $\\mathbf { x } \\in U$ . Each point in $U$ is called a $k$ -dimensional ultrasingular solution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[310,556,686,570]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Deflation conjecture for the irreducible component ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,577,794,638]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The deflation process raised in [7, 8] focuses on isolated singular solutions. In this section, we generalize it to the case of $k$ -dimensional ultrasingular irreducible components. More details of the conjecture in [37] for ultrasingular solutions are given. Similar discussions are given in [16]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,645,792,676]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. The first step of the deflation process. Let $V \\subseteq \\mathbf { V } ( F )$ be a $k$ -dimensional ultrasingular irreducible component, which has a nonzero Zariski open set ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[385,681,612,696]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0310/0c37971724cae152ad6a2e87fd4ff035cb3cf46acfbbab52ad2333c53bcb4ff8.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nU _ { 0 } \\subseteq V \\quad \\mathrm { w i t h } \\quad k < \\Re ( J ( \\mathbf { x } ) ) = n _ { 0 }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,702,717,717]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $\\mathbf { x } \\in U _ { 0 }$ . Fix a $k$ -dimensional ultrasingular solution $\\hat { \\mathbf { x } } _ { 1 } \\in U _ { 0 }$ . So we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[433,722,563,738]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0224/4f5c87dcce185c323263b9ce2d995c76344ed82ebcf8e378a291e702aaa4c655.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nk < \\mathcal { N } ( J ( \\hat { \\mathbf { x } } _ { 1 } ) ) = n _ { 0 } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,742,712,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Then, choose $R _ { 1 } \\in \\mathbb { C } ^ { n _ { 0 } \\times n }$ and a vector $d _ { 1 } \\in \\mathbb { C } ^ { n _ { 0 } }$ randomly, such that the matrix ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[459,761,534,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0533/9a4053ac8bfa159b7c8c52a92d9127dadce7307948ab53ad41f6c28a493f5ca0.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\left[ \\begin{array} { c } { J ( \\hat { \\bf x } _ { 1 } ) } \\\\ { R _ { 1 } } \\end{array} \\right] ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,797,570,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is of full (column) rank, and therefore the linear system ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[426,815,571,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0400/908b6182089da0bb0cc9fdb330a1b3bbe540f1d37beb64cc6d29025d0b3bc609.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\left[ \\begin{array} { c } { J ( \\hat { \\mathbf { x } } _ { 1 } ) } \\\\ { R _ { 1 } } \\end{array} \\right] \\mathbf { x } = \\left[ \\begin{array} { c } { \\mathbf { 0 } } \\\\ { d _ { 1 } } \\end{array} \\right]\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[200,853,794,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"has a unique solution $\\mathbf { x } _ { 2 } = \\hat { \\mathbf { x } } _ { 2 } \\neq \\mathbf { 0 }$ . By the discussion in Section 3.1 of [16], we can see that besides $\\hat { \\bf x } _ { 1 }$ , for almost all $\\hat { \\mathbf { x } } \\in V$ , the equation (3.4) also has a unique solution. Let $\\mathbf { X } _ { 2 } \\in \\mathbb { C } ^ { n }$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[444,119,552,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,121,214,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[202,145,794,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"be new variables and fixing $R _ { 1 }$ for all points in $V$ . Then the first step of deflation of $F$ is defined by: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[320,176,678,227]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0015/aba54a3ee98f1447d36aa50b2975330fb5f18861de0203a9778b939ae3f6be6d.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) = \\left[ \\begin{array} { c } { F ( \\mathbf { x } _ { 1 } ) } \\\\ { \\left[ \\begin{array} { c } { J ( \\mathbf { x } _ { 1 } ) } \\\\ { R _ { 1 } } \\end{array} \\right] \\mathbf { x } _ { 2 } - \\left[ \\begin{array} { c } { \\mathbf { 0 } } \\\\ { d _ { 1 } } \\end{array} \\right] } \\end{array} \\right] , \\mathrm { f o r ~ a l l ~ } \\mathbf { x } _ { 1 } \\in V .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,228,632,242]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"So $( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } )$ is a solution of the new polynomial system $F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[222,242,789,257]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When $m \\geq n$ , let $\\pi _ { n } : \\mathbb { C } ^ { m } \\to \\mathbb { C } ^ { n }$ denote the natural projection map, which is defined by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[385,265,611,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"1001/6a48497b0546f58c0a374df72e67d7f20556e66e859d2ba55badd6d9d5daf767.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\pi _ { n } : ( x _ { 1 } , x _ { 2 } , . . . x _ { m } ) \\mapsto ( x _ { 1 } , x _ { 2 } , . . . x _ { n } ) .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,286,647,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $\\mathbf { V } ( F _ { 1 } )$ denote the solution set of $F _ { 1 }$ . For $U _ { 0 }$ defined in (3.1), let ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[370,308,627,324]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0225/da140e3c13cdb60753a4c745c47a23e4431cab89886e46e819b470557ca2090b.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nW _ { 1 } = \\{ y \\in { \\bf V } ( F _ { 1 } ) | \\pi _ { n } ( y ) \\in U _ { 0 } \\} \\subset { \\bf V } ( F _ { 1 } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,330,792,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and $\\overline { { W _ { 1 } } }$ be the Zariski closure of $W _ { 1 }$ . By the discussion of Lemma 4.6 of [16], we also have the following lemma. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,368,792,398]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lemma 3.1. $\\overline { { W _ { 1 } } }$ is an irreducible component of $V ( F _ { 1 } )$ which is generically isomorphic to $V .$ . In particular, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[428,400,570,417]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0471/0bc9698b9d44ffb977b4c1c81211636b0eb5260c5598b009f6fabcd1782ac594.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\dim { \\overline { { W _ { 1 } } } } = \\dim V = k .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,426,794,470]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $J _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } )$ denote the Jacobian of $F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } )$ . Then by Proposition 4 and Remark 5 of [27], with probability one, there is an open neighbourhood $\\tilde { U } _ { 1 }$ of $( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } )$ such that the nullity ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[382,473,614,489]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0849/b58ef91f2f05ad293e4b8c7d96de7b53ab98c85c0f1c612376f4fc17f2619234.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { \\Re ( J _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) ) = \\Re ( J _ { 1 } ( \\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } ) ) = n _ { 1 } , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,492,423,507]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) \\in \\tilde { U } _ { 1 }$ . Then we let ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[447,511,552,530]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0160/30587ae5cf6198d55721448b9fd60583004a74bff8cb1f55bfd15768de762e19.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nU _ { 1 } = { \\overline { { W } } } _ { 1 } \\cap { \\tilde { U } } _ { 1 } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,540,795,631]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. The second and subsequent steps. In (3.8), if $n _ { 1 } = k$ , then $( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } )$ is a $k$ -dimensional semiregular zero of $F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } )$ , so the singularity of $F ( \\mathbf { x } )$ at $\\hat { \\bf x } _ { 1 }$ and its neighbourhood is “deflated”. However, $( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } )$ may still be an ultrasingular zero of $F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } )$ , that is, $n _ { 1 } > k$ . In this case, we can repeat the same deflation process above for $F _ { 1 }$ and obtain a new polynomial system $F _ { 2 }$ . More precisely, we can find and fix $R _ { 2 } \\in \\mathbb { C } ^ { n _ { 1 } \\times 2 n }$ and $d _ { 2 } \\in \\mathbb { C } ^ { n _ { 1 } }$ such that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[254,633,704,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0706/292b07f7f69b4807a461ccd0d2ffd93eba164c316c0a2f62a7c219e58b47eae5.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { 2 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , \\mathbf { x } _ { 3 } , \\mathbf { x } _ { 4 } ) = \\left[ \\begin{array} { c } { F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) } \\\\ { \\left[ \\begin{array} { c } { J _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) } \\\\ { R _ { 2 } } \\end{array} \\right] \\left[ \\begin{array} { c } { \\mathbf { x } _ { 3 } } \\\\ { \\mathbf { x } _ { 4 } } \\end{array} \\right] - \\left[ \\begin{array} { c } { \\mathbf { 0 } } \\\\ { d _ { 2 } } \\end{array} \\right] } \\end{array} \\right] \\mathrm { f o r ~ a l l ~ } \\mathbf { x } _ { 1 } \\in V ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,686,794,717]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and the solution $( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } )$ extends to a solution $( \\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } , \\hat { \\mathbf { x } } _ { 3 } , \\hat { \\mathbf { x } } _ { 4 } )$ of $F _ { 2 }$ , uniquely. Let $\\mathbf { V } ( F _ { 2 } )$ denote the solution set of $F _ { 2 }$ . For $U _ { 0 }$ and $\\pi _ { n }$ defined in (3.1) and (3.6) respectively, let ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[370,723,625,739]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0556/6202b503e88cea86482fadc66c8fd6dc8dd0059f93b4a4a83d925bb15d87de70.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nW _ { 2 } = \\{ y \\in { \\bf V } ( F _ { 2 } ) | \\pi _ { n } ( y ) \\in U _ { 0 } \\} \\subset { \\bf V } ( F _ { 2 } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,746,794,792]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and $\\overline { { W _ { 2 } } }$ be the Zariski closure of $W _ { 2 }$ . Then following the same reason as Lemma 3.1, we also have $\\dim \\overline { { W _ { 2 } } } ~ = ~ k$ . Just as (3.9), there is also a neighbourhood $U _ { 2 } ~ \\subseteq ~ \\overline { { { W _ { 2 } } } }$ of $( \\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } , \\hat { \\mathbf { x } } _ { 3 } , \\hat { \\mathbf { x } } _ { 4 } )$ such that the nullity ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[338,799,656,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0541/77472d2d18b3e498c572af79ae2ac6c154e9560929c65183c5f925bc218efbc1.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { \\mathrm { \\mathcal { N } } ( J _ { 2 } ( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , { \\bf x } _ { 3 } , { \\bf x } _ { 4 } ) ) = \\mathrm { \\mathcal { N } } ( J _ { 2 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } , \\hat { \\bf x } _ { 3 } , \\hat { \\bf x } _ { 4 } ) ) = n _ { 2 } , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,821,380,837]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , { \\bf x } _ { 3 } , { \\bf x } _ { 4 } ) \\in U _ { 2 }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,837,794,866]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Generally, assume $( \\hat { \\mathbf { x } } _ { 1 } , . . . , \\hat { \\mathbf { x } } _ { 2 ^ { i } } )$ is an ultrasingular zero of $F _ { i } ( \\mathbf { x } _ { 1 } , . . . , \\mathbf { x } _ { 2 ^ { i } } )$ after $i$ steps of deflation. Let ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[375,868,622,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0538/5c4671442872745a5a89aadda1150b7e1084af830e57aa771fa125f17f0ead2c.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nW _ { i } = \\{ y \\in { \\bf V } ( F _ { i } ) | \\pi _ { n } ( y ) \\in U _ { 0 } \\} \\subset { \\bf V } ( F _ { i } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[297,118,702,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[784,119,794,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,143,795,178]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and $\\overline { { W _ { i } } }$ be the Zariski closure of $W _ { i }$ . Then di $\\mathrm { \\Omega } _ { \\mathrm { n } } \\overline { { W _ { i } } } \\mathrm { ~ = ~ } k$ and the Jacobian $J _ { i } ( \\mathbf { x } _ { 1 } , . . . , \\mathbf { x } _ { 2 ^ { i } } )$ maintains a nullity $n _ { i } > k$ , in a neighborhood $U _ { i } \\subset \\overline { { W _ { i } } }$ of $( \\hat { \\mathbf { x } } _ { 1 } , . . . , \\hat { \\mathbf { x } } _ { 2 ^ { i } } )$ . That is, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[361,183,635,199]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0857/e644700bff01e71558d40d2cc3ba816e4c00baaf9c20ac5ac303cdfd482ea993.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { \\Re ( J _ { i } ( \\mathbf { x } _ { 1 } , . . . , \\mathbf { x } _ { 2 ^ { i } } ) ) = \\Re ( J _ { i } ( \\hat { \\mathbf { x } } _ { 1 } , . . . , \\hat { \\mathbf { x } } _ { 2 ^ { i } } ) ) = n _ { i } , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,204,692,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $( \\mathbf { x } _ { 1 } , . . . , \\mathbf { x } _ { 2 ^ { i } } ) \\in U _ { i }$ . Then the next deflation step expands the system to ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[284,223,714,295]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0138/8f18dc6b7c9a5ffb355fb6f520b32107ab4cc73e401457e6e2bbb1e3971a548e.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { i + 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , . . . , \\mathbf { x } _ { 2 ^ { i + 1 } } ) = \\left[ \\begin{array} { c } { F _ { i } ( \\mathbf { x } _ { 1 } , . . . , \\mathbf { x } _ { 2 ^ { i } } ) } \\\\ { \\left[ \\begin{array} { c } { J _ { i } ( \\mathbf { x } _ { 1 } , . . . , \\mathbf { x } _ { 2 ^ { i } } ) } \\\\ { R _ { i + 1 } } \\end{array} \\right] \\left[ \\begin{array} { c } { \\mathbf { x } _ { 2 ^ { i } + 1 } } \\\\ { \\vdots } \\\\ { \\mathbf { x } _ { 2 ^ { i + 1 } } } \\end{array} \\right] - \\left[ \\begin{array} { c } { \\mathbf { 0 } } \\\\ { d _ { i + 1 } } \\end{array} \\right] } \\end{array} \\right] ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[199,301,794,333]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for all $\\mathbf { x } _ { 1 } \\in V$ , where $R _ { i + 1 } \\in \\mathbb { C } ^ { n _ { i } \\times 2 ^ { i } n }$ and $d _ { i + 1 } \\in \\mathbb { C } ^ { n _ { i } }$ are (randomly) chosen and fixed such that almost all points of $\\overline { { W _ { i } } }$ extend to a solution of $F _ { i + 1 }$ , uniquely. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,340,669,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Theorem 3.2. In the deflation process above, for $k$ , $n _ { 0 }$ and $n _ { i }$ , we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[421,362,575,377]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0092/ae5da3087f35d5f2599d8021021752bea0979f47f579f42942ac3cf44c575a03.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nk \\leq n _ { i } \\leq \\cdots \\leq n _ { 1 } \\leq n _ { 0 } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,382,795,428]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for each $i \\geq 1$ . Moreover, suppose that $J _ { i } ( \\hat { { \\pmb x } } _ { 1 } , . . . , \\hat { { \\pmb x } } _ { 2 ^ { i } } ) \\in \\mathbb { C } ^ { a _ { i } \\times 2 ^ { i } n }$ for some $a _ { i }$ . Let $J _ { i } ( \\hat { { \\mathbf { x } } } _ { 1 } ) \\in$ $\\mathbb { C } ^ { a _ { i } \\times n }$ be the submatrix of $J _ { i } ( \\hat { \\pmb x } _ { 1 } , . . . , \\hat { \\pmb x } _ { 2 ^ { i } } )$ which is obtained by taking the first n columns of $J _ { i } ( \\hat { { \\pmb x } } _ { 1 } , . . . , \\hat { { \\pmb x } } _ { 2 ^ { i } } )$ . Then ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[429,429,568,444]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"1002/6b448f474a4c6f16f9310f907bdf74983e9813da2e06d2d472fe2e4ae29b9e9e.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { i } = n - r a n k J _ { i } ( \\hat { \\pmb x } _ { 1 } ) .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,452,794,497]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Proof. By Lemma 3.1, we can see that without changing its dimension, after each step of deflation, the $k$ -dimensional ultrasingular irreducible component is embedded into a new $k$ -dimensional irreducible component. So we have $k \\leq n _ { i }$ for each $i$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,498,795,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For $n _ { i } \\le \\cdots \\le n _ { 1 } \\le n _ { 0 }$ , it suffices to show that $n _ { 1 } \\leq n _ { 0 }$ by the recursive process of the deflation. From (3.5), we know that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[318,531,678,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0703/12759e6d0114348aa65c290113adf897fd7c05f03804ac78aa277557d849be16.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nJ _ { 1 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } ) = \\left[ \\begin{array} { c c } { J ( \\hat { \\bf x } _ { 1 } ) } & { { \\bf 0 } } \\\\ { J \\left( \\left( J ( \\hat { \\bf x } _ { 1 } ) \\hat { \\bf x } _ { 2 } \\right) , \\hat { \\bf x } _ { 1 } \\right) } & { J ( \\hat { \\bf x } _ { 1 } ) } \\\\ { { \\bf 0 } } & { R _ { 1 } } \\end{array} \\right] \\in \\mathbb { C } ^ { ( 2 m + n _ { 0 } ) \\times 2 n } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,583,794,613]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $J ( ( J ( \\hat { \\mathbf { x } } _ { 1 } ) \\hat { \\mathbf { x } } _ { 2 } ) , \\hat { \\mathbf { x } } _ { 1 } )$ is the partial Jacobian of $J ( \\mathbf { x } _ { 1 } ) \\mathbf { x } _ { 2 }$ with respect to $\\mathbf { X } _ { 1 }$ which takes the value at $( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } )$ . By the choice of $R _ { 1 }$ , we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[415,619,578,635]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0779/753a1a4af202bd99b588e5353e3a4e2f970f134a05f89934380eb4b9800d9570.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nr a n k J _ { 1 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } ) \\geq n _ { 0 } + n .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,641,429,655]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"So $n _ { 1 } = 2 n - r a n$ k $J _ { 1 } ( \\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } ) \\le n _ { 0 }$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,656,794,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For (3.17), when $i = 0$ , the proof is followed by $J _ { 0 } ( \\hat { \\mathbf { x } } _ { 1 } ) = J ( \\hat { \\mathbf { x } } _ { 1 } )$ . For $i \\geq 1$ , from (3.15) and the choice of $R _ { i }$ in each step, we only show the case when $i = 1$ . The others are similar too. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[225,700,540,717]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When $i = 1$ , for $J _ { 1 } ( \\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } )$ , from (3.18), we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[397,719,601,768]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0297/90532118e688d2de2632abc54bd38f15dbee8087b26d6dd76d1ad5ec08bf20d3.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nJ _ { 1 } ( \\hat { \\mathbf { x } } _ { 1 } ) = \\left[ \\begin{array} { c } { J ( \\hat { \\mathbf { x } } _ { 1 } ) } \\\\ { J ( ( J ( \\hat { \\mathbf { x } } _ { 1 } ) \\hat { \\mathbf { x } } _ { 2 } ) , \\hat { \\mathbf { x } } _ { 1 } ) } \\\\ { \\mathbf { 0 } } \\end{array} \\right] .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,772,792,801]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, by choice of $R _ { 1 }$ , we can see that the submatrix obtained by taking columns $n + 1$ to $2 n$ : ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[460,797,537,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0401/a7ffb369219fb86d976379daa0ca9bbf5a5948783a2004dd6d2ea26d80af3296.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\left[ \\begin{array} { c } { \\mathbf { 0 } } \\\\ { J ( \\hat { \\mathbf { x } } _ { 1 } ) } \\\\ { R _ { 1 } } \\end{array} \\right]\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,848,387,862]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is of full column rank $n$ . So ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[352,868,643,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0301/d47ac1284e7e140aac85389452e2d9e62a5aeebb2a5f9973d57168bb196ae2f2.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { 1 } = 2 n - r a n k J _ { 1 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } ) = n - r a n k J _ { 1 } ( \\hat { \\bf x } _ { 1 } ) .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[444,119,553,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,121,214,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,171,794,215]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Remark 3.3. For the points in $V \\backslash U _ { 0 }$ which are geometric singular, we can also apply the deflation process defined in (3.15) to them. Similar to (3.16), with the same reason, we still have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[436,218,562,233]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0070/5a6af1d71e576ff5be4996ffde0c5a2fbc66d8e6ce6d84ed51bbab0eb71a726f.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { i } \\le \\cdots \\le n _ { 1 } \\le n _ { 0 } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,236,508,251]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However, for points in $V \\backslash U _ { 0 }$ , we can see that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[477,257,521,273]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0155/c6077b4996a2363966e42386b2d6fffc88553b5d424167a5cabe931599a5ac70.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { i } < k\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[200,279,794,309]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"can be happen for some $i$ , see Example 3.6 and 3.7. So deflation process provides lower bound of local dimension for them. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,310,794,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From (3.19), we can see that after each deflation step, the addition of new nonzero submatrices to the bottom of the first $n$ columns is the reason that makes the nullities decrease. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,362,794,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. The deflation conjecture. By Theorem 3.2, we can see that the nullity $n _ { i }$ can not be always strictly decreased. It should be stabilized after a finite number of steps. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[200,401,794,431]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Definition 3.4. Suppose that $\\hat { \\mathbf { x } }$ is a solution of $F ( \\mathbf { x } )$ . With notations above, for the deflation process (3.15), let $i _ { 0 } \\geq 0$ be the smallest integer such that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[403,438,593,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0055/45738e70ff968c9f423951cba657ae3c4284a1b38ec99eb7140c3b446c104046.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { i + 1 } = n _ { i } \\qquad { \\mathrm { f o r ~ a l l } } \\quad i \\geq i _ { 0 } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,460,241,474]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Then ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[450,476,545,492]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0688/70727b812b0474630690f19b3616549734a9405ae2693ece7d9efe4747f046ad.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } )\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,494,444,510]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is called the deflation sequence of $\\hat { \\mathbf { x } }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,517,792,547]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Definition 3.5. Let $\\hat { \\mathbf { x } } \\in \\mathbf { V } ( F )$ with local dimension $\\dim _ { \\hat { \\mathbf { x } } } \\mathbf { V } ( F ) = k$ . Let $( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } )$ denote its deflation sequence. If ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[472,549,524,565]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0930/8f0e35e08dcbf55036039153454c92a002c39c2065977740728d0128364c6ec5.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { i _ { 0 } } = k ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,569,794,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"then we say that the deflation sequence $( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } )$ is regular and $\\hat { \\mathbf { x } }$ has a regular deflation process. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,606,794,637]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Example 3.6. Let $F ( x , y ) = y ^ { 2 } - x ^ { 3 }$ with $z _ { 1 } = ( 0 , 0 )$ and $z _ { 2 } = ( 1 , 1 )$ in $\\mathbf { V } ( F )$ . By direct computer verification, the first 4 numbers of their deflation sequences are ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[313,642,681,660]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } ) = ( 2 , 1 , 1 , 0 )$ and $( 1 , 1 , 1 , 1 )$ , respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,665,794,710]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Example 3.7. Let $F ( x , y , z ) = x ^ { 2 } - y ^ { 2 } z$ be the Whitney umbrella. Consider the three points of ${ \\bf V } ( F ) \\colon ( 2 , 2 , 1 ) , ( 0 , 0 , 1 )$ and $( 0 , 0 , 0 )$ . The first 4 numbers of their deflation sequences are: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,712,718,729]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } ) = ( 2 , 2 , 2 , 2 ) , ( 3 , 2 , 1 , 1 )$ and (3, 2, 2, 1), respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,736,794,781]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is proved in [7, 26] that all isolated singular solutions have regular deflation processes. For $k$ -dimensional ultrasingular irreducible components, Zeng’s conjecture in [37, Sect. 9] can be formalised as follows. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,789,794,849]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conjecture 1 (Deflation Conjecture). Let $V \\subseteq \\mathbf { V } ( F )$ be a $k$ -dimensional ultrasingular irreducible component. So there is a nonempty Zariski open set $U \\subseteq V$ which consists of geometric smooth points and a constant number $n _ { 0 }$ such that $\\mathcal { N } ( J ( \\mathbf { x } ) ) = n _ { 0 } > k$ for all $\\mathbf { x } \\in U$ . We have: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[227,853,794,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(1) The recursive deflation process (3.15) terminates in finitely many steps such that the deflation sequences of all $\\mathbf { x } \\in U$ are equal and regular. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[297,119,702,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[779,148,794,160]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"\u0003 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[784,119,794,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[228,146,795,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(2) For the point ${ \\hat { \\mathbf { x } } } \\in V \\backslash U$ with deflation sequence $( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } ) , n _ { i _ { 0 } }$ is a lower bound of its local dimension. That is, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[441,183,555,199]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0992/06a263ad11003c2d0d02e18298050cc0d8547418ef2d04b488fa68be006d5d28.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\dim _ { \\hat { \\mathbf { x } } } \\mathbf { V } ( F ) \\geq n _ { i _ { 0 } } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,205,794,252]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Remark 3.8. In [16], using the results in [2], Hauenstein and Wampler showed that Conjecture 1 holds for their strong deflation. Leykin et al.’s deflation process can also be given a similar conjecture [26], and similarly for other deflation processes in the literatures. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,258,794,335]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Remark 3.9. If Conjecture 1 is true, the number in the deflation sequence provides upper bounds of the local dimensions of geometric smooth points. The last number of the deflation sequence is a lower bound of the local dimensions of the geometric singular points. This leads to the problem of determining the singularity of a solution (see also Section 6.2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,343,794,434]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Remark 3.10. Given a set of solutions of a polynomial system. We usually don’t know the relations between them, such as if they lie on a same irreducible component. So if we apply the deflation process to them, the $R _ { i }$ and $d _ { i }$ defined in (3.15) are chosen separately for each solution. Thus, in practical numerical experiment, if we don’t know the relation between the solutions, the deflation process is the same as the deflation process for isolated solutions in [7, 8]. For example, the solutions of Brent equations studied in Section 5. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[357,448,640,462]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. On realization of the deflation process ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,469,794,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this section, the details of the construction of the Jacobians of the first 3 steps of the deflation process raised in [7, 8] are given. Although they may not be new, we have not seen them in the literatures. We can see that the Jacobians are not hard to be realized numerically. So it is a useful tool for the determination of local dimensions of the algebraic sets. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,545,794,604]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Firstly, we introduce some notations. The original variable $\\mathbf { x } = [ x _ { 1 } , \\cdots , x _ { n } ] ^ { \\mathbf { T } }$ will be denoted by $\\mathbf { X } _ { 1 }$ in accordance with the notation for the auxiliary (vector) variables $\\mathbf { x } _ { 2 } , \\mathbf { x } _ { 3 } , \\ldots$ etc. For any fixed or variable vector $\\mathbf { y } = [ y _ { 1 } , . . . , y _ { n } ] ^ { \\mathbf { T } }$ , the directional differentiation operator along $\\mathbf { y }$ is defined as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[379,603,617,637]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0510/dc335322cc56983e55cb9758a8fee0112eba2507ebd2f04bcb2b72ea85e2e488.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\nabla _ { \\mathbf { y } } = y _ { 1 } { \\frac { \\partial } { \\partial x _ { 1 } } } + y _ { 2 } { \\frac { \\partial } { \\partial x _ { 2 } } } + \\cdots + y _ { n } { \\frac { \\partial } { \\partial x _ { n } } } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,642,632,656]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lemma 4.1. The composite of $\\nabla _ { \\mathbf y }$ and $\\nabla _ { z }$ is commutative, that is, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[454,662,544,679]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0098/9d386f69cdc73f1e1653a4df81030404349159a226e2ef6e3ddb4eae61d2d834.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\nabla _ { y } \\nabla _ { z } = \\nabla _ { z } \\nabla _ { y }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,685,446,707]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Proof. Since $\\begin{array} { r } { \\frac { \\partial ^ { 2 } } { \\partial x _ { i } \\partial x _ { j } } = \\frac { \\partial ^ { 2 } } { \\partial x _ { j } \\partial x _ { i } } } \\end{array}$ , we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[341,710,656,808]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0407/da0350784860eecafaaf59b356ff9bce9ca992119c26dfb6833a3f905d7ea4c4.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n{ \\begin{array} { r l } & { \\nabla _ { \\mathbf { y } } \\nabla _ { \\mathbf { z } } = \\nabla _ { \\mathbf { y } } \\left( z _ { 1 } { \\frac { \\partial } { \\partial x _ { 1 } } } + z _ { 2 } { \\frac { \\partial } { \\partial x _ { 2 } } } + \\cdots + z _ { n } { \\frac { \\partial } { \\partial x _ { n } } } \\right) } \\\\ & { \\qquad = \\displaystyle \\sum _ { i = 1 } ^ { n } \\sum _ { j = 1 } ^ { n } y _ { i } z _ { j } { \\frac { \\partial ^ { 2 } } { \\partial x _ { i } \\partial x _ { j } } } = \\sum _ { i = 1 } ^ { n } \\sum _ { j = 1 } ^ { n } z _ { i } y _ { j } { \\frac { \\partial ^ { 2 } } { \\partial x _ { i } \\partial x _ { j } } } } \\\\ & { \\qquad = \\nabla _ { \\mathbf { z } } \\nabla _ { \\mathbf { y } } . } \\end{array} }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[222,832,669,848]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For any variable $\\mathbf { u } = ( u _ { 1 } , . . . , u _ { n } ) ^ { \\mathbf { T } }$ , the gradient operator is defined by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[406,852,589,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0439/0e8a0b7d393379a08c1fbe9e29c39eb75b4ee158ce08e1921eca35f425a5ad91.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\triangle _ { \\bf u } = \\left[ \\frac { \\partial } { \\partial u _ { 1 } } , \\frac { \\partial } { \\partial u _ { 2 } } , \\cdot \\cdot \\cdot , \\frac { \\partial } { \\partial u _ { n } } \\right] ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[779,810,794,823]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"□ ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,121,214,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[444,119,552,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,145,620,161]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"whose “dot product” with a vector $\\mathbf { v } = [ \\nu _ { 1 } , . . . , \\nu _ { n } ] ^ { \\mathbf { T } }$ is defined as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[369,165,627,196]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0979/fe61f8aefe7b9f1165c503b551336eccba66e1286a6cbf48464fb0d01821fe90.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf { v } \\cdot \\triangle _ { \\mathbf { u } } = \\nu _ { 1 } \\frac { \\partial } { \\partial u _ { 1 } } + \\nu _ { 2 } \\frac { \\partial } { \\partial u _ { 2 } } + \\cdot \\cdot \\cdot + \\nu _ { n } \\frac { \\partial } { \\partial u _ { n } } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,200,423,215]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"So we have $\\nabla _ { \\mathbf y } = \\mathbf y \\cdot { \\boldsymbol \\triangle } _ { \\mathbf x } = \\mathbf y \\cdot { \\boldsymbol \\triangle } _ { { \\mathbf x } _ { 1 } }$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[207,215,794,244]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $J ( \\mathbf { x } )$ be the Jacobian of the polynomial system $F ( \\mathbf { x } ) = [ f _ { 1 } ( \\mathbf { x } ) , f _ { 2 } ( \\mathbf { x } ) , . . . f _ { m } ( \\mathbf { x } ) ] ^ { \\mathrm { { T } } }$ . Then $J ( \\mathbf { x } ) \\mathbf { y }$ can be denoted by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[411,244,588,315]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0945/801ec0b9177a13fa3601c7b1953089bcdbba0f17b5e91db3357fbd14467fab0b.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { J ( \\mathbf { x } ) \\mathbf { y } = \\nabla _ { \\mathbf { y } } F = \\left[ \\begin{array} { c } { \\nabla _ { \\mathbf { y } } f _ { 1 } } \\\\ { \\nabla _ { \\mathbf { y } } f _ { 2 } } \\\\ { \\vdots } \\\\ { \\nabla _ { \\mathbf { y } } f _ { m } } \\end{array} \\right] . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,316,294,332]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Similarly, set ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[419,330,578,401]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0824/af0d27aa382ce59d872a0cf0eb8fc81ffa4011388097a43590432071733e3b6b.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } F = \\left[ \\begin{array} { c } { \\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } f _ { 1 } } \\\\ { \\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } f _ { 2 } } \\\\ { \\vdots } \\\\ { \\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } f _ { m } } \\end{array} \\right] .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[197,404,794,435]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $G ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , . . . , \\mathbf { x } _ { k } ) : \\mathbb { C } ^ { k n } \\mathbb { C } ^ { m }$ be a polynomial system and $G = [ g _ { 1 } , g _ { 2 } , . . . , g _ { m } ] ^ { \\mathbf { T } }$ , its partial Jacobian with respect to some $\\mathbf { x } _ { i } = [ x _ { i 1 } , . . . , x _ { i n } ] ^ { \\mathbf { T } }$ is defined by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[349,439,647,510]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0541/2b1921c7678a88e913bd67293ec4ff1f8d07025ca1de59987aa04a2fb515f30a.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { J ( G , \\mathbf { x } _ { i } ) : = \\left[ { \\begin{array} { c } { \\triangle _ { \\mathbf { x } _ { i } } g _ { 1 } } \\\\ { \\triangle _ { \\mathbf { x } _ { i } } g _ { 2 } } \\\\ { \\vdots } \\\\ { \\triangle _ { \\mathbf { x } _ { i } } g _ { m } } \\end{array} } \\right] = \\left[ { \\begin{array} { c c c } { \\frac { \\partial g _ { 1 } } { \\partial x _ { i 1 } } } & { \\cdot \\cdot \\cdot } & { \\frac { \\partial g _ { 1 } } { \\partial x _ { i n } } } \\\\ { \\vdots } & & { \\vdots } \\\\ { \\frac { \\partial g _ { m } } { \\partial x _ { i 1 } } } & { \\cdot \\cdot \\cdot } & { \\frac { \\partial g _ { m } } { \\partial x _ { i n } } } \\end{array} } \\right] . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[207,512,794,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $J ( J ( \\mathbf { x } ) \\mathbf { v } , \\mathbf { x } )$ be the partial Jacobian of $J ( \\mathbf { x } ) \\mathbf { v }$ with respect to $\\mathbf { X }$ , and similarly for $J ( J ( J ( \\mathbf { x } ) \\mathbf { w } , \\mathbf { x } ) \\mathbf { v } , \\mathbf { x } )$ . Then we have the following lemma. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,551,289,565]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lemma 4.2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[341,563,656,633]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0649/d82fe33819df5ecd6dc980a5c0bfc3ae94cc8488195bef1e51429f21029cc0d3.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { J ( J ( x ) \\nu , x ) \\pmb { u } = \\nabla _ { \\pmb { u } } \\nabla _ { \\nu } F = \\left[ \\begin{array} { c } { \\nabla _ { \\pmb { u } } \\nabla _ { \\nu } f _ { 1 } } \\\\ { \\nabla _ { \\pmb { u } } \\nabla _ { \\nu } f _ { 2 } } \\\\ { \\vdots } \\\\ { \\nabla _ { \\pmb { u } } \\nabla _ { \\nu } f _ { m } } \\end{array} \\right] = \\nabla _ { \\nu } \\nabla _ { \\pmb { u } } F . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[290,637,707,708]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0127/f8a9dbbcb3570b2ff886c225e55d59d9c01f61a7bb378e36455de1821c0b230e.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { J ( J ( J ( \\pmb { x } ) \\pmb { w } , \\pmb { x } ) \\pmb { \\nu } , \\pmb { x } ) \\pmb { u } = \\nabla _ { \\pmb { u } } \\nabla _ { \\pmb { \\nu } } \\nabla _ { \\pmb { w } } F = \\left[ \\begin{array} { c } { \\nabla _ { \\pmb { u } } \\nabla _ { \\pmb { \\nu } } \\nabla _ { \\pmb { w } } f _ { 1 } } \\\\ { \\nabla _ { \\pmb { u } } \\nabla _ { \\pmb { \\nu } } \\nabla _ { \\pmb { w } } f _ { 2 } } \\\\ { \\vdots } \\\\ { \\nabla _ { \\pmb { u } } \\nabla _ { \\pmb { \\nu } } \\nabla _ { \\pmb { w } } f _ { m } } \\end{array} \\right] = \\nabla _ { \\pmb { u } } \\nabla _ { b } \\nabla _ { \\pmb { c } } F , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,709,483,724]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where a, $\\pmb { b }$ , c is any permutation of $\\dot { \\boldsymbol { u } } , \\boldsymbol { \\nu } , \\boldsymbol { w }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,732,714,747]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Proof. The proof is followed by Lemma 4.1. Since for $i = 1 , 2 , . . . , m$ , we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[441,752,557,768]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0067/f80f10585e9f46f982b23cf68ee5dff14bef1c590daa9f207e41e0a52dccf163.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } f _ { i } = \\nabla _ { \\mathbf { v } } \\nabla _ { \\mathbf { u } } f _ { i }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,775,232,787]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[419,789,576,805]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0346/b183bdfeeae608f6d84fffec1687eb76e3a9d6b8533dcee4be93f2037fda3a95.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } \\nabla _ { \\mathbf { w } } f _ { i } = \\nabla _ { \\mathbf { a } } \\nabla _ { \\mathbf { b } } \\nabla _ { \\mathbf { c } } f _ { i } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,808,486,823]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where a, b, c is any permutation of $\\mathbf { u } , \\mathbf { v } , \\mathbf { w }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,830,794,861]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the partial Jacobians of $\\nabla _ { \\mathbf { u } } F ( \\mathbf { x } )$ , $\\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } F ( \\mathbf { x } )$ and $\\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } \\nabla _ { \\mathbf { w } } F ( \\mathbf { x } )$ , we have the following formulas. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,868,498,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lemma 4.3. With notation in (4.1), we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[297,118,702,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[779,809,794,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"\u0003 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[784,119,794,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[230,147,784,208]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(1) $J ( \\nabla _ { \\boldsymbol { \\mathbf { u } } } F ( \\boldsymbol { \\mathbf { x } } ) , \\boldsymbol { \\mathbf { \\nu } } ) = \\boldsymbol { \\mathbf { 0 } } ,$ , \n(2) $J ( \\nabla _ { u } F ( x ) , u ) = J ( x ) ,$ , \n(3) $\\begin{array} { r l } & { J ( \\nabla _ { \\nu } \\nabla _ { u } F ( x ) , u ) = J ( \\nabla _ { u } \\nabla _ { \\nu } F ( x ) , u ) = J ( \\nabla _ { \\nu } F ( x ) , x ) , } \\\\ & { J ( \\nabla _ { \\nu } \\nabla _ { w } \\nabla _ { u } F ( x ) , u ) = J ( \\nabla _ { \\nu } \\nabla _ { u } \\nabla _ { w } F ( x ) , u ) = J ( \\nabla _ { u } \\nabla _ { \\nu } \\nabla _ { w } F ( x ) , u ) = J ( \\nabla _ { \\nu } \\nabla _ { w } F ( x ) , x ) . } \\end{array}$ \n(4) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,218,645,233]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Proof. The proof is followed by direct verification and Lemma 4.2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,250,794,295]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With preparation above, in the following we describe the first 3 steps of the deflation process explicitly. From this, we can obtain the first 4 numbers $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ of the deflation sequence. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[207,295,794,325]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Step 0. Given a polynomial system $F ( \\mathbf { x } ) = [ f _ { 1 } ( \\mathbf { x } ) , f _ { 2 } ( \\mathbf { x } ) , . . . f _ { m } ( \\mathbf { x } ) ] ^ { \\mathbf { T } }$ , whose Jacobian is $J ( \\mathbf { x } )$ . Given a solution $\\hat { \\mathbf { x } } \\in \\mathbf { V } ( F )$ . Then ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[434,337,562,353]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0779/ff0f9c8b84dcf11b327b5330f56a3aa9915692226af37d42d81a37b15be01e64.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { 0 } = n - r a n k J ( \\hat { \\bf x } )\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[202,363,655,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is the nullity which is the first number of the deflation sequence of $\\hat { \\mathbf { x } }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,380,795,424]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Step 1. Let $n _ { 0 }$ and $\\hat { \\mathbf { x } } _ { 1 } = \\hat { \\mathbf { x } }$ be the number and solution in Step 0, respectively. We choose a random matrix $R _ { 1 } \\in \\mathbb { C } ^ { n _ { 0 } \\times n }$ and a random vector $d _ { 1 } \\in \\mathbb { C } ^ { n _ { 0 } }$ . By (3.5), the first deflation of $F ( \\mathbf { x } )$ is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[405,428,591,477]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0966/459358043da0f996b7206c3b45532b5d1213fe883692dafcf6a6f0d4c1b3bd2f.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) = \\left[ \\begin{array} { c } { F ( \\mathbf { x } _ { 1 } ) } \\\\ { J ( \\mathbf { x } _ { 1 } ) \\mathbf { x } _ { 2 } } \\\\ { R _ { 1 } \\mathbf { x } _ { 2 } - d _ { 1 } } \\end{array} \\right] ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,484,325,497]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"whose Jacobian is ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[362,500,633,549]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0088/1f966ee4fa245c622e2594480c2bb5a8fd783fabbbf9bc4cdfe40c058df55edd.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nJ _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) = \\left[ \\begin{array} { c c } { J ( \\mathbf { x } _ { 1 } ) } & { \\mathbf { 0 } } \\\\ { J ( \\nabla _ { \\mathbf { x } _ { 2 } } F ( \\mathbf { x } _ { 1 } ) , \\mathbf { x } _ { 1 } ) } & { J ( \\mathbf { x } _ { 1 } ) } \\\\ { \\mathbf { 0 } } & { R _ { 1 } } \\end{array} \\right] ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,555,465,570]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $J ( \\nabla _ { \\mathbf { x } _ { 2 } } F ( \\mathbf { x } _ { 1 } ) , \\mathbf { x } _ { 1 } ) = J ( J ( \\mathbf { x } _ { 1 } ) \\mathbf { x } _ { 2 } , \\mathbf { x } _ { 1 } )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[210,571,792,599]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fixing $\\hat { \\bf X } _ { 1 }$ , let $\\hat { \\bf x } _ { 2 }$ be the solution of the linear system $F _ { 1 } ( \\hat { \\bf x } _ { 1 } , { \\bf x } _ { 2 } ) = { \\bf 0 }$ (see also (3.4)). Then we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[411,607,584,623]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"1019/a424f165dd33f63daf4803e9231b9981fae96f5807248dcf2fab9db91a368dc7.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { 1 } = 2 n - r a n k J _ { 1 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,631,560,646]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which is the second number of the deflation sequence. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,647,794,693]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Step 2. Let $n _ { 1 }$ and $( \\hat { \\mathbf { x } } _ { 1 } , ~ \\hat { \\mathbf { x } } _ { 2 } )$ be the number and solution in Step 1, respectively. We choose a random matrix $R _ { 2 } \\in \\mathbb { C } ^ { n _ { 1 } \\times 2 n }$ and a random vector $d _ { 2 } \\in \\mathbb { C } ^ { n _ { 1 } }$ . If we continue taking the deflation process on $F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } )$ , then by (3.15) we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[328,702,669,782]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0376/ace18a8c6efc65ab480bb562b4d126b1060ac1516a9a918f380b2efc4df43b9a.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { 2 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , \\mathbf { x } _ { 3 } , \\mathbf { x } _ { 4 } ) = \\left[ \\begin{array} { c } { F _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) } \\\\ { J _ { 1 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } ) \\left[ \\begin{array} { c } { \\mathbf { x } _ { 3 } } \\\\ { \\mathbf { x } _ { 4 } } \\end{array} \\right] } \\\\ { R _ { 2 } \\left[ \\begin{array} { c } { \\mathbf { x } _ { 3 } } \\\\ { \\mathbf { x } _ { 4 } } \\end{array} \\right] - d _ { 2 } } \\end{array} \\right] = \\left[ \\begin{array} { c } { g _ { 1 } } \\\\ { g _ { 2 } } \\\\ { \\vdots } \\\\ { g _ { 7 } } \\end{array} \\right] ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,790,423,805]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and from (4.2) and (4.3) we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[214,813,748,888]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0534/c5ce67ee471946b5e1c61e58666a8dbaadfa06fed741af72308d85ed07f715b2.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l } & { g _ { 1 } = F ( { \\bf x } _ { 1 } ) , g _ { 2 } = J ( { \\bf x } _ { 1 } ) { \\bf x } _ { 2 } = \\nabla _ { { \\bf x } _ { 2 } } F ( { \\bf x } _ { 1 } ) , g _ { 3 } = R _ { 1 } { \\bf x } _ { 2 } - d _ { 1 } , g _ { 4 } = J ( { \\bf x } _ { 1 } ) { \\bf x } _ { 3 } = \\nabla _ { { \\bf x } _ { 3 } } F ( { \\bf x } _ { 1 } ) , } \\\\ & { g _ { 5 } = J ( \\nabla _ { { \\bf x } _ { 2 } } F ( { \\bf x } _ { 1 } ) , { \\bf x } _ { 1 } ) { \\bf x } _ { 3 } + J ( { \\bf x } _ { 1 } ) { \\bf x } _ { 4 } = \\nabla _ { { \\bf x } _ { 3 } } \\nabla _ { { \\bf x } _ { 2 } } F ( { \\bf x } _ { 1 } ) + \\nabla _ { { \\bf x } _ { 4 } } F ( { \\bf x } _ { 1 } ) , } \\\\ & { g _ { 6 } = R _ { 1 } { \\bf x } _ { 4 } , g _ { 7 } = R _ { 2 } \\left[ \\begin{array} { c } { { \\bf x } _ { 3 } } \\\\ { { \\bf x } _ { 4 } } \\end{array} \\right] - d _ { 2 } . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[444,119,552,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,119,218,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[779,220,794,232]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"□ ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[202,146,795,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $J _ { 2 } ( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , { \\bf x } _ { 3 } , { \\bf x } _ { 4 } )$ be the Jacobian of $F _ { 2 } ( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , { \\bf x } _ { 3 } , { \\bf x } _ { 4 } )$ . It consists of $7 \\times 4 = 2 8$ partial Jacobian blocks, which can be seen as follows ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[334,179,663,251]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0799/00adda7095ebe84c6f85fdff82198af5e32f1de54b0c7d30eae1c0913bfb786c.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { J _ { 2 } ( \\mathbf x _ { 1 } , \\mathbf x _ { 2 } , \\mathbf x _ { 3 } , \\mathbf x _ { 4 } ) = \\left[ { \\begin{array} { c c c } { J ( g _ { 1 } , \\mathbf x _ { 1 } ) } & { \\cdots \\cdot } & { J ( g _ { 1 } , \\mathbf x _ { 4 } ) } \\\\ { J ( g _ { 2 } , \\mathbf x _ { 1 } ) } & { \\cdots \\cdot } & { J ( g _ { 2 } , \\mathbf x _ { 4 } ) } \\\\ { \\vdots } & { } & { \\vdots } \\\\ { J ( g _ { 7 } , \\mathbf x _ { 1 } ) } & { \\cdots \\cdot } & { J ( g _ { 7 } , \\mathbf x _ { 4 } ) } \\end{array} } \\right] . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[200,255,792,284]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In (4.6), we only describe the partial Jacobians $J ( g _ { 5 } , \\mathbf { x } _ { 2 } )$ , by Lemma 4.3, which can be calculated as follows ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[334,285,663,343]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0546/f8ec2b847793e70a8dadea13fbcecd625f9da97b02a4e23fe29e2e92290393f7.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l } & { J ( g _ { 5 } , \\mathbf { x } _ { 2 } ) = J \\left( \\nabla _ { \\mathbf { x } _ { 3 } } \\nabla _ { \\mathbf { x } _ { 2 } } F ( \\mathbf { x } _ { 1 } ) , \\mathbf { x } _ { 2 } \\right) + J \\left( \\nabla _ { \\mathbf { x } _ { 4 } } F ( \\mathbf { x } _ { 1 } ) , \\mathbf { x } _ { 2 } \\right) } \\\\ & { \\quad \\quad \\quad = J \\left( \\nabla _ { \\mathbf { x } _ { 2 } } \\nabla _ { \\mathbf { x } _ { 3 } } F ( \\mathbf { x } _ { 1 } ) , \\mathbf { x } _ { 2 } \\right) + \\mathbf { 0 } } \\\\ & { \\quad \\quad \\quad = J \\left( \\nabla _ { \\mathbf { x } _ { 3 } } F ( \\mathbf { x } _ { 1 } ) , \\mathbf { x } _ { 1 } \\right) . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,347,566,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The other partial Jacobians are not hard to be obtained. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,362,794,391]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fixing $\\hat { \\mathbf { X } } _ { 1 } , \\hat { \\mathbf { X } } _ { 2 }$ , let $\\hat { \\mathbf { X } } _ { 3 } , \\hat { \\mathbf { X } } _ { 4 }$ be the solution of the linear system $F _ { 2 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } , { \\bf x } _ { 3 } , { \\bf x } _ { 4 } ) = { \\bf 0 }$ . Then we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[390,392,606,409]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0633/d7f6295ea0ea19949cb9558454511fdf436d54a5c81395f98d681681c3538196.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { 2 } = 4 n - r a n k J _ { 2 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } , \\hat { \\bf x } _ { 3 } , \\hat { \\bf x } _ { 4 } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,410,545,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which is the third number of the deflation sequence. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,426,794,472]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Step 3. Let $n _ { 2 }$ and $( \\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } , \\hat { \\mathbf { x } } _ { 3 } , \\hat { \\mathbf { x } } _ { 4 } )$ be the number and solution in Step 2, respectively. We choose a random matrix $R _ { 3 } \\in \\mathbb { C } ^ { n _ { 2 } \\times 4 n }$ and a random vector $d _ { 3 } \\in \\mathbb { C } ^ { n _ { 2 } }$ . If we continue taking the deflation process on $F _ { 2 } ( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , { \\bf x } _ { 3 } , { \\bf x } _ { 4 } )$ , then by (3.15) we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[303,476,692,613]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0417/2facba96f6f4fdcdb3b250907558fd0c5886d4fc4cba3545c45f192d6cb0ff1d.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { 3 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , . . . , \\mathbf { x } _ { 8 } ) = [ \\begin{array} { c } { F _ { 2 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , \\mathbf { x } _ { 3 } , \\mathbf { x } _ { 4 } ) } \\\\ { [ \\begin{array} { c } { \\mathbf { x } _ { 5 } } \\\\ { J _ { 2 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , \\mathbf { x } _ { 3 } , \\mathbf { x } _ { 4 } ) } \\\\ { \\mathbf { x } _ { 7 } } \\\\ { \\mathbf { x } _ { 8 } } \\end{array} ] } = [ { \\begin{array} { c } { \\mathbf { x } _ { 1 } } \\\\ { \\mathbf { x } _ { 6 } } \\\\ { \\mathbf { x } _ { 7 } } \\\\ { \\vdots } \\\\ { \\mathbf { x } _ { 1 5 } } \\end{array} } ] , \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,617,462,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and from (4.4), (4.5) and (4.6) we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[323,633,669,886]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0964/6a7e14aa1f21fdbedaf3567c8bff7b3876c18f3ad509d6426fcbd25f224c8da2.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l } & { h _ { i } = \\delta _ { i } , \\quad \\mathrm { f o r } \\quad ( 1 - 1 , 2 , . . . , 2 , . } \\\\ & { h _ { i } = V _ { i } , V _ { i } ( \\mathbf { x } _ { 1 } ) , } \\\\ & { h _ { i } = V _ { i } , \\quad \\mathrm { f o r } \\quad ( 1 ) , } \\\\ & { h _ { i } = V _ { i } , \\quad \\mathrm { f o r } \\quad ( \\mathbf { x } _ { 1 } ) + \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) , } \\\\ & { h _ { i } = V _ { i } \\times \\nabla _ { x } , \\quad \\mathrm { f o r } \\quad ( 1 ) , } \\\\ & { h _ { i } = \\nabla _ { x } \\nabla _ { x } , \\quad \\mathrm { f o r } \\quad ( 1 ) + \\nabla _ { x } , \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) + \\nabla _ { x } , \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) , } \\\\ & { h _ { i } = \\nabla _ { x } , \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) + \\nabla _ { x } , \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) , } \\\\ & { \\qquad \\quad + \\nabla _ { x } \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) + \\nabla _ { x } , F ( \\mathbf { x } _ { 1 } ) , } \\\\ & { h _ { i } = R \\times \\nabla _ { x } , \\quad } \\\\ & { h _ { i } = R \\times \\left[ \\begin{array} { l } { \\mathbf { x } _ { 1 } } \\\\ { \\mathbf { x } _ { 2 } } \\\\ { \\mathbf { x } _ { 3 } } \\\\ { \\mathbf { x } _ { 4 } } \\end{array} \\right] } \\\\ & { h _ { i } = R \\times \\left[ \\begin{array} { l } { \\mathbf { x } _ { 1 } } \\\\ { \\mathbf { x } _ { 5 } } \\\\ { \\mathbf { x } _ { 5 } } \\\\ { \\mathbf { x } _ { 5 } } \\\\ { \\mathbf { x } _ { 6 } } \\end{array} \\right] - d _ { 3 } } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[295,118,700,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[779,119,792,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,146,795,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let $J _ { 3 } ( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , . . . , { \\bf x } _ { 8 } )$ be the Jacobian of $F _ { 3 } ( { \\bf x } _ { 1 } , { \\bf x } _ { 2 } , . . . , { \\bf x } _ { 8 } )$ . It consists of $1 5 \\times 8 = 1 2 0$ partial Jacobian blocks, which can be seen as follows ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[330,181,666,255]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0653/57062bdc5aa8f2f9dc836dad49b4d7f7cc5055085d2cc265d0c316eb175076bf.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { J _ { 3 } ( \\mathbf { x } _ { 1 } , \\mathbf { x } _ { 2 } , . . . , \\mathbf { x } _ { 8 } ) = \\left[ { \\begin{array} { c c c } { J ( h _ { 1 } , \\mathbf { x } _ { 1 } ) } & { \\cdot \\cdot \\cdot } & { J ( h _ { 1 } , \\mathbf { x } _ { 8 } ) } \\\\ { J ( h _ { 2 } , \\mathbf { x } _ { 1 } ) } & { \\cdot \\cdot \\cdot } & { J ( h _ { 2 } , \\mathbf { x } _ { 8 } ) } \\\\ { \\vdots } & { } & { \\vdots } \\\\ { J ( h _ { 1 5 } , \\mathbf { x } _ { 1 } ) } & { \\cdot \\cdot \\cdot } & { J ( h _ { 1 5 } , \\mathbf { x } _ { 8 } ) } \\end{array} } \\right] . } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[209,261,794,290]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In (4.10), we only describe the partial Jacobians $J ( h _ { 1 2 } , { \\bf x } _ { 2 } )$ and $J ( h _ { 1 2 } , { \\bf x } _ { 3 } )$ . By Lemma 4.3 we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[310,292,687,332]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0466/70d9c1fc50fd8124a79269ff1020365afd39d43b1533085aa3213a4a79d12425.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l } & { J ( h _ { 1 2 } , { \\mathbf x } _ { 2 } ) = J \\left( \\nabla _ { { \\mathbf x } _ { 5 } } \\nabla _ { { \\mathbf x } _ { 3 } } \\nabla _ { { \\mathbf x } _ { 2 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 2 } \\right) + J \\left( \\nabla _ { { \\mathbf x } _ { 7 } } \\nabla _ { { \\mathbf x } _ { 2 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 2 } \\right) } \\\\ & { \\quad \\quad \\quad = J \\left( \\nabla _ { { \\mathbf x } _ { 5 } } \\nabla _ { { \\mathbf x } _ { 3 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 1 } \\right) + J \\left( \\nabla _ { { \\mathbf x } _ { 7 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 1 } \\right) , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,338,232,352]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[310,356,687,395]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0564/642d486600bfc59e6f3a678fe3f85f1bbf80b7e2d9517d83a910162590cfedad.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l } & { J ( h _ { 1 2 } , { \\mathbf x } _ { 3 } ) = J \\left( \\nabla _ { { \\mathbf x } _ { 5 } } \\nabla _ { { \\mathbf x } _ { 3 } } \\nabla _ { { \\mathbf x } _ { 2 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 3 } \\right) + J \\left( \\nabla _ { { \\mathbf x } _ { 6 } } \\nabla _ { { \\mathbf x } _ { 3 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 3 } \\right) } \\\\ & { \\quad \\quad \\quad = J \\left( \\nabla _ { { \\mathbf x } _ { 5 } } \\nabla _ { { \\mathbf x } _ { 2 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 1 } \\right) + J \\left( \\nabla _ { { \\mathbf x } _ { 6 } } F ( { \\mathbf x } _ { 1 } ) , { \\mathbf x } _ { 1 } \\right) } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[223,400,700,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fixing $\\hat { \\mathbf { x } } _ { 1 } , \\hat { \\mathbf { x } } _ { 2 } , \\hat { \\mathbf { x } } _ { 3 } , \\hat { \\mathbf { x } } _ { 4 }$ , let $\\hat { \\mathbf { x } } _ { 5 } , \\hat { \\mathbf { x } } _ { 6 } , \\hat { \\mathbf { x } } _ { 7 } , \\hat { \\mathbf { x } } _ { 8 }$ be the solution of the linear system ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[383,424,612,440]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0971/be3a9b3f42a05c420d457ce981b20e3a3ebf288843610cca604486055b6af6ce.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nF _ { 3 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } , \\hat { \\bf x } _ { 3 } , \\hat { \\bf x } _ { 4 } , { \\bf x } _ { 5 } , { \\bf x } _ { 6 } , { \\bf x } _ { 7 } , { \\bf x } _ { 8 } ) = { \\bf 0 } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,448,299,462]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Then we have ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[392,465,604,482]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0531/51abc5b181aa09e6168a403e465dc53609f40bd4e1e6eb4609fabc062bfa6020.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nn _ { 3 } = 8 n - r a n k J _ { 3 } ( \\hat { \\bf x } _ { 1 } , \\hat { \\bf x } _ { 2 } , . . . , \\hat { \\bf x } _ { 8 } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,487,557,502]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which is the fourth number of the deflation sequence. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[218,502,718,518]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the polynomial system $F = [ f _ { 1 } , f _ { 2 } , . . . f _ { m } ] ^ { \\mathrm { T } }$ , the degree of $F$ is defined by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[382,525,614,541]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0215/6bbecf17a2046ff92832362535f445265d85e5ef6d532d243fe4a8d859706bc0.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nD e g F = \\operatorname* { m a x } \\{ D e g f _ { i } | i = 1 , 2 , . . . m \\} ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,549,794,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $D e g \\ f _ { i }$ are the degrees of the polynomials $f _ { i }$ . So from above analysis, we have the following proposition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,589,792,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Proposition 4.4. If Deg $F = 3$ , in the deflation process (3.15), the Jacobians $J _ { i } ( { \\pmb x } _ { 1 } , . . . , { \\pmb x } _ { 2 ^ { i } } )$ are builded up by $R _ { i }$ and the following partial Jacobians ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[379,628,617,643]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0915/a57f33c8c6de7d074ca85495c9c4becee4f626a1b6f7630579ea79cb7d0b514a.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nJ ( x ) , J ( \\nabla _ { u } F ( x ) , x ) , J ( \\nabla _ { u } \\nabla _ { \\nu } F ( x ) , x ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,651,578,667]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\pmb { u }$ , v are (partial) solutions of the extended system. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[200,676,794,707]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Proof. Since Deg $F = 3$ , we can see that $J ( \\nabla _ { \\mathbf { u } } \\nabla _ { \\mathbf { v } } \\nabla _ { \\mathbf { w } } F ( \\mathbf { x } ) , \\mathbf { x } ) = \\mathbf { 0 }$ , for any solutions u, v, w of the extended system. \u0003 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,719,795,750]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The degree of the polynomial systems obtained by tensor decompositions of tensors of order 3 are all of degree 3, such as the Brent equations in next section. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[346,770,653,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5. Numerical experiments on Brent equations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,791,794,838]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Firstly, we recall the definition of Brent equations (see also [28]). Let $V _ { 1 } ~ = ~ \\mathbb { C } ^ { m \\times n }$ , $V _ { 2 } = \\mathbb { C } ^ { n \\times p }$ and $V _ { 3 } = \\mathbb { C } ^ { p \\times m }$ denote the set of complex $m \\times n , n \\times p$ and $p \\times m$ matrices, respectively. The matrix multiplication tensor is defined by (see e.g. [5, 24]) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[302,843,694,886]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0541/da3cbb4bfbfd3f30db7af38a6687a0e3b022152beafae7f10f983b948025f038.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\left. m , n , p \\right. = \\sum _ { i = 1 } ^ { m } \\sum _ { j = 1 } ^ { n } \\sum _ { k = 1 } ^ { p } e _ { i j } \\otimes e _ { j k } \\otimes e _ { k i } \\in \\mathbb { C } ^ { m \\times n } \\otimes \\mathbb { C } ^ { n \\times p } \\otimes \\mathbb { C } ^ { p \\times m } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[444,119,552,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,119,218,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[204,146,795,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $e _ { i j }$ denotes the matrix with a 1 in the ith row and jth column, and other entries are 0. Finding a tensor decomposition of $\\langle m , n , p \\rangle$ with rank $r$ is equivalent to find solutions of a system of polynomial equations called the Brent equations, which is given as follows: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[380,196,616,237]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0797/955b53ff5149277cd01b7d6fc483b675941b677d29c6bba2f1c84b662b84e1e2.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\sum _ { i = 1 } ^ { r } \\alpha _ { i _ { 1 } , i _ { 2 } } ^ { ( i ) } \\beta _ { j _ { 1 } , j _ { 2 } } ^ { ( i ) } \\gamma _ { k _ { 1 } , k _ { 2 } } ^ { ( i ) } = \\delta _ { i _ { 2 } , j _ { 1 } } \\delta _ { j _ { 2 } , k _ { 1 } } \\delta _ { k _ { 2 } , i _ { 1 } } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[207,241,790,275]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $ \\mathbf { \\mu } _ { , i _ { 1 } } \\in \\{ 1 , 2 , . . . , m \\} , ~ i _ { 2 } , ~ j _ { 1 } \\in \\{ 1 , 2 , . . . , n \\} , ~ j _ { 2 } , k _ { 1 } \\in \\{ 1 , 2 , . . . , p \\} , ~ \\delta _ { i j } \\ : \\mathbf { i } _ { 1 }$ s the Kronecker symbol, $\\alpha _ { i _ { 1 } , i _ { 2 } } ^ { ( i ) } , \\beta _ { j _ { 1 } , j _ { 2 } } ^ { ( i ) }$ and $\\gamma _ { k _ { 1 } , k _ { 2 } } ^ { ( i ) }$ are unknown variables. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,275,794,335]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the following, the polynomial system in (5.2) is called the Brent equations of type $[ m , n , p | r ]$ , which is denoted by $B ( m , n , p | r )$ . We can see that the polynomial system $B ( m , n , p | r )$ has $( m n + n p + p m ) r$ variables and $( m n p ) ^ { 2 }$ equations. So $B ( m , n , p | r )$ can be considered as a polynomial mapping: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[377,340,620,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0345/8074a01783d2e81d166a4c352a4dcd694b76503a7b3de450ba124b28fce6cf96.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nB ( m , n , p | r ) \\colon \\mathbb { C } ^ { ( m n + n p + p m ) r } \\to \\mathbb { C } ^ { ( m n p ) ^ { 2 } } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[200,366,805,396]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Usually, $B ( m , n , p | r )$ is an overdetermined polynomial system. The solution set of $B ( m , n , p | r )$ over $\\mathbb { C }$ is denoted by $\\mathbf { V } ( m , n , p | r )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,397,795,505]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the convenience of coding, an order can be given for the variables in (5.2). For example, for $i = 1 , 2 , . . . r$ let $A _ { i } = \\bar { \\left( \\alpha _ { i _ { 1 } , i _ { 2 } } ^ { ( i ) } \\right) } \\in \\mathbb { C } ^ { m \\times n }$ , $B _ { i } = \\big ( \\beta _ { j _ { 1 } , j _ { 2 } } ^ { ( i ) } \\big ) \\in \\mathbb { C } ^ { n \\times p }$ \u0011 ∈ Cn×p and Ci = \u0010γ(i)k1 ,k2 \u0011 $\\mathbb { C } ^ { n \\times p }$ . For any matrix in $\\mathbb { C } ^ { a \\times b }$ , define the columnwise vectorization map $C \\colon \\mathbb { C } ^ { a \\times b } \\mathbb { C } ^ { a b \\times 1 }$ by concatenating the columns of the matrix in $\\mathbb { C } ^ { a \\times b }$ as a column vector of $\\mathbb { C } ^ { a b \\times 1 }$ (or $\\mathbb { C } ^ { a b }$ ). For example, let $\\boldsymbol { a } = \\left[ \\begin{array} { l l } { a _ { 1 1 } } & { a _ { 1 2 } } \\\\ { a _ { 2 1 } } & { a _ { 2 2 } } \\end{array} \\right] \\in \\mathbb { C } ^ { 2 \\times 2 }$ , then $C ( { \\boldsymbol { a } } ) = [ a _ { 1 1 } , a _ { 2 1 } , a _ { 1 2 } , a _ { 2 2 } ] ^ { \\mathbf { T } } \\in \\mathbb { C } ^ { 4 }$ . For $i = 1 , 2 , . . . r$ , let ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[403,503,593,553]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0585/baecd1fda12865cd4b6ad460d0c4c6584c99ca8778f3c0bc727e2f8dede515c0.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf { x } _ { i } = \\left[ \\begin{array} { c } { C ( A _ { i } ) } \\\\ { C ( B _ { i } ) } \\\\ { C ( C _ { i } ) } \\end{array} \\right] \\in \\mathbb { C } ^ { m n + n p + p m } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[205,555,488,569]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Then we can order the variables in (5.2) by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[410,577,588,631]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0733/1da1febf7a727083c6e76ddfb0d2b4236f22290ba0f5c4b2bf62a9c05bfc2d69.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\mathbf { x } = \\left[ \\begin{array} { c } { \\mathbf { x } _ { 1 } } \\\\ { \\vdots } \\\\ { \\mathbf { x } _ { r } } \\end{array} \\right] \\in \\mathbb { C } ^ { ( m n + n p + p m ) r } .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,637,794,683]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the following of this section, we report our experimental results. By Theorem 3.2 and Remark 3.3, the deflation sequence tells us the bound of the local dimension. We can see that the as $r$ in (5.2) decreases, singular solutions become more and more. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,694,633,709]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.1. Deflation test on $\\mathbf { V } ( 2 , 2 , 2 | 7 )$ : Strassen’s classical solution. ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[204,710,795,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For $B ( 2 , 2 , 2 | 7 )$ , it is an underdetermined system which has $m = 6 4$ equations and $n = 8 4$ variables. So from equation (3) of [36], we know that for any $p \\in \\mathbf { V } ( 2 , 2 , 2 | 7 )$ , its local dimension has a lower bound ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[357,762,638,779]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0256/f7d9f26527013ae1f1fd45f6b5aad5ec34d5c1fcc43ef02c3b0279caba7fed0f.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n2 0 = 8 4 - 6 4 = n - m \\leq \\mathrm { d i m } _ { p } \\mathbf { V } ( 2 , 2 , 2 | 7 ) .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[204,784,797,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In particular, for the classical solution of $B ( 2 , 2 , 2 | 7 )$ given by Strassen [34] (see also [5, 24]), after doing deflation 3 times, the first 4 numbers of deflation sequence are ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,844,709,861]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"So its local dimension should be 23. Moreover, $\\mathrm { d i m } { \\bf V } ( 2 , 2 , 2 | 7 )$ should be 23. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,867,717,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Remark 5.1. It was proved in [10] that $\\mathbf { V } ( 2 , 2 , 2 | 7 )$ has projective dimension 9. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[297,118,702,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[779,119,792,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,147,442,161]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.2. Deflation test on $\\mathbf { V } ( 3 , 3 , 3 | 2 3 )$ . ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[204,162,812,252]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the website [17], using SAT solvers Heule et al. provided 17376 solutions in $\\mathbf { V } ( 3 , 3 , 3 | 2 3 )$ which are inequivalent under the de Groote group action [5, 9]. We take deflation test on these solutions. We found that most of these solutions are ultrasingular. Let $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ be the first 4 numbers of the deflation sequence. Overall, from the experimental result, we can see that $7 6 \\leq n _ { 0 } \\leq 9 5$ (see also [28, Sect. 3]). After doing deflation 3 times, we can see that $7 0 \\leq n _ { 3 } \\leq 8 6$ . The data can be found on [29]. The results are summarized below. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,260,795,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.2.1. The first step of deflation. Among the 17376 solutions, after doing the first step of deflation, there are 16511 solutions whose nullities of Jacobians are strictly decreased, that is, $n _ { 0 } > n _ { 1 }$ . Let $d _ { 1 } = n _ { 0 } - n _ { 1 }$ . Then the numerical experiment tells us that $0 \\leq d _ { 1 } \\leq 2 3$ . The distribution is as follows. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[227,332,769,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0889/8d953cce634d073654a6c6eda0a05c5887f126911062c6bf7669d823853ebea9.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":"<table><tr><td rowspan=1 colspan=1>d =no-n1</td><td rowspan=1 colspan=1>d1=0</td><td rowspan=1 colspan=1>d=01≤d≤3</td><td rowspan=1 colspan=1>4≤d≤10</td><td rowspan=1 colspan=1>11≤d ≤23</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>865</td><td rowspan=1 colspan=1>5495</td><td rowspan=1 colspan=1>9375</td><td rowspan=1 colspan=1>1641</td><td rowspan=1 colspan=1>17376</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[202,392,795,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.2.2. The second step of deflation. After doing the second step of deflation, there are 16206 solutions whose nullities of Jacobians are strictly decreased, that is, $n _ { 1 } > n _ { 2 }$ . Let $d _ { 2 } = n _ { 1 } - n _ { 2 }$ . Then the numerical experiment tells us that $0 \\leq d _ { 2 } \\leq 1 0$ . The distribution is as follows. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[276,464,718,498]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0959/dc8e859db3bcf62b99f2f92cf6e216c847478217227940949054db7a025c9f80.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":"<table><tr><td rowspan=1 colspan=1>d =n1-n2</td><td rowspan=1 colspan=1>d=0</td><td rowspan=1 colspan=1>1≤d≤3</td><td rowspan=1 colspan=1>4≤d≤10</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>1168</td><td rowspan=1 colspan=1>14732</td><td rowspan=1 colspan=1>1476</td><td rowspan=1 colspan=1>17376</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[204,525,795,616]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.2.3. The third step of deflation. In this step, there are only 978 solutions whose nullities of Jacobians are strictly decreased, that is, $n _ { 2 } > n _ { 3 }$ . Let $d _ { 3 } = n _ { 2 } - n _ { 3 }$ . Then the numerical experiment tells us that $0 \\leq d _ { 3 } \\leq 5$ . By Theorem 3.2, we know that $n _ { 2 } \\geq n _ { 3 }$ . However, due to the test is numerical, some errors appear for 41 solutions, that is, $n _ { 2 } - n _ { 3 } < 0$ . On the other hand, if we restart the deflation process separately for these solutions, we can find that $n _ { 2 } \\geq n _ { 3 }$ . The distribution can be seen as follows. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[240,628,754,662]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0828/5b85a76ca6df5a58d485752c7998f81093d752dcdf553631532bb7cc4c3be6da.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":"<table><tr><td rowspan=1 colspan=1>d =n-n3</td><td rowspan=1 colspan=1>d=0</td><td rowspan=1 colspan=1>d=1</td><td rowspan=1 colspan=1>d=12≤d≤5</td><td rowspan=1 colspan=1>Error (d <0)</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>16357</td><td rowspan=1 colspan=1>795</td><td rowspan=1 colspan=1>183</td><td rowspan=1 colspan=1>41</td><td rowspan=1 colspan=1>17376</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[205,679,795,724]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The first 4 numbers of deflation sequence of Laderman’s solution [23] are (76,76,76,76). The first 4 numbers of deflation sequence of Smirnov’s solution [33] in $\\mathbf { V } ( 3 , 3 , 3 | 2 3 )$ are (87,82,79,79). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,733,442,747]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.3. Deflation test on $\\mathbf { V } ( 4 , 4 , 4 | 4 9 )$ . ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[204,748,794,792]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In [13, 14], Fawzi et al. provided 14236 solutions in $\\mathbf { V } ( 4 , 4 , 4 | 4 9 )$ , which are inequivalent under the isotopy group action. We take deflation on these points and find that the ultrasingular solutions are relatively small among all the 14236 solutions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,794,794,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Note that $B ( 4 , 4 , 4 | 4 9 )$ has 2352 variables and 4096 equations. For each solution, it takes about 10 minutes for the computation of $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ . It will spend a lot of time if we take the first 3 steps of deflation for all 14236 solutions. On the other hand, the time for the computation of $( n _ { 0 } , n _ { 1 } )$ is relatively acceptable. So we firstly take the first step of deflation on Fawzi et al.’s solutions and obtain $( n _ { 0 } , n _ { 1 } )$ of the 14236 solutions, the data can be found on [29]. The distribution is summarized as follows. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[444,119,552,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,121,218,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[323,143,673,178]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0823/91a2a313f4d521082a62a17bbec4d9cd795a44da9cbab1f0031878cc1686421f.jpg","list_items":null,"page_idx":"14","sub_type":null,"table_body":"<table><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1>n=no=197</td><td rowspan=1 colspan=1>no >n1</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>13530</td><td rowspan=1 colspan=1>706</td><td rowspan=1 colspan=1>14236</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[204,198,797,272]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Secondly, from above table, for the 13530 solutions whose $n _ { 0 } = n _ { 1 } = 1 9 7$ , we randomly choose 100 solutions and take the second and third deflation steps to obtain $( n _ { 2 } , n _ { 3 } )$ . For all the 100 solutions, we find that $n _ { 2 } = n _ { 3 } = 1 9 7$ , so the first 4 numbers of their deflation sequences are all equal to: (197,197,197,197). So this implies that for all 13530 solutions we should have $n _ { 0 } = n _ { 1 } = n _ { 2 } = n _ { 3 } = 1 9 7$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,273,813,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the remaining 706 solutions, their first 4 numbers of deflation sequences $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ are computed. We found that: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[232,306,493,352]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(1) $1 5 1 \\leq n _ { 0 } \\leq 2 0 8$ ; \n(2) $1 4 5 \\le n _ { 3 } \\le 1 8 2$ ; \n(3) for most solutions we have $n _ { 2 } = n _ { 3 }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,361,547,375]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.4. Deflation test on other well-known solutions. ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[204,376,795,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Firstly, the first 4 numbers of deflation sequence Smirnov’s solution [33] that lies in $\\mathbf { V } ( 3 , 3 , 6 | 4 0 )$ are: (131, 131, 131, 131). So it seems that this solution is semiregular. Recently, Kauers and Moosbauer found many new solutions of $B ( m , n , p | r )$ and put them on Github [20, 21]. We take deflation process for some solutions that are suitable to the complex field. The first 4 numbers of deflation sequence are summarized in Table 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[383,464,614,542]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0058/56ac8a66a750f83f465453d0e7b0f9b6d643ef61dcf8d0ae0e6b187daa21a103.jpg","list_items":null,"page_idx":"14","sub_type":null,"table_body":"<table><tr><td rowspan=1 colspan=1>(m,n,plr)</td><td rowspan=1 colspan=1>(no,ni,n2,n3)</td></tr><tr><td rowspan=1 colspan=1>(3,4,5|47)</td><td rowspan=1 colspan=1>(152,149,148,148)</td></tr><tr><td rowspan=1 colspan=1>(4,4,5|62)</td><td rowspan=1 colspan=1>(201,194,193,193)</td></tr><tr><td rowspan=1 colspan=1>(4,5,5|76)</td><td rowspan=1 colspan=1>(251,251,251,251)</td></tr><tr><td rowspan=1 colspan=1>(5,5,5|97)</td><td rowspan=1 colspan=1>(395,344,339,339)</td></tr></table>","table_caption":"[]","table_footnote":"[\"Table 1. Deflation sequences for some solutions in [20, 21] \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[205,569,823,614]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Table 1, $( m , n , p | r )$ means the solution lie in the set $\\mathbf { V } ( m , n , p | r )$ , which can be found in the Github database of the article [20, 21]. In particular, the computation of (395, 344, 339, 339) for (5, 5, 5|97) spends the time about 4.8 hours on our server. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,623,491,637]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.5. Deflation test on natural algorithms. ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,638,795,698]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When $r = m n p$ , the definition of $\\langle m , n , p \\rangle$ in (5.1) provides a solution of $B ( m , n , p | m n p )$ which is denoted by $N ( m , n , p )$ . Before Strassen’s algorithm [34], we usually use the algorithm induced in (5.1) for the computation of matrix multiplication. So we call $N ( m , n , p )$ the natural algorithm. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,699,794,758]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Intuitively, $N ( m , n , p )$ should be semiregular. So we should have $n _ { 0 } = n _ { 1 } = n _ { 2 } = n _ { 3 }$ for their deflation sequences. When $2 \\leq m , n , p \\leq 4$ , our experimental results are summarized in Table 2. In Table 2, it is interesting to see that there is a big drop between $n _ { 1 }$ and $n _ { 2 }$ . It tells us that the natural algorithms are geometric singular. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[379,772,617,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6. final remarks and open problems ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[204,792,794,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6.1. The deflation sequence as an invariant. In [28, Quest. 3.15], we observed that the rank of Jacobian of $B ( m , n , p | r )$ may be served as an invariant to decide the equivalent classes under the de Groote group action [5, 9]. Further discussions of de Groote group action can be seen from [18, 24, 35], etc. In this paper, from the numerical experiment, we also find that the deflation sequences are unchanged when the solutions are transformed by the de Groote group action. So we have the following question. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[299,119,704,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[779,121,792,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[390,143,607,270]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0477/e1842f38b4c3c7610040d77191bf3e489f754368b63e925fe435db0b5074f14b.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":"<table><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1>(no,ni,n2,n3)</td></tr><tr><td rowspan=1 colspan=1>N(2,2,2)</td><td rowspan=1 colspan=1>(40,40,32,22)</td></tr><tr><td rowspan=1 colspan=1>N(2,2,3)</td><td rowspan=1 colspan=1>(72,72,48,34)</td></tr><tr><td rowspan=1 colspan=1>N(2,3,3)</td><td rowspan=1 colspan=1>(126,126,54,50)</td></tr><tr><td rowspan=1 colspan=1>N(3,3,3)</td><td rowspan=1 colspan=1>(216,216,72,72)</td></tr><tr><td rowspan=1 colspan=1>N(3,3,4)</td><td rowspan=1 colspan=1>(324,324,96,96)</td></tr><tr><td rowspan=1 colspan=1>N(3,4,4)</td><td rowspan=1 colspan=1>(480,480,126,126)</td></tr><tr><td rowspan=1 colspan=1>N(4,4,4)</td><td rowspan=1 colspan=1>(704,704,164,164)</td></tr></table>","table_caption":"[]","table_footnote":"[\"Table 2. Deflation sequences for natural algorithms \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[204,300,795,329]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Question 6.1. For two points in $\\mathbf { V } ( m , n , p | r )$ , if their deflation sequences are different, do they also lie in different group orbits under the de Groote group action? ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,337,794,398]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the deflation sequence $( n _ { 0 } , n _ { 1 } , . . . ) , n _ { 0 }$ is the nullity of Jacobian. So the deflation sequence contains more information and is more useful to distinguish the equivalent classes. For the solutions in [17], in our numerical experiment, it is easy to find two deflation sequences $( n _ { 0 } , n _ { 1 } , . . . )$ and $( n _ { 0 } ^ { \\prime } , n _ { 1 } ^ { \\prime } , . . . )$ such that $n _ { 0 } = n _ { 0 } ^ { \\prime }$ but $n _ { 1 } \\neq n _ { 1 } ^ { \\prime }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,398,792,457]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However, for the solutions provied in [14], almost all solutions have the deflation sequence:(197,197,197,197). So in this case, distinguishing equivalent classes by deflation sequences is not so effective. On the other hand, this implies that the tensor rank of h4, 4, 4i should be less than 49. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,465,792,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6.2. Deciding the singularity of a solution. Given a polynomial system and a solution. Which type of the solution belongs to: numerical smooth/singular or geometric smooth/singular? The deflation sequence only tells us partial information about the type. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[204,518,794,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6.3. The real deflation process. By now, the deflation processes in [7, 8, 16, 26] are given for the complex algebraic set. In practical, the polynomial system we are interested is often of real coefficients and has real solutions. For example, the Brent equations are of this type. Is the results in [7, 8, 16, 26] also suitable to the real algebraic set? For example, it is not hard to see that Conjecture 1 also has a real counterpart. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,602,794,678]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6.4. On local real dimension and local complex dimension. From the relation between fast matrix algorithms and solutions of the Brent equations [5, 18], we can see that integer, rational and real solutions are more useful than complex solutions. For real solutions of the Brent equation, we want to know the difference between the local real dimension and local complex dimension. Related discussions are given in the paper [15]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,684,794,744]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6.5. On the numerical determination of local dimension. On how to determine the local dimension, Kuo and Li provided a numerical method in [22]. In addition, in the neighbourhood of the solution, the convergence behavior under the rank- $r$ projection iteration in [37] can also help us identify the local dimension of the solution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[436,756,560,770]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[205,777,815,838]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Xin Li is supported by National Natural Science Foundation of China (Grant No.11801506). Liping Zhang is supported by the Zhejiang Provincial Natural Science Foundation of China (Grant No. LY21A010015) and Grant 11601484, the National Natural Science Foundation, People’s Republic of China. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[202,839,794,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The discussion with Professor Zhonggang Zeng of Northeastern Illinois University inspired us a lot. We are grateful to him for so many valuable comments and suggestions. We are grateful to Yuan Feng, Xiaodong Ding, Liaoyuan Zeng, Changfeng Ma and Jinyan ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,121,218,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[444,119,552,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[205,147,794,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fan for their kind supports and suggestions. Many thanks to Professor Petr Tichavsk ´y for many helpful discussions when we prepare this paper. Xin Li show his appreciation to Yaqiong Zhang for her support and patience. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[460,220,535,233]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[204,234,794,886]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. D. J. Bates, Jonathan D. Hauenstein, C. Peterson, Andrew J. Sommese, A numerical local dimensions test for points on the solution set of a system of polynomial equations SIAM J. Numer. Anal. 47(2009), no.5, 3608-3623. \n2. D.J. Bates, J.D. Hauenstein, C. Peterson, A.J. Sommese, Numerical decomposition of the rank-deficiency set of a matrix of multivariate polynomials, in: L. Robbiano, J. Abbott (Eds.), Approximate Commutative Algebra, Springer Vienna, Vienna, 2010, pp. 55-77. \n3. D. J. Bates, J. D. Hauenstein, A. J. Sommese, and C. W. Wampler, Numerically solving polynomial systems with Bertini, Software, Environments, and Tools, vol. 25, Society for Industrial and Applied Mathematics (SIAM), Philadelphia, PA, 2013. \n4. D. J. Bates, D. Eklund, J. D. Hauenstein, and C. Peterson. Excess intersections and numerical irreducible decompositions. In 2021 23rd International Symposium on Symbolic and Numeric Algorithms for Scientific Computing (SYNASC), pages 52-60, 2021. \n5. Vladimir P. Burichenko, Symmetries of matrix multiplication algorithms I, arXiv:1508.01110, 2015. \n6. David A. Cox, J. Little, D. O’Shea, Ideals, varieties, and algorithms. Fourth edition. Undergraduate Texts in Mathematics. Springer, 2015. \n7. Barry H. Dayton, Zhonggang Zeng, Computing the multiplicity structure in solving polynomial systems. ISSAC’05, 116-123, ACM, New York, 2005. \n8. Barry H. Dayton, Tien-Yien Li, Zhonggang Zeng, Multiple zeros of nonlinear systems. Math. Comp. 80(2011), no.276, 2143-2168. \n9. H.F. de Groote, On varieties of optimal algorithms for the computation of bilinear mappings. I. The isotropy group of a bilinear mapping, Theor. Comput. Sci. 7(1978), 1-24. \n10. H.F. de Groote, On varieties of optimal algorithms for the computation of bilinear mappings. II. Optimal algorithms for $2 \\times 2$ matrix multiplication, Theor. Comput. Sci. 7(1978), 127-148. \n11. W. Decker, F. O. Schreyer, Varieties, Gr ¨obner Bases, and Algebraic Curves. To appear. 2007. \n12. V. de Silva, L.-H. Lim, Tensor rank and the ill-posedness of the best low-rank approximation problem. SIAM J. Matrix Anal. Appl. 30(2008), no.3, 1084-1127. \n13. A. Fawzi et al. Discovering faster matrix multiplication algorithms with reinforcement learning. Nature, 610:47-53, 2022. \n14. A. Fawzi et al. Discovering faster matrix multiplication algorithms with reinforcement learning. Github: https://github.com/deepmind/alphatensor/, 2022. \n15. K. Harris, Jonathan D. Hauenstein, Agnes Szanto, Smooth points on semi-algebraic sets. J. Symbolic Comput. 116(2023), 183-212. \n16. Jonathan D. Hauenstein, Charles W. Wampler Isosingular sets and deflation. Found. Comput. Math. 13(2013), no.3, 371-403. \n17. Marijn J. H. Heule, M. Kauers, M. Seidl, Matrix multiplication repository. http://www.algebra.uni-linz.ac.at/research/matrix-multiplication/. Accessed: 2019- 04-26. \n18. Marijn J. H. Heule, M. Kauers, M. Seidl, New ways to multiply $3 \\times 3$ -matrices, J. Symbolic Comput. 104(2021), 899-916. \n19. Christopher J. Hillar, Lek-Heng Lim, Most tensor problems are NP-hard. J. ACM 60(2013), no.6, Art.45, 39pp. \n20. M. Kauers, J. Moosbauer, Flip Graphs for Matrix Multiplication, ISSAC’23: 381-388, ACM, Tromso, Norway, 2023. \n21. M. Kauers, J. Moosbauer, Some New Non-Commutative Matrix Multiplication Algorithms of Size $( n , m , 6 )$ , arXiv:2306.00882v1, 2023. https://github.com/jakobmoosbauer/flips \n22. Y. C. Kuo, T. Y. Li, Determining dimension of the solution component that contains a computed zero of a polynomial system, J. Math. Anal. Appl. 338(2008), no.2, 840-851. \n23. Julian D. Laderman, A noncommutative algorithm for multiplying $3 \\times 3$ matrices using 23 multiplications. Bull. Amer. Math. Soc. 82(1976), no.1, 126-128. \n24. J. M. Landsberg, Geometry and complexity theory. Cambridge Studies in Advanced Mathematics, 169. Cambridge University Press, Cambridge, 2017. \n25. P. Lairez, M. Safey El Din, Computing the dimension of real algebraic sets. ISSAC’21, 257-264, ACM, New York. \n26. Anton Leykin, Jan Verschelde, Ailing Zhao, Newton’s method with deflation for isolated singularities of polynomial systems. Theoret. Comput. Sci. 359(2006), no.1-3, 111-122. \n27. A. D. Lewis, Semicontinuity of rank and nullity and some consequences, https://mast.queensu.ca/˜andrew/notes/pdf/2009a.pdf, preprint 2009. \n28. X. Li, Y. Bao, L. Zhang, On the local dimensions of solutions of Brent equations, arXiv:2303.09754. \n29. X. Li, Github: https://github.com/Xinli-zjut. \n30. T. Ojika, S. Watanabe, T. Mitsui, Deflation algorithm for the multiple roots of a system of nonlinear equations. J. Math. Anal. Appl. 96(1983), no.2, 463-479. \n31. T. Ojika, Modified deflation algorithm for the solution of singular problems. I. A system of nonlinear algebraic equations. J. Math. Anal. Appl. 123(1987), no.1, 199-221. \n32. A.J. Sommese, C.W. Wampler, The Numerical Solution of Systems of Polynomials Arising in Engineering and Science, World Scientific, Singapore, 2005. \n33. A. V. Smirnov, The bilinear complexity and practical algorithms for matrix multiplication. Comput. Math. Math. Phys. 53(2013), no.12, 1781-1795. \n34. V. Strassen, Gaussian elimination is not optimal, Numer. Math. 13(1969), 354-356. \n35. Petr Tichavsk ´y, Characterization of Decomposition of Matrix Multiplication Tensors, arXiv:2104.05323v1, 2021. \n36. C. W. Wampler, J. D. Hauenstein, A. J. Sommese, Mechanism mobility and a local dimension test, Mechanism and Machine Theory, 46(2011) 1193-1206. \n37. Zhonggang Zeng, A Newton’s iteration converges quadratically to nonisolated solutions too, Math. Comp. 92(2023), no.344, 2795-2824. Department of Mathematics, Zhejiang University of Technology, Hangzhou 310023, P. R. China Email address: xinli1019@126.com (Xin Li) School of Mathematical Sciences, Qufu Normal University, Qufu 273165, P. R. China Email address: zhanglp06@gmail.com (Liping Zhang) School of Mathematics and Statistics, Fujian Normal University, 350117 Fuzhou, P.R. China Email address: keyifen@fjnu.edu.cn (Yifen Ke) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[299,119,702,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[781,121,792,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[202,147,795,541]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[205,121,218,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"18 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[444,121,552,130]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LI, ZHANG, AND KE ","text_format":null,"text_level":null,"type":"discarded"}],"string":"[\n {\n \"bbox\": \"[238,185,758,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[382,243,616,256]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"XIN LI, LIPING ZHANG, AND YIFEN KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[263,279,735,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract. In this paper, a classical deflation process raised by Dayton, Li and Zeng is realized for the Brent equations, which provides new bounds for local dimensions of the solution set. Originally, this deflation process focuses on isolated solutions. We generalize it to the case of irreducible components and a related conjecture is given. We analysis its realization and apply it to the Brent equations. The decrease of the nullities is easily observed. So the deflation process can be served as a useful tool for determining the local dimensions. In addition, our result implies that along with the decrease of the tensor rank, the singular solutions will become more and more. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[446,422,552,438]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,445,792,489]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In [18, Sect. 8], Heule et al. raised the question: what is the dimension of the solution set of Brent equations? Following our last paper [28], using the deflation process raised in [7, 8], we continue discussing the local dimensions of solutions of Brent equations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,491,792,551]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $F ( \\\\mathbf { x } ) : \\\\mathbb { C } ^ { n } \\\\to \\\\mathbb { C } ^ { m }$ be a polynomial system with solution set $\\\\mathbf { V } ( F )$ . Let $J ( \\\\mathbf { x } ) \\\\in \\\\mathbb { C } ^ { m \\\\times n }$ be the Jacobian of $F ( \\\\mathbf { x } )$ . Given a solution $\\\\hat { \\\\mathbf { x } } \\\\in \\\\mathbf { V } ( F )$ and let $\\\\dim _ { \\\\hat { \\\\mathbf { x } } } \\\\mathbf { V } ( F )$ denote its local dimension. The Jacobian criterion of [11, Theorem 4.1.12] tells us that the nullity of $J ( \\\\hat { \\\\mathbf { x } } )$ is an upper bound of $\\\\dim _ { \\\\hat { \\\\mathbf { x } } } \\\\mathbf { V } ( F )$ : \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[398,556,598,571]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0096/e123a326fdf2c8d3709317f606e259c75718059fdae874f3e768cf2450f8146d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\dim _ { \\\\hat { \\\\mathbf { x } } } \\\\mathbf { V } ( F ) \\\\leq n - \\\\operatorname { r a n k } \\\\left( J ( { \\\\hat { \\\\mathbf { x } } } ) \\\\right) .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,578,500,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Usually, (1.1) may be not an equality, that is, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[398,597,598,613]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0290/40045791fd9820ba5bba6493445648dc91781166921dcba98aaddaac92977b6c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathrm { d i m } _ { \\\\hat { \\\\mathbf { x } } } \\\\mathbf { V } ( F ) < n - \\\\mathrm { r a n k } \\\\left( J ( \\\\hat { \\\\mathbf { x } } ) \\\\right) .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,617,794,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When (1.2) happens, in numerical algebraic geometry, the solution $\\\\hat { \\\\mathbf { x } }$ is said to be singular (or ultrasingular) [3, 32, 37]. It is well-known that the locally quadratical convergence of Newton’s method is only guaranteed when (1.1) is an equality (see e.g. [37]). Near the neighbourhood of singular solutions, Newton’s method often loses its locally quadratical convergence. In order to recover Newton’s method and turn (1.1) into an equality, the “deflation” technique is introduced, which is also a useful tool for the estimation of local dimensions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,724,794,844]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The deflation technique was firstly introduced by Ojika [30, 31] for the isolated solution. After that many improvements and generalizations were given [7, 8, 16, 26]. Given a polynomial system and a solution. A deflation process produces a new expanded polynomial system and a new expanded solution. For a generic (smooth) point, the nullity of Jacobian of the new expanded solution can be much closer to its local dimension. For isolated singular solutions, it was shown in [7, 8, 26] that the nullity will decrease to zero after a finite number of steps. For a positive dimensional irreducible component, Hauenstein and Wampler introduced a new form of deflation called strong deflation [16], and they refer to the deflation process raised in [7, 8, 26] as weak deflation. Through strong deflation process, Hauenstein and Wampler proved that their deflation sequence will decrease to the local dimension of the generic (smooth) points of the irreducible component [16, Lemma 4.7]. For the other (singular) points, the stabilized number of the (strong) deflation sequence will be no greater than their local dimension [16, Sect.5.3]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[220,858,705,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2020 Mathematics Subject Classification. Primary 14Q15; Secondary 65H10. Key words and phrases. Deflation, Singularity, Brent equations, Local dimension, Jacobian. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[22,218,62,696]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[493,888,503,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,146,794,222]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,222,794,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the (weak) deflation raised in [7, 8, 26], it focuses on the isolated solutions. However, it is not hard to see that it is also suitable to the positive dimensional solutions. In [37, Sect. 9], in order to recover the quadratic convergence rate of Newton’s iteration at ultrasingular zeroes, Zeng conjectured that for generic (smooth) points, the weak deflation process will also terminate at the local dimension of positive dimensional solutions after a finite number of steps. That is, similar properties of strong deflation in [16] also hold for the weak deflation process raised in [7, 8] under the positive dimensional generalization. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,329,794,463]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"By Lemma 4.7 of [16], the strong deflation can turn (1.1) into an equality. However, it will introduce much more new variables and polynomials than the weak deflation. So the implementation of strong deflation is not so practical for large polynomial systems, such as the Brent equations. In addition, the local dimension determination methods raised in [1, 25, 36] are also not suitable to large polynomial systems, too. Let $\\\\langle m , n , p \\\\rangle$ denote the matrix multiplication tensor. We find that it is convenient to calculate the first 4 numbers of the weak deflation sequences for $m n p \\\\leq 1 2 5$ . So our results imply that the weak deflation is a useful tool for determining the local dimensions for polynomial systems arising in the field of bilinear complexity [24]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,479,794,660]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Organization and main results. Firstly, after some preliminaries, more details of the conjecture in [37] are given, see Section 2 and Conjecture 1 in Section 3. Some elementary results are discussed, which are similar to those in [16]. Secondly, the constructions of the Jacobians in the first three steps of the deflation process in [7, 8] are analysed, which are also suitable for other steps, see Section 4. Thirdly, numerical experiments are given for the solutions of the Brent equations, see Section 5. The first 4 numbers of the deflation sequences of many known solutions (see e.g. [14, 17]) are calculated, which provide bounds for their local dimensions. Some interesting results are found. For example, the local dimension of Strassen’s classical solution should be 23, see Section 5.1. For the solutions provided in [17], after the first deflation step, we find that most solutions are singular. This provides a new numerical evidence that finding the tensor decomposition of low rank is hard [12, 19]. Some remarks and open problems are given in Section 6. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,661,794,720]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our numerical results are obtained by Matlab2022a. Some codes and data can be found on [29]. The numerical experiments are taken on the server of ZJUT with the configuration: Intel(R) Xeon(R) Silver 4210R CPU running at 2.40GHz plus $2 . 3 9 \\\\mathrm { G H z }$ and 256 GB memory. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[442,744,553,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Preliminaries \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,766,794,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Throughout this paper, $\\\\mathbb { C }$ is the complex field. The vector space of $m \\\\times n$ complex matrices is denoted by $\\\\mathbb { C } ^ { m \\\\times n }$ . Let $\\\\mathbb { C } ^ { n }$ (or $\\\\mathbb { C } ^ { n \\\\times 1 }$ ) denote the $n$ -dimensional column vector space over $\\\\mathbb { C }$ . Given a matrix $A \\\\in \\\\mathbb { C } ^ { m \\\\times n }$ . Let rank $( A )$ denote the rank of $A$ . The nullity of $A$ is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[455,832,540,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0155/002270b871ed02c907b436a1653f36b6047095c752cd6405f71b4ac2b81f2dc2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn - \\\\operatorname { r a n k } ( A ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[199,853,795,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which is the dimension of the null space of $A$ and denoted by $\\\\Im ( A )$ . In the following, the deflation process always refers to the deflation process raised in [7, 8] or its generalization. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[444,121,552,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,121,214,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,146,794,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $F : \\\\mathbb { C } ^ { n } \\\\to \\\\mathbb { C } ^ { m }$ be a polynomial system. So there exist $m$ polynomials $f _ { i } : \\\\mathbb { C } ^ { n } \\\\to \\\\mathbb { C }$ $( i = 1 , 2 , . . . m )$ such that $F = [ f _ { 1 } , f _ { 2 } , . . . f _ { m } ] ^ { \\\\mathbf { T } }$ . The solution set of $F$ over $\\\\mathbb { C }$ is called an algebraic set and denoted by $\\\\mathbf { V } ( F )$ , that is, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[336,198,660,213]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0990/341cbbdc8f69933b3267aa23c1bff2f9b8ed6a1e874af392279b38533a26981b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf { V } ( F ) = \\\\{ \\\\mathbf { x } \\\\in \\\\mathbb { C } ^ { n } | f _ { 1 } ( \\\\mathbf { x } ) = f _ { 2 } ( \\\\mathbf { x } ) = \\\\cdots = f _ { m } ( \\\\mathbf { x } ) = 0 \\\\} .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,218,794,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $J ( \\\\mathbf { x } )$ denote the Jacobian matrix of $F ( \\\\mathbf { x } )$ . So $J ( \\\\mathbf { x } ) \\\\in \\\\mathbb { C } ^ { m \\\\times n }$ . An algebraic set $\\\\mathbf { V }$ is reducible if there exist nonempty algebraic sets $V _ { 1 } , V _ { 2 } \\\\subsetneq \\\\mathbf { V }$ such that $\\\\mathbf { V } = V _ { 1 } \\\\cup V _ { 2 }$ . $\\\\mathbf { V }$ is irreducible if no such decomposition exists. Each algebraic set $\\\\mathbf { V }$ can be decomposed into a unique finite union of irreducible algebraic subsets: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[419,285,578,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0106/08debd2d5ced935a3557cdc5c00798969a592291c165821ba44bc348be714089.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf { V } = V _ { 1 } \\\\cup V _ { 2 } \\\\cup \\\\cdots \\\\cup V _ { r } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,305,794,426]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $V _ { i }$ is called the irreducible component of $\\\\mathbf { V }$ . For an irreducible component $V$ , the set of manifold points in $V$ is connected and its dimension as a complex manifold is defined to be the dimension of $V$ , denoted dim $V$ [4, 32]. If $\\\\dim V \\\\ = \\\\ k$ , $V$ is said to be a $k$ - dimensional irreducible component. The local dimension of a point $\\\\mathbf { x } \\\\in \\\\mathbf { V }$ is the maximal dimension of the irreducible components of $\\\\mathbf { V }$ that contain $\\\\mathbf { X }$ , which is denoted by $\\\\dim _ { \\\\mathbf { X } } \\\\mathbf { V }$ . For an irreducible component $V$ , a property $P$ holds generically on $V$ if there is a nonempty Zariski open set $U \\\\subseteq V$ such that $P$ holds on $V$ . Each point of $U$ is called a generic point of $V$ with respect to $P$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[200,426,792,458]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Considering $\\\\mathbf { V } ( F )$ as a geometric object in $\\\\mathbb { C } ^ { n }$ , we have the following definition which makes a slight change of [15, Def. 2.1]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[200,464,794,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Definition 2.1. A point $\\\\mathbf { x } _ { 0 } \\\\in \\\\mathbf { V } ( F )$ is called geometric smooth, if there exists a unique irreducible component $V \\\\subseteq \\\\mathbf { V } ( F )$ containing $\\\\mathbf { X } _ { 0 }$ such that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[431,501,566,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0408/8e5a33f781f775328b474d785c120475b0f94a40f8ab071a823de0228db5449d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\dim T _ { \\\\mathbf { x } _ { 0 } } ( V ) = \\\\dim V\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[207,522,794,553]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $T _ { \\\\mathbf { x } _ { 0 } } ( V )$ is the tangent space of $V$ at $\\\\mathbf { X } _ { 0 }$ . Otherwise, $\\\\mathbf { X } _ { 0 }$ is called a geometric singular point of $\\\\mathbf { V } ( F )$ . The set of all geometric singular points of $\\\\mathbf { V } ( F )$ is denoted by $\\\\mathrm { S i n g } _ { G } ( \\\\mathbf { V } ( F ) )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[207,560,792,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is well-known that geometric smooth points are generic on an irreducible component. On the other hand, we have the following definition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,598,794,643]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Definition 2.2. Let $F ( \\\\mathbf { x } )$ be a polynomial system whose solution set and Jacobian are $\\\\mathbf { V } ( F )$ and $J ( \\\\mathbf { x } )$ , respectively. A point $\\\\mathbf { x } _ { 0 } \\\\in \\\\mathbf { V } ( F )$ is called numerical smooth, if there exists a unique irreducible component $V \\\\subseteq \\\\mathbf { V } ( F )$ containing $\\\\mathbf { X } _ { 0 }$ such that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[437,648,560,665]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0580/531c8e085a258b7c8fbe605640a94cc483be999d501c83156994d60df6091913.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathcal { N } ( J ( \\\\mathbf { x } _ { 0 } ) ) = \\\\dim V .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,670,795,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Otherwise, $\\\\mathbf { X } _ { 0 }$ is called a numerical singular point of $\\\\mathbf { V } ( F )$ . The set of all numerical singular points of $\\\\mathbf { V } ( F )$ is denoted by $\\\\mathrm { S i n g } _ { N } ( { \\\\bf V } ( F ) )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,708,602,723]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Remark 2.3. It is well-known that if $\\\\mathbf { x } _ { 0 } \\\\in \\\\mathrm { S i n g } _ { N } ( \\\\mathbf { V } ( F ) )$ , then \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[418,728,578,746]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0927/70a4bd5516ef01aa34310b65a332e43431d54d0c7b755fe5d4fb58c6444ed6ca.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { \\\\mathcal { N } ( J ( \\\\mathbf { x } _ { 0 } ) ) > \\\\mathrm { d i m } _ { \\\\mathbf { x } _ { 0 } } \\\\mathbf { V } ( F ) . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,751,795,795]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Comparing Definition 2.1 and 2.2, we know that numerical smooth points are geometric smooth. However, numerical singular points may contain geometric smooth points. For example, the irreducible components with multiplicity greater than one [3, Example 8.10]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[223,796,555,811]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the polynomial system $F = [ f _ { 1 } , f _ { 2 } , . . . , f _ { m } ] ^ { \\\\mathrm { T } }$ , let \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,816,604,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0310/6c51f3f55b8eee1f4c9e0c4269cf6920ba1c3f8a99402355b0e791d4b4bca9a9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\langle f _ { 1 } , f _ { 2 } , . . . , f _ { m } \\\\rangle \\\\subseteq \\\\mathbb { C } [ x _ { 1 } , x _ { 2 } , . . . , x _ { n } ]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,838,792,867]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"denote the ideal generated by $f _ { i }$ . On the other hand, let $\\\\mathbf { I } ( \\\\mathbf { V } ( F ) )$ denote the vanishing ideal on $\\\\mathbf { V } ( F )$ : \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[308,868,687,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0550/dad4b5a12ed7b0d9ed54fbc28740af19b84febd2ab24e87b165711ff0ca80ca1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf { I } ( \\\\mathbf { V } ( F ) ) = \\\\{ f \\\\in \\\\mathbb { C } [ x _ { 1 } , x _ { 2 } , . . . , x _ { n } ] | f ( \\\\mathbf { x } ) = 0 { \\\\mathrm { ~ f o r ~ a l l ~ } } \\\\mathbf { x } \\\\in \\\\mathbf { V } ( F ) \\\\} .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[297,119,702,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[784,121,794,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,146,794,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"By Proposition 2 of [6, Sect.6 Chapter 9] and Corollary 9 of [6, Sect.7 Chapter 9], we know that if \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[415,176,581,193]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0956/74c3a6d5fe7acf803b188ac767d69215e5ed961192cf0112b84facd468634217.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\langle f _ { 1 } , f _ { 2 } , . . . , f _ { m } \\\\rangle = \\\\mathbf { I } ( \\\\mathbf { V } ( F ) ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,195,794,241]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"then Definition 2.1 and 2.2 are equivalent, that is, the geometric smooth (resp. singular) points and numerical smooth (resp. singular) points are the same. However, for any polynomial system $F = [ f _ { 1 } , f _ { 2 } , . . . , f _ { m } ] ^ { \\\\mathrm { T } }$ , it is well-known that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[415,246,581,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0175/d7b403e1e22af4b690f45a66f2df4fbc8f78f282e3a908e9a09c1dd299b93229.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\langle f _ { 1 } , f _ { 2 } , . . . , f _ { m } \\\\rangle \\\\subseteq \\\\mathbf { I } ( \\\\mathbf { V } ( F ) ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[200,266,794,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and deciding if they are equal is usually hard. So, for those polynomial systems we are interested, the geometric smooth points may be numerical singular. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,304,794,349]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The definition of semiregularity and ultrasingularity of [37] are formalised to irreducible components as follows. For the definition of intersection multiplicity of an irreducible component, we refer to [3, Sec. 11.3]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,356,794,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Definition 2.4. For a polynomial system $F$ , given a $k$ -dimensional irreducible component $V \\\\subseteq \\\\mathbf { V } ( F )$ . If all geometric smooth points are numerical smooth, then we call $V$ is a $k$ - dimensional semiregular irreducible component. That is, there is a nonempty Zariski open set $U \\\\subseteq V$ such that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[387,417,607,433]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0586/95569077def9de3842409ab00cb9616722073537c2dfa8150293b8ddcae755bd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nk = \\\\dim _ { \\\\mathbf { x } } \\\\mathbf { V } ( F ) = T _ { \\\\mathbf { x } } V = \\\\mathcal { N } ( J ( \\\\mathbf { x } ) ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[207,435,709,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $\\\\mathbf { x } \\\\in U$ . Each point in $U$ is called a $k$ -dimensional semiregular solution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,450,794,510]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, if all geometric smooth points are numerical singular and have the same intersection multiplicity, then we call $V$ is a $k$ -dimensional ultrasingular irreducible component. That is, there is a nonempty Zariski open set $U \\\\subseteq V$ and a constant positive number $n _ { 0 }$ such that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[369,511,625,526]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0437/8d00fc33a6d413fd39b6ba5d7851bd8c061343de7d8af444da9d5f0cf5bb8ae5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nk = \\\\dim _ { \\\\mathbf { x } } { \\\\mathbf V } ( F ) = T _ { \\\\mathbf { x } } V < \\\\Re ( J ( \\\\mathbf { x } ) ) = n _ { 0 } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,529,715,545]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $\\\\mathbf { x } \\\\in U$ . Each point in $U$ is called a $k$ -dimensional ultrasingular solution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[310,556,686,570]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Deflation conjecture for the irreducible component \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,577,794,638]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The deflation process raised in [7, 8] focuses on isolated singular solutions. In this section, we generalize it to the case of $k$ -dimensional ultrasingular irreducible components. More details of the conjecture in [37] for ultrasingular solutions are given. Similar discussions are given in [16]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,645,792,676]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. The first step of the deflation process. Let $V \\\\subseteq \\\\mathbf { V } ( F )$ be a $k$ -dimensional ultrasingular irreducible component, which has a nonzero Zariski open set \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[385,681,612,696]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0310/0c37971724cae152ad6a2e87fd4ff035cb3cf46acfbbab52ad2333c53bcb4ff8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nU _ { 0 } \\\\subseteq V \\\\quad \\\\mathrm { w i t h } \\\\quad k < \\\\Re ( J ( \\\\mathbf { x } ) ) = n _ { 0 }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,702,717,717]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $\\\\mathbf { x } \\\\in U _ { 0 }$ . Fix a $k$ -dimensional ultrasingular solution $\\\\hat { \\\\mathbf { x } } _ { 1 } \\\\in U _ { 0 }$ . So we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[433,722,563,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0224/4f5c87dcce185c323263b9ce2d995c76344ed82ebcf8e378a291e702aaa4c655.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nk < \\\\mathcal { N } ( J ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) ) = n _ { 0 } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,742,712,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Then, choose $R _ { 1 } \\\\in \\\\mathbb { C } ^ { n _ { 0 } \\\\times n }$ and a vector $d _ { 1 } \\\\in \\\\mathbb { C } ^ { n _ { 0 } }$ randomly, such that the matrix \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[459,761,534,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0533/9a4053ac8bfa159b7c8c52a92d9127dadce7307948ab53ad41f6c28a493f5ca0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\left[ \\\\begin{array} { c } { J ( \\\\hat { \\\\bf x } _ { 1 } ) } \\\\\\\\ { R _ { 1 } } \\\\end{array} \\\\right] ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,797,570,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is of full (column) rank, and therefore the linear system \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[426,815,571,852]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0400/908b6182089da0bb0cc9fdb330a1b3bbe540f1d37beb64cc6d29025d0b3bc609.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\left[ \\\\begin{array} { c } { J ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) } \\\\\\\\ { R _ { 1 } } \\\\end{array} \\\\right] \\\\mathbf { x } = \\\\left[ \\\\begin{array} { c } { \\\\mathbf { 0 } } \\\\\\\\ { d _ { 1 } } \\\\end{array} \\\\right]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[200,853,794,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"has a unique solution $\\\\mathbf { x } _ { 2 } = \\\\hat { \\\\mathbf { x } } _ { 2 } \\\\neq \\\\mathbf { 0 }$ . By the discussion in Section 3.1 of [16], we can see that besides $\\\\hat { \\\\bf x } _ { 1 }$ , for almost all $\\\\hat { \\\\mathbf { x } } \\\\in V$ , the equation (3.4) also has a unique solution. Let $\\\\mathbf { X } _ { 2 } \\\\in \\\\mathbb { C } ^ { n }$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[444,119,552,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,121,214,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[202,145,794,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"be new variables and fixing $R _ { 1 }$ for all points in $V$ . Then the first step of deflation of $F$ is defined by: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[320,176,678,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0015/aba54a3ee98f1447d36aa50b2975330fb5f18861de0203a9778b939ae3f6be6d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) = \\\\left[ \\\\begin{array} { c } { F ( \\\\mathbf { x } _ { 1 } ) } \\\\\\\\ { \\\\left[ \\\\begin{array} { c } { J ( \\\\mathbf { x } _ { 1 } ) } \\\\\\\\ { R _ { 1 } } \\\\end{array} \\\\right] \\\\mathbf { x } _ { 2 } - \\\\left[ \\\\begin{array} { c } { \\\\mathbf { 0 } } \\\\\\\\ { d _ { 1 } } \\\\end{array} \\\\right] } \\\\end{array} \\\\right] , \\\\mathrm { f o r ~ a l l ~ } \\\\mathbf { x } _ { 1 } \\\\in V .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,228,632,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"So $( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } )$ is a solution of the new polynomial system $F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[222,242,789,257]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When $m \\\\geq n$ , let $\\\\pi _ { n } : \\\\mathbb { C } ^ { m } \\\\to \\\\mathbb { C } ^ { n }$ denote the natural projection map, which is defined by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[385,265,611,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"1001/6a48497b0546f58c0a374df72e67d7f20556e66e859d2ba55badd6d9d5daf767.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\pi _ { n } : ( x _ { 1 } , x _ { 2 } , . . . x _ { m } ) \\\\mapsto ( x _ { 1 } , x _ { 2 } , . . . x _ { n } ) .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,286,647,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $\\\\mathbf { V } ( F _ { 1 } )$ denote the solution set of $F _ { 1 }$ . For $U _ { 0 }$ defined in (3.1), let \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[370,308,627,324]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0225/da140e3c13cdb60753a4c745c47a23e4431cab89886e46e819b470557ca2090b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ { 1 } = \\\\{ y \\\\in { \\\\bf V } ( F _ { 1 } ) | \\\\pi _ { n } ( y ) \\\\in U _ { 0 } \\\\} \\\\subset { \\\\bf V } ( F _ { 1 } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,330,792,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and $\\\\overline { { W _ { 1 } } }$ be the Zariski closure of $W _ { 1 }$ . By the discussion of Lemma 4.6 of [16], we also have the following lemma. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,368,792,398]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lemma 3.1. $\\\\overline { { W _ { 1 } } }$ is an irreducible component of $V ( F _ { 1 } )$ which is generically isomorphic to $V .$ . In particular, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[428,400,570,417]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0471/0bc9698b9d44ffb977b4c1c81211636b0eb5260c5598b009f6fabcd1782ac594.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\dim { \\\\overline { { W _ { 1 } } } } = \\\\dim V = k .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,426,794,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $J _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } )$ denote the Jacobian of $F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } )$ . Then by Proposition 4 and Remark 5 of [27], with probability one, there is an open neighbourhood $\\\\tilde { U } _ { 1 }$ of $( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } )$ such that the nullity \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[382,473,614,489]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0849/b58ef91f2f05ad293e4b8c7d96de7b53ab98c85c0f1c612376f4fc17f2619234.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { \\\\Re ( J _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) ) = \\\\Re ( J _ { 1 } ( \\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } ) ) = n _ { 1 } , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,492,423,507]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) \\\\in \\\\tilde { U } _ { 1 }$ . Then we let \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[447,511,552,530]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0160/30587ae5cf6198d55721448b9fd60583004a74bff8cb1f55bfd15768de762e19.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nU _ { 1 } = { \\\\overline { { W } } } _ { 1 } \\\\cap { \\\\tilde { U } } _ { 1 } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,540,795,631]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. The second and subsequent steps. In (3.8), if $n _ { 1 } = k$ , then $( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } )$ is a $k$ -dimensional semiregular zero of $F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } )$ , so the singularity of $F ( \\\\mathbf { x } )$ at $\\\\hat { \\\\bf x } _ { 1 }$ and its neighbourhood is “deflated”. However, $( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } )$ may still be an ultrasingular zero of $F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } )$ , that is, $n _ { 1 } > k$ . In this case, we can repeat the same deflation process above for $F _ { 1 }$ and obtain a new polynomial system $F _ { 2 }$ . More precisely, we can find and fix $R _ { 2 } \\\\in \\\\mathbb { C } ^ { n _ { 1 } \\\\times 2 n }$ and $d _ { 2 } \\\\in \\\\mathbb { C } ^ { n _ { 1 } }$ such that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[254,633,704,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0706/292b07f7f69b4807a461ccd0d2ffd93eba164c316c0a2f62a7c219e58b47eae5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { 2 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , \\\\mathbf { x } _ { 3 } , \\\\mathbf { x } _ { 4 } ) = \\\\left[ \\\\begin{array} { c } { F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) } \\\\\\\\ { \\\\left[ \\\\begin{array} { c } { J _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) } \\\\\\\\ { R _ { 2 } } \\\\end{array} \\\\right] \\\\left[ \\\\begin{array} { c } { \\\\mathbf { x } _ { 3 } } \\\\\\\\ { \\\\mathbf { x } _ { 4 } } \\\\end{array} \\\\right] - \\\\left[ \\\\begin{array} { c } { \\\\mathbf { 0 } } \\\\\\\\ { d _ { 2 } } \\\\end{array} \\\\right] } \\\\end{array} \\\\right] \\\\mathrm { f o r ~ a l l ~ } \\\\mathbf { x } _ { 1 } \\\\in V ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,686,794,717]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and the solution $( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } )$ extends to a solution $( \\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } , \\\\hat { \\\\mathbf { x } } _ { 3 } , \\\\hat { \\\\mathbf { x } } _ { 4 } )$ of $F _ { 2 }$ , uniquely. Let $\\\\mathbf { V } ( F _ { 2 } )$ denote the solution set of $F _ { 2 }$ . For $U _ { 0 }$ and $\\\\pi _ { n }$ defined in (3.1) and (3.6) respectively, let \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[370,723,625,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0556/6202b503e88cea86482fadc66c8fd6dc8dd0059f93b4a4a83d925bb15d87de70.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ { 2 } = \\\\{ y \\\\in { \\\\bf V } ( F _ { 2 } ) | \\\\pi _ { n } ( y ) \\\\in U _ { 0 } \\\\} \\\\subset { \\\\bf V } ( F _ { 2 } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,746,794,792]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and $\\\\overline { { W _ { 2 } } }$ be the Zariski closure of $W _ { 2 }$ . Then following the same reason as Lemma 3.1, we also have $\\\\dim \\\\overline { { W _ { 2 } } } ~ = ~ k$ . Just as (3.9), there is also a neighbourhood $U _ { 2 } ~ \\\\subseteq ~ \\\\overline { { { W _ { 2 } } } }$ of $( \\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } , \\\\hat { \\\\mathbf { x } } _ { 3 } , \\\\hat { \\\\mathbf { x } } _ { 4 } )$ such that the nullity \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[338,799,656,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0541/77472d2d18b3e498c572af79ae2ac6c154e9560929c65183c5f925bc218efbc1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { \\\\mathrm { \\\\mathcal { N } } ( J _ { 2 } ( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , { \\\\bf x } _ { 3 } , { \\\\bf x } _ { 4 } ) ) = \\\\mathrm { \\\\mathcal { N } } ( J _ { 2 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } , \\\\hat { \\\\bf x } _ { 3 } , \\\\hat { \\\\bf x } _ { 4 } ) ) = n _ { 2 } , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,821,380,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , { \\\\bf x } _ { 3 } , { \\\\bf x } _ { 4 } ) \\\\in U _ { 2 }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,837,794,866]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Generally, assume $( \\\\hat { \\\\mathbf { x } } _ { 1 } , . . . , \\\\hat { \\\\mathbf { x } } _ { 2 ^ { i } } )$ is an ultrasingular zero of $F _ { i } ( \\\\mathbf { x } _ { 1 } , . . . , \\\\mathbf { x } _ { 2 ^ { i } } )$ after $i$ steps of deflation. Let \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[375,868,622,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0538/5c4671442872745a5a89aadda1150b7e1084af830e57aa771fa125f17f0ead2c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ { i } = \\\\{ y \\\\in { \\\\bf V } ( F _ { i } ) | \\\\pi _ { n } ( y ) \\\\in U _ { 0 } \\\\} \\\\subset { \\\\bf V } ( F _ { i } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[297,118,702,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[784,119,794,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,143,795,178]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and $\\\\overline { { W _ { i } } }$ be the Zariski closure of $W _ { i }$ . Then di $\\\\mathrm { \\\\Omega } _ { \\\\mathrm { n } } \\\\overline { { W _ { i } } } \\\\mathrm { ~ = ~ } k$ and the Jacobian $J _ { i } ( \\\\mathbf { x } _ { 1 } , . . . , \\\\mathbf { x } _ { 2 ^ { i } } )$ maintains a nullity $n _ { i } > k$ , in a neighborhood $U _ { i } \\\\subset \\\\overline { { W _ { i } } }$ of $( \\\\hat { \\\\mathbf { x } } _ { 1 } , . . . , \\\\hat { \\\\mathbf { x } } _ { 2 ^ { i } } )$ . That is, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[361,183,635,199]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0857/e644700bff01e71558d40d2cc3ba816e4c00baaf9c20ac5ac303cdfd482ea993.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { \\\\Re ( J _ { i } ( \\\\mathbf { x } _ { 1 } , . . . , \\\\mathbf { x } _ { 2 ^ { i } } ) ) = \\\\Re ( J _ { i } ( \\\\hat { \\\\mathbf { x } } _ { 1 } , . . . , \\\\hat { \\\\mathbf { x } } _ { 2 ^ { i } } ) ) = n _ { i } , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,204,692,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $( \\\\mathbf { x } _ { 1 } , . . . , \\\\mathbf { x } _ { 2 ^ { i } } ) \\\\in U _ { i }$ . Then the next deflation step expands the system to \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[284,223,714,295]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0138/8f18dc6b7c9a5ffb355fb6f520b32107ab4cc73e401457e6e2bbb1e3971a548e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { i + 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , . . . , \\\\mathbf { x } _ { 2 ^ { i + 1 } } ) = \\\\left[ \\\\begin{array} { c } { F _ { i } ( \\\\mathbf { x } _ { 1 } , . . . , \\\\mathbf { x } _ { 2 ^ { i } } ) } \\\\\\\\ { \\\\left[ \\\\begin{array} { c } { J _ { i } ( \\\\mathbf { x } _ { 1 } , . . . , \\\\mathbf { x } _ { 2 ^ { i } } ) } \\\\\\\\ { R _ { i + 1 } } \\\\end{array} \\\\right] \\\\left[ \\\\begin{array} { c } { \\\\mathbf { x } _ { 2 ^ { i } + 1 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\mathbf { x } _ { 2 ^ { i + 1 } } } \\\\end{array} \\\\right] - \\\\left[ \\\\begin{array} { c } { \\\\mathbf { 0 } } \\\\\\\\ { d _ { i + 1 } } \\\\end{array} \\\\right] } \\\\end{array} \\\\right] ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[199,301,794,333]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for all $\\\\mathbf { x } _ { 1 } \\\\in V$ , where $R _ { i + 1 } \\\\in \\\\mathbb { C } ^ { n _ { i } \\\\times 2 ^ { i } n }$ and $d _ { i + 1 } \\\\in \\\\mathbb { C } ^ { n _ { i } }$ are (randomly) chosen and fixed such that almost all points of $\\\\overline { { W _ { i } } }$ extend to a solution of $F _ { i + 1 }$ , uniquely. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,340,669,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Theorem 3.2. In the deflation process above, for $k$ , $n _ { 0 }$ and $n _ { i }$ , we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[421,362,575,377]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0092/ae5da3087f35d5f2599d8021021752bea0979f47f579f42942ac3cf44c575a03.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nk \\\\leq n _ { i } \\\\leq \\\\cdots \\\\leq n _ { 1 } \\\\leq n _ { 0 } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,382,795,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for each $i \\\\geq 1$ . Moreover, suppose that $J _ { i } ( \\\\hat { { \\\\pmb x } } _ { 1 } , . . . , \\\\hat { { \\\\pmb x } } _ { 2 ^ { i } } ) \\\\in \\\\mathbb { C } ^ { a _ { i } \\\\times 2 ^ { i } n }$ for some $a _ { i }$ . Let $J _ { i } ( \\\\hat { { \\\\mathbf { x } } } _ { 1 } ) \\\\in$ $\\\\mathbb { C } ^ { a _ { i } \\\\times n }$ be the submatrix of $J _ { i } ( \\\\hat { \\\\pmb x } _ { 1 } , . . . , \\\\hat { \\\\pmb x } _ { 2 ^ { i } } )$ which is obtained by taking the first n columns of $J _ { i } ( \\\\hat { { \\\\pmb x } } _ { 1 } , . . . , \\\\hat { { \\\\pmb x } } _ { 2 ^ { i } } )$ . Then \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[429,429,568,444]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"1002/6b448f474a4c6f16f9310f907bdf74983e9813da2e06d2d472fe2e4ae29b9e9e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { i } = n - r a n k J _ { i } ( \\\\hat { \\\\pmb x } _ { 1 } ) .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,452,794,497]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Proof. By Lemma 3.1, we can see that without changing its dimension, after each step of deflation, the $k$ -dimensional ultrasingular irreducible component is embedded into a new $k$ -dimensional irreducible component. So we have $k \\\\leq n _ { i }$ for each $i$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,498,795,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For $n _ { i } \\\\le \\\\cdots \\\\le n _ { 1 } \\\\le n _ { 0 }$ , it suffices to show that $n _ { 1 } \\\\leq n _ { 0 }$ by the recursive process of the deflation. From (3.5), we know that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[318,531,678,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0703/12759e6d0114348aa65c290113adf897fd7c05f03804ac78aa277557d849be16.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nJ _ { 1 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } ) = \\\\left[ \\\\begin{array} { c c } { J ( \\\\hat { \\\\bf x } _ { 1 } ) } & { { \\\\bf 0 } } \\\\\\\\ { J \\\\left( \\\\left( J ( \\\\hat { \\\\bf x } _ { 1 } ) \\\\hat { \\\\bf x } _ { 2 } \\\\right) , \\\\hat { \\\\bf x } _ { 1 } \\\\right) } & { J ( \\\\hat { \\\\bf x } _ { 1 } ) } \\\\\\\\ { { \\\\bf 0 } } & { R _ { 1 } } \\\\end{array} \\\\right] \\\\in \\\\mathbb { C } ^ { ( 2 m + n _ { 0 } ) \\\\times 2 n } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,583,794,613]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $J ( ( J ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) \\\\hat { \\\\mathbf { x } } _ { 2 } ) , \\\\hat { \\\\mathbf { x } } _ { 1 } )$ is the partial Jacobian of $J ( \\\\mathbf { x } _ { 1 } ) \\\\mathbf { x } _ { 2 }$ with respect to $\\\\mathbf { X } _ { 1 }$ which takes the value at $( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } )$ . By the choice of $R _ { 1 }$ , we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[415,619,578,635]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0779/753a1a4af202bd99b588e5353e3a4e2f970f134a05f89934380eb4b9800d9570.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nr a n k J _ { 1 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } ) \\\\geq n _ { 0 } + n .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,641,429,655]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"So $n _ { 1 } = 2 n - r a n$ k $J _ { 1 } ( \\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } ) \\\\le n _ { 0 }$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,656,794,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For (3.17), when $i = 0$ , the proof is followed by $J _ { 0 } ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) = J ( \\\\hat { \\\\mathbf { x } } _ { 1 } )$ . For $i \\\\geq 1$ , from (3.15) and the choice of $R _ { i }$ in each step, we only show the case when $i = 1$ . The others are similar too. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[225,700,540,717]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When $i = 1$ , for $J _ { 1 } ( \\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } )$ , from (3.18), we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[397,719,601,768]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0297/90532118e688d2de2632abc54bd38f15dbee8087b26d6dd76d1ad5ec08bf20d3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nJ _ { 1 } ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) = \\\\left[ \\\\begin{array} { c } { J ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) } \\\\\\\\ { J ( ( J ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) \\\\hat { \\\\mathbf { x } } _ { 2 } ) , \\\\hat { \\\\mathbf { x } } _ { 1 } ) } \\\\\\\\ { \\\\mathbf { 0 } } \\\\end{array} \\\\right] .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,772,792,801]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, by choice of $R _ { 1 }$ , we can see that the submatrix obtained by taking columns $n + 1$ to $2 n$ : \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[460,797,537,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0401/a7ffb369219fb86d976379daa0ca9bbf5a5948783a2004dd6d2ea26d80af3296.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\left[ \\\\begin{array} { c } { \\\\mathbf { 0 } } \\\\\\\\ { J ( \\\\hat { \\\\mathbf { x } } _ { 1 } ) } \\\\\\\\ { R _ { 1 } } \\\\end{array} \\\\right]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,848,387,862]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is of full column rank $n$ . So \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[352,868,643,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0301/d47ac1284e7e140aac85389452e2d9e62a5aeebb2a5f9973d57168bb196ae2f2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { 1 } = 2 n - r a n k J _ { 1 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } ) = n - r a n k J _ { 1 } ( \\\\hat { \\\\bf x } _ { 1 } ) .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[444,119,553,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,121,214,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,171,794,215]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Remark 3.3. For the points in $V \\\\backslash U _ { 0 }$ which are geometric singular, we can also apply the deflation process defined in (3.15) to them. Similar to (3.16), with the same reason, we still have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[436,218,562,233]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0070/5a6af1d71e576ff5be4996ffde0c5a2fbc66d8e6ce6d84ed51bbab0eb71a726f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { i } \\\\le \\\\cdots \\\\le n _ { 1 } \\\\le n _ { 0 } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,236,508,251]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However, for points in $V \\\\backslash U _ { 0 }$ , we can see that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[477,257,521,273]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0155/c6077b4996a2363966e42386b2d6fffc88553b5d424167a5cabe931599a5ac70.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { i } < k\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[200,279,794,309]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"can be happen for some $i$ , see Example 3.6 and 3.7. So deflation process provides lower bound of local dimension for them. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,310,794,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From (3.19), we can see that after each deflation step, the addition of new nonzero submatrices to the bottom of the first $n$ columns is the reason that makes the nullities decrease. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,362,794,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. The deflation conjecture. By Theorem 3.2, we can see that the nullity $n _ { i }$ can not be always strictly decreased. It should be stabilized after a finite number of steps. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[200,401,794,431]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Definition 3.4. Suppose that $\\\\hat { \\\\mathbf { x } }$ is a solution of $F ( \\\\mathbf { x } )$ . With notations above, for the deflation process (3.15), let $i _ { 0 } \\\\geq 0$ be the smallest integer such that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[403,438,593,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0055/45738e70ff968c9f423951cba657ae3c4284a1b38ec99eb7140c3b446c104046.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { i + 1 } = n _ { i } \\\\qquad { \\\\mathrm { f o r ~ a l l } } \\\\quad i \\\\geq i _ { 0 } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,460,241,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Then \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[450,476,545,492]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0688/70727b812b0474630690f19b3616549734a9405ae2693ece7d9efe4747f046ad.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } )\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,494,444,510]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is called the deflation sequence of $\\\\hat { \\\\mathbf { x } }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,517,792,547]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Definition 3.5. Let $\\\\hat { \\\\mathbf { x } } \\\\in \\\\mathbf { V } ( F )$ with local dimension $\\\\dim _ { \\\\hat { \\\\mathbf { x } } } \\\\mathbf { V } ( F ) = k$ . Let $( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } )$ denote its deflation sequence. If \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[472,549,524,565]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0930/8f0e35e08dcbf55036039153454c92a002c39c2065977740728d0128364c6ec5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { i _ { 0 } } = k ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,569,794,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"then we say that the deflation sequence $( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } )$ is regular and $\\\\hat { \\\\mathbf { x } }$ has a regular deflation process. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,606,794,637]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Example 3.6. Let $F ( x , y ) = y ^ { 2 } - x ^ { 3 }$ with $z _ { 1 } = ( 0 , 0 )$ and $z _ { 2 } = ( 1 , 1 )$ in $\\\\mathbf { V } ( F )$ . By direct computer verification, the first 4 numbers of their deflation sequences are \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[313,642,681,660]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } ) = ( 2 , 1 , 1 , 0 )$ and $( 1 , 1 , 1 , 1 )$ , respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,665,794,710]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Example 3.7. Let $F ( x , y , z ) = x ^ { 2 } - y ^ { 2 } z$ be the Whitney umbrella. Consider the three points of ${ \\\\bf V } ( F ) \\\\colon ( 2 , 2 , 1 ) , ( 0 , 0 , 1 )$ and $( 0 , 0 , 0 )$ . The first 4 numbers of their deflation sequences are: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,712,718,729]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } ) = ( 2 , 2 , 2 , 2 ) , ( 3 , 2 , 1 , 1 )$ and (3, 2, 2, 1), respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,736,794,781]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is proved in [7, 26] that all isolated singular solutions have regular deflation processes. For $k$ -dimensional ultrasingular irreducible components, Zeng’s conjecture in [37, Sect. 9] can be formalised as follows. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,789,794,849]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conjecture 1 (Deflation Conjecture). Let $V \\\\subseteq \\\\mathbf { V } ( F )$ be a $k$ -dimensional ultrasingular irreducible component. So there is a nonempty Zariski open set $U \\\\subseteq V$ which consists of geometric smooth points and a constant number $n _ { 0 }$ such that $\\\\mathcal { N } ( J ( \\\\mathbf { x } ) ) = n _ { 0 } > k$ for all $\\\\mathbf { x } \\\\in U$ . We have: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[227,853,794,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(1) The recursive deflation process (3.15) terminates in finitely many steps such that the deflation sequences of all $\\\\mathbf { x } \\\\in U$ are equal and regular. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[297,119,702,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[779,148,794,160]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\\u0003 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[784,119,794,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[228,146,795,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(2) For the point ${ \\\\hat { \\\\mathbf { x } } } \\\\in V \\\\backslash U$ with deflation sequence $( n _ { 0 } , n _ { 1 } , . . . , n _ { i _ { 0 } } ) , n _ { i _ { 0 } }$ is a lower bound of its local dimension. That is, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[441,183,555,199]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0992/06a263ad11003c2d0d02e18298050cc0d8547418ef2d04b488fa68be006d5d28.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\dim _ { \\\\hat { \\\\mathbf { x } } } \\\\mathbf { V } ( F ) \\\\geq n _ { i _ { 0 } } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,205,794,252]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Remark 3.8. In [16], using the results in [2], Hauenstein and Wampler showed that Conjecture 1 holds for their strong deflation. Leykin et al.’s deflation process can also be given a similar conjecture [26], and similarly for other deflation processes in the literatures. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,258,794,335]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Remark 3.9. If Conjecture 1 is true, the number in the deflation sequence provides upper bounds of the local dimensions of geometric smooth points. The last number of the deflation sequence is a lower bound of the local dimensions of the geometric singular points. This leads to the problem of determining the singularity of a solution (see also Section 6.2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,343,794,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Remark 3.10. Given a set of solutions of a polynomial system. We usually don’t know the relations between them, such as if they lie on a same irreducible component. So if we apply the deflation process to them, the $R _ { i }$ and $d _ { i }$ defined in (3.15) are chosen separately for each solution. Thus, in practical numerical experiment, if we don’t know the relation between the solutions, the deflation process is the same as the deflation process for isolated solutions in [7, 8]. For example, the solutions of Brent equations studied in Section 5. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[357,448,640,462]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. On realization of the deflation process \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,469,794,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this section, the details of the construction of the Jacobians of the first 3 steps of the deflation process raised in [7, 8] are given. Although they may not be new, we have not seen them in the literatures. We can see that the Jacobians are not hard to be realized numerically. So it is a useful tool for the determination of local dimensions of the algebraic sets. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,545,794,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Firstly, we introduce some notations. The original variable $\\\\mathbf { x } = [ x _ { 1 } , \\\\cdots , x _ { n } ] ^ { \\\\mathbf { T } }$ will be denoted by $\\\\mathbf { X } _ { 1 }$ in accordance with the notation for the auxiliary (vector) variables $\\\\mathbf { x } _ { 2 } , \\\\mathbf { x } _ { 3 } , \\\\ldots$ etc. For any fixed or variable vector $\\\\mathbf { y } = [ y _ { 1 } , . . . , y _ { n } ] ^ { \\\\mathbf { T } }$ , the directional differentiation operator along $\\\\mathbf { y }$ is defined as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[379,603,617,637]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0510/dc335322cc56983e55cb9758a8fee0112eba2507ebd2f04bcb2b72ea85e2e488.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\nabla _ { \\\\mathbf { y } } = y _ { 1 } { \\\\frac { \\\\partial } { \\\\partial x _ { 1 } } } + y _ { 2 } { \\\\frac { \\\\partial } { \\\\partial x _ { 2 } } } + \\\\cdots + y _ { n } { \\\\frac { \\\\partial } { \\\\partial x _ { n } } } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,642,632,656]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lemma 4.1. The composite of $\\\\nabla _ { \\\\mathbf y }$ and $\\\\nabla _ { z }$ is commutative, that is, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[454,662,544,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0098/9d386f69cdc73f1e1653a4df81030404349159a226e2ef6e3ddb4eae61d2d834.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\nabla _ { y } \\\\nabla _ { z } = \\\\nabla _ { z } \\\\nabla _ { y }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,685,446,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Proof. Since $\\\\begin{array} { r } { \\\\frac { \\\\partial ^ { 2 } } { \\\\partial x _ { i } \\\\partial x _ { j } } = \\\\frac { \\\\partial ^ { 2 } } { \\\\partial x _ { j } \\\\partial x _ { i } } } \\\\end{array}$ , we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[341,710,656,808]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0407/da0350784860eecafaaf59b356ff9bce9ca992119c26dfb6833a3f905d7ea4c4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n{ \\\\begin{array} { r l } & { \\\\nabla _ { \\\\mathbf { y } } \\\\nabla _ { \\\\mathbf { z } } = \\\\nabla _ { \\\\mathbf { y } } \\\\left( z _ { 1 } { \\\\frac { \\\\partial } { \\\\partial x _ { 1 } } } + z _ { 2 } { \\\\frac { \\\\partial } { \\\\partial x _ { 2 } } } + \\\\cdots + z _ { n } { \\\\frac { \\\\partial } { \\\\partial x _ { n } } } \\\\right) } \\\\\\\\ & { \\\\qquad = \\\\displaystyle \\\\sum _ { i = 1 } ^ { n } \\\\sum _ { j = 1 } ^ { n } y _ { i } z _ { j } { \\\\frac { \\\\partial ^ { 2 } } { \\\\partial x _ { i } \\\\partial x _ { j } } } = \\\\sum _ { i = 1 } ^ { n } \\\\sum _ { j = 1 } ^ { n } z _ { i } y _ { j } { \\\\frac { \\\\partial ^ { 2 } } { \\\\partial x _ { i } \\\\partial x _ { j } } } } \\\\\\\\ & { \\\\qquad = \\\\nabla _ { \\\\mathbf { z } } \\\\nabla _ { \\\\mathbf { y } } . } \\\\end{array} }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[222,832,669,848]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For any variable $\\\\mathbf { u } = ( u _ { 1 } , . . . , u _ { n } ) ^ { \\\\mathbf { T } }$ , the gradient operator is defined by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[406,852,589,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0439/0e8a0b7d393379a08c1fbe9e29c39eb75b4ee158ce08e1921eca35f425a5ad91.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\triangle _ { \\\\bf u } = \\\\left[ \\\\frac { \\\\partial } { \\\\partial u _ { 1 } } , \\\\frac { \\\\partial } { \\\\partial u _ { 2 } } , \\\\cdot \\\\cdot \\\\cdot , \\\\frac { \\\\partial } { \\\\partial u _ { n } } \\\\right] ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[779,810,794,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"□ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,121,214,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[444,119,552,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,145,620,161]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"whose “dot product” with a vector $\\\\mathbf { v } = [ \\\\nu _ { 1 } , . . . , \\\\nu _ { n } ] ^ { \\\\mathbf { T } }$ is defined as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[369,165,627,196]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0979/fe61f8aefe7b9f1165c503b551336eccba66e1286a6cbf48464fb0d01821fe90.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf { v } \\\\cdot \\\\triangle _ { \\\\mathbf { u } } = \\\\nu _ { 1 } \\\\frac { \\\\partial } { \\\\partial u _ { 1 } } + \\\\nu _ { 2 } \\\\frac { \\\\partial } { \\\\partial u _ { 2 } } + \\\\cdot \\\\cdot \\\\cdot + \\\\nu _ { n } \\\\frac { \\\\partial } { \\\\partial u _ { n } } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,200,423,215]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"So we have $\\\\nabla _ { \\\\mathbf y } = \\\\mathbf y \\\\cdot { \\\\boldsymbol \\\\triangle } _ { \\\\mathbf x } = \\\\mathbf y \\\\cdot { \\\\boldsymbol \\\\triangle } _ { { \\\\mathbf x } _ { 1 } }$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[207,215,794,244]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $J ( \\\\mathbf { x } )$ be the Jacobian of the polynomial system $F ( \\\\mathbf { x } ) = [ f _ { 1 } ( \\\\mathbf { x } ) , f _ { 2 } ( \\\\mathbf { x } ) , . . . f _ { m } ( \\\\mathbf { x } ) ] ^ { \\\\mathrm { { T } } }$ . Then $J ( \\\\mathbf { x } ) \\\\mathbf { y }$ can be denoted by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[411,244,588,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0945/801ec0b9177a13fa3601c7b1953089bcdbba0f17b5e91db3357fbd14467fab0b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { J ( \\\\mathbf { x } ) \\\\mathbf { y } = \\\\nabla _ { \\\\mathbf { y } } F = \\\\left[ \\\\begin{array} { c } { \\\\nabla _ { \\\\mathbf { y } } f _ { 1 } } \\\\\\\\ { \\\\nabla _ { \\\\mathbf { y } } f _ { 2 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\nabla _ { \\\\mathbf { y } } f _ { m } } \\\\end{array} \\\\right] . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,316,294,332]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Similarly, set \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[419,330,578,401]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0824/af0d27aa382ce59d872a0cf0eb8fc81ffa4011388097a43590432071733e3b6b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } F = \\\\left[ \\\\begin{array} { c } { \\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } f _ { 1 } } \\\\\\\\ { \\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } f _ { 2 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } f _ { m } } \\\\end{array} \\\\right] .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[197,404,794,435]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $G ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , . . . , \\\\mathbf { x } _ { k } ) : \\\\mathbb { C } ^ { k n } \\\\mathbb { C } ^ { m }$ be a polynomial system and $G = [ g _ { 1 } , g _ { 2 } , . . . , g _ { m } ] ^ { \\\\mathbf { T } }$ , its partial Jacobian with respect to some $\\\\mathbf { x } _ { i } = [ x _ { i 1 } , . . . , x _ { i n } ] ^ { \\\\mathbf { T } }$ is defined by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[349,439,647,510]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0541/2b1921c7678a88e913bd67293ec4ff1f8d07025ca1de59987aa04a2fb515f30a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { J ( G , \\\\mathbf { x } _ { i } ) : = \\\\left[ { \\\\begin{array} { c } { \\\\triangle _ { \\\\mathbf { x } _ { i } } g _ { 1 } } \\\\\\\\ { \\\\triangle _ { \\\\mathbf { x } _ { i } } g _ { 2 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\triangle _ { \\\\mathbf { x } _ { i } } g _ { m } } \\\\end{array} } \\\\right] = \\\\left[ { \\\\begin{array} { c c c } { \\\\frac { \\\\partial g _ { 1 } } { \\\\partial x _ { i 1 } } } & { \\\\cdot \\\\cdot \\\\cdot } & { \\\\frac { \\\\partial g _ { 1 } } { \\\\partial x _ { i n } } } \\\\\\\\ { \\\\vdots } & & { \\\\vdots } \\\\\\\\ { \\\\frac { \\\\partial g _ { m } } { \\\\partial x _ { i 1 } } } & { \\\\cdot \\\\cdot \\\\cdot } & { \\\\frac { \\\\partial g _ { m } } { \\\\partial x _ { i n } } } \\\\end{array} } \\\\right] . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[207,512,794,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $J ( J ( \\\\mathbf { x } ) \\\\mathbf { v } , \\\\mathbf { x } )$ be the partial Jacobian of $J ( \\\\mathbf { x } ) \\\\mathbf { v }$ with respect to $\\\\mathbf { X }$ , and similarly for $J ( J ( J ( \\\\mathbf { x } ) \\\\mathbf { w } , \\\\mathbf { x } ) \\\\mathbf { v } , \\\\mathbf { x } )$ . Then we have the following lemma. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,551,289,565]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lemma 4.2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[341,563,656,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0649/d82fe33819df5ecd6dc980a5c0bfc3ae94cc8488195bef1e51429f21029cc0d3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { J ( J ( x ) \\\\nu , x ) \\\\pmb { u } = \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\nu } F = \\\\left[ \\\\begin{array} { c } { \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\nu } f _ { 1 } } \\\\\\\\ { \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\nu } f _ { 2 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\nu } f _ { m } } \\\\end{array} \\\\right] = \\\\nabla _ { \\\\nu } \\\\nabla _ { \\\\pmb { u } } F . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[290,637,707,708]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0127/f8a9dbbcb3570b2ff886c225e55d59d9c01f61a7bb378e36455de1821c0b230e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { J ( J ( J ( \\\\pmb { x } ) \\\\pmb { w } , \\\\pmb { x } ) \\\\pmb { \\\\nu } , \\\\pmb { x } ) \\\\pmb { u } = \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\pmb { \\\\nu } } \\\\nabla _ { \\\\pmb { w } } F = \\\\left[ \\\\begin{array} { c } { \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\pmb { \\\\nu } } \\\\nabla _ { \\\\pmb { w } } f _ { 1 } } \\\\\\\\ { \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\pmb { \\\\nu } } \\\\nabla _ { \\\\pmb { w } } f _ { 2 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { \\\\pmb { \\\\nu } } \\\\nabla _ { \\\\pmb { w } } f _ { m } } \\\\end{array} \\\\right] = \\\\nabla _ { \\\\pmb { u } } \\\\nabla _ { b } \\\\nabla _ { \\\\pmb { c } } F , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,709,483,724]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where a, $\\\\pmb { b }$ , c is any permutation of $\\\\dot { \\\\boldsymbol { u } } , \\\\boldsymbol { \\\\nu } , \\\\boldsymbol { w }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,732,714,747]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Proof. The proof is followed by Lemma 4.1. Since for $i = 1 , 2 , . . . , m$ , we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[441,752,557,768]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0067/f80f10585e9f46f982b23cf68ee5dff14bef1c590daa9f207e41e0a52dccf163.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } f _ { i } = \\\\nabla _ { \\\\mathbf { v } } \\\\nabla _ { \\\\mathbf { u } } f _ { i }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,775,232,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[419,789,576,805]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0346/b183bdfeeae608f6d84fffec1687eb76e3a9d6b8533dcee4be93f2037fda3a95.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } \\\\nabla _ { \\\\mathbf { w } } f _ { i } = \\\\nabla _ { \\\\mathbf { a } } \\\\nabla _ { \\\\mathbf { b } } \\\\nabla _ { \\\\mathbf { c } } f _ { i } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,808,486,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where a, b, c is any permutation of $\\\\mathbf { u } , \\\\mathbf { v } , \\\\mathbf { w }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,830,794,861]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the partial Jacobians of $\\\\nabla _ { \\\\mathbf { u } } F ( \\\\mathbf { x } )$ , $\\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } F ( \\\\mathbf { x } )$ and $\\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } \\\\nabla _ { \\\\mathbf { w } } F ( \\\\mathbf { x } )$ , we have the following formulas. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,868,498,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lemma 4.3. With notation in (4.1), we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[297,118,702,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[779,809,794,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\\u0003 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[784,119,794,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[230,147,784,208]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(1) $J ( \\\\nabla _ { \\\\boldsymbol { \\\\mathbf { u } } } F ( \\\\boldsymbol { \\\\mathbf { x } } ) , \\\\boldsymbol { \\\\mathbf { \\\\nu } } ) = \\\\boldsymbol { \\\\mathbf { 0 } } ,$ , \\n(2) $J ( \\\\nabla _ { u } F ( x ) , u ) = J ( x ) ,$ , \\n(3) $\\\\begin{array} { r l } & { J ( \\\\nabla _ { \\\\nu } \\\\nabla _ { u } F ( x ) , u ) = J ( \\\\nabla _ { u } \\\\nabla _ { \\\\nu } F ( x ) , u ) = J ( \\\\nabla _ { \\\\nu } F ( x ) , x ) , } \\\\\\\\ & { J ( \\\\nabla _ { \\\\nu } \\\\nabla _ { w } \\\\nabla _ { u } F ( x ) , u ) = J ( \\\\nabla _ { \\\\nu } \\\\nabla _ { u } \\\\nabla _ { w } F ( x ) , u ) = J ( \\\\nabla _ { u } \\\\nabla _ { \\\\nu } \\\\nabla _ { w } F ( x ) , u ) = J ( \\\\nabla _ { \\\\nu } \\\\nabla _ { w } F ( x ) , x ) . } \\\\end{array}$ \\n(4) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,218,645,233]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Proof. The proof is followed by direct verification and Lemma 4.2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,250,794,295]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With preparation above, in the following we describe the first 3 steps of the deflation process explicitly. From this, we can obtain the first 4 numbers $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ of the deflation sequence. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[207,295,794,325]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Step 0. Given a polynomial system $F ( \\\\mathbf { x } ) = [ f _ { 1 } ( \\\\mathbf { x } ) , f _ { 2 } ( \\\\mathbf { x } ) , . . . f _ { m } ( \\\\mathbf { x } ) ] ^ { \\\\mathbf { T } }$ , whose Jacobian is $J ( \\\\mathbf { x } )$ . Given a solution $\\\\hat { \\\\mathbf { x } } \\\\in \\\\mathbf { V } ( F )$ . Then \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[434,337,562,353]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0779/ff0f9c8b84dcf11b327b5330f56a3aa9915692226af37d42d81a37b15be01e64.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { 0 } = n - r a n k J ( \\\\hat { \\\\bf x } )\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[202,363,655,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is the nullity which is the first number of the deflation sequence of $\\\\hat { \\\\mathbf { x } }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,380,795,424]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Step 1. Let $n _ { 0 }$ and $\\\\hat { \\\\mathbf { x } } _ { 1 } = \\\\hat { \\\\mathbf { x } }$ be the number and solution in Step 0, respectively. We choose a random matrix $R _ { 1 } \\\\in \\\\mathbb { C } ^ { n _ { 0 } \\\\times n }$ and a random vector $d _ { 1 } \\\\in \\\\mathbb { C } ^ { n _ { 0 } }$ . By (3.5), the first deflation of $F ( \\\\mathbf { x } )$ is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[405,428,591,477]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0966/459358043da0f996b7206c3b45532b5d1213fe883692dafcf6a6f0d4c1b3bd2f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) = \\\\left[ \\\\begin{array} { c } { F ( \\\\mathbf { x } _ { 1 } ) } \\\\\\\\ { J ( \\\\mathbf { x } _ { 1 } ) \\\\mathbf { x } _ { 2 } } \\\\\\\\ { R _ { 1 } \\\\mathbf { x } _ { 2 } - d _ { 1 } } \\\\end{array} \\\\right] ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,484,325,497]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"whose Jacobian is \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[362,500,633,549]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0088/1f966ee4fa245c622e2594480c2bb5a8fd783fabbbf9bc4cdfe40c058df55edd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nJ _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) = \\\\left[ \\\\begin{array} { c c } { J ( \\\\mathbf { x } _ { 1 } ) } & { \\\\mathbf { 0 } } \\\\\\\\ { J ( \\\\nabla _ { \\\\mathbf { x } _ { 2 } } F ( \\\\mathbf { x } _ { 1 } ) , \\\\mathbf { x } _ { 1 } ) } & { J ( \\\\mathbf { x } _ { 1 } ) } \\\\\\\\ { \\\\mathbf { 0 } } & { R _ { 1 } } \\\\end{array} \\\\right] ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,555,465,570]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $J ( \\\\nabla _ { \\\\mathbf { x } _ { 2 } } F ( \\\\mathbf { x } _ { 1 } ) , \\\\mathbf { x } _ { 1 } ) = J ( J ( \\\\mathbf { x } _ { 1 } ) \\\\mathbf { x } _ { 2 } , \\\\mathbf { x } _ { 1 } )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[210,571,792,599]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fixing $\\\\hat { \\\\bf X } _ { 1 }$ , let $\\\\hat { \\\\bf x } _ { 2 }$ be the solution of the linear system $F _ { 1 } ( \\\\hat { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } ) = { \\\\bf 0 }$ (see also (3.4)). Then we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[411,607,584,623]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"1019/a424f165dd33f63daf4803e9231b9981fae96f5807248dcf2fab9db91a368dc7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { 1 } = 2 n - r a n k J _ { 1 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,631,560,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which is the second number of the deflation sequence. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,647,794,693]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Step 2. Let $n _ { 1 }$ and $( \\\\hat { \\\\mathbf { x } } _ { 1 } , ~ \\\\hat { \\\\mathbf { x } } _ { 2 } )$ be the number and solution in Step 1, respectively. We choose a random matrix $R _ { 2 } \\\\in \\\\mathbb { C } ^ { n _ { 1 } \\\\times 2 n }$ and a random vector $d _ { 2 } \\\\in \\\\mathbb { C } ^ { n _ { 1 } }$ . If we continue taking the deflation process on $F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } )$ , then by (3.15) we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[328,702,669,782]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0376/ace18a8c6efc65ab480bb562b4d126b1060ac1516a9a918f380b2efc4df43b9a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { 2 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , \\\\mathbf { x } _ { 3 } , \\\\mathbf { x } _ { 4 } ) = \\\\left[ \\\\begin{array} { c } { F _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) } \\\\\\\\ { J _ { 1 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } ) \\\\left[ \\\\begin{array} { c } { \\\\mathbf { x } _ { 3 } } \\\\\\\\ { \\\\mathbf { x } _ { 4 } } \\\\end{array} \\\\right] } \\\\\\\\ { R _ { 2 } \\\\left[ \\\\begin{array} { c } { \\\\mathbf { x } _ { 3 } } \\\\\\\\ { \\\\mathbf { x } _ { 4 } } \\\\end{array} \\\\right] - d _ { 2 } } \\\\end{array} \\\\right] = \\\\left[ \\\\begin{array} { c } { g _ { 1 } } \\\\\\\\ { g _ { 2 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { g _ { 7 } } \\\\end{array} \\\\right] ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,790,423,805]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and from (4.2) and (4.3) we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[214,813,748,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0534/c5ce67ee471946b5e1c61e58666a8dbaadfa06fed741af72308d85ed07f715b2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l } & { g _ { 1 } = F ( { \\\\bf x } _ { 1 } ) , g _ { 2 } = J ( { \\\\bf x } _ { 1 } ) { \\\\bf x } _ { 2 } = \\\\nabla _ { { \\\\bf x } _ { 2 } } F ( { \\\\bf x } _ { 1 } ) , g _ { 3 } = R _ { 1 } { \\\\bf x } _ { 2 } - d _ { 1 } , g _ { 4 } = J ( { \\\\bf x } _ { 1 } ) { \\\\bf x } _ { 3 } = \\\\nabla _ { { \\\\bf x } _ { 3 } } F ( { \\\\bf x } _ { 1 } ) , } \\\\\\\\ & { g _ { 5 } = J ( \\\\nabla _ { { \\\\bf x } _ { 2 } } F ( { \\\\bf x } _ { 1 } ) , { \\\\bf x } _ { 1 } ) { \\\\bf x } _ { 3 } + J ( { \\\\bf x } _ { 1 } ) { \\\\bf x } _ { 4 } = \\\\nabla _ { { \\\\bf x } _ { 3 } } \\\\nabla _ { { \\\\bf x } _ { 2 } } F ( { \\\\bf x } _ { 1 } ) + \\\\nabla _ { { \\\\bf x } _ { 4 } } F ( { \\\\bf x } _ { 1 } ) , } \\\\\\\\ & { g _ { 6 } = R _ { 1 } { \\\\bf x } _ { 4 } , g _ { 7 } = R _ { 2 } \\\\left[ \\\\begin{array} { c } { { \\\\bf x } _ { 3 } } \\\\\\\\ { { \\\\bf x } _ { 4 } } \\\\end{array} \\\\right] - d _ { 2 } . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[444,119,552,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,119,218,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[779,220,794,232]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"□ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[202,146,795,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $J _ { 2 } ( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , { \\\\bf x } _ { 3 } , { \\\\bf x } _ { 4 } )$ be the Jacobian of $F _ { 2 } ( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , { \\\\bf x } _ { 3 } , { \\\\bf x } _ { 4 } )$ . It consists of $7 \\\\times 4 = 2 8$ partial Jacobian blocks, which can be seen as follows \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[334,179,663,251]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0799/00adda7095ebe84c6f85fdff82198af5e32f1de54b0c7d30eae1c0913bfb786c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { J _ { 2 } ( \\\\mathbf x _ { 1 } , \\\\mathbf x _ { 2 } , \\\\mathbf x _ { 3 } , \\\\mathbf x _ { 4 } ) = \\\\left[ { \\\\begin{array} { c c c } { J ( g _ { 1 } , \\\\mathbf x _ { 1 } ) } & { \\\\cdots \\\\cdot } & { J ( g _ { 1 } , \\\\mathbf x _ { 4 } ) } \\\\\\\\ { J ( g _ { 2 } , \\\\mathbf x _ { 1 } ) } & { \\\\cdots \\\\cdot } & { J ( g _ { 2 } , \\\\mathbf x _ { 4 } ) } \\\\\\\\ { \\\\vdots } & { } & { \\\\vdots } \\\\\\\\ { J ( g _ { 7 } , \\\\mathbf x _ { 1 } ) } & { \\\\cdots \\\\cdot } & { J ( g _ { 7 } , \\\\mathbf x _ { 4 } ) } \\\\end{array} } \\\\right] . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[200,255,792,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In (4.6), we only describe the partial Jacobians $J ( g _ { 5 } , \\\\mathbf { x } _ { 2 } )$ , by Lemma 4.3, which can be calculated as follows \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[334,285,663,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0546/f8ec2b847793e70a8dadea13fbcecd625f9da97b02a4e23fe29e2e92290393f7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l } & { J ( g _ { 5 } , \\\\mathbf { x } _ { 2 } ) = J \\\\left( \\\\nabla _ { \\\\mathbf { x } _ { 3 } } \\\\nabla _ { \\\\mathbf { x } _ { 2 } } F ( \\\\mathbf { x } _ { 1 } ) , \\\\mathbf { x } _ { 2 } \\\\right) + J \\\\left( \\\\nabla _ { \\\\mathbf { x } _ { 4 } } F ( \\\\mathbf { x } _ { 1 } ) , \\\\mathbf { x } _ { 2 } \\\\right) } \\\\\\\\ & { \\\\quad \\\\quad \\\\quad = J \\\\left( \\\\nabla _ { \\\\mathbf { x } _ { 2 } } \\\\nabla _ { \\\\mathbf { x } _ { 3 } } F ( \\\\mathbf { x } _ { 1 } ) , \\\\mathbf { x } _ { 2 } \\\\right) + \\\\mathbf { 0 } } \\\\\\\\ & { \\\\quad \\\\quad \\\\quad = J \\\\left( \\\\nabla _ { \\\\mathbf { x } _ { 3 } } F ( \\\\mathbf { x } _ { 1 } ) , \\\\mathbf { x } _ { 1 } \\\\right) . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,347,566,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The other partial Jacobians are not hard to be obtained. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,362,794,391]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fixing $\\\\hat { \\\\mathbf { X } } _ { 1 } , \\\\hat { \\\\mathbf { X } } _ { 2 }$ , let $\\\\hat { \\\\mathbf { X } } _ { 3 } , \\\\hat { \\\\mathbf { X } } _ { 4 }$ be the solution of the linear system $F _ { 2 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } , { \\\\bf x } _ { 3 } , { \\\\bf x } _ { 4 } ) = { \\\\bf 0 }$ . Then we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[390,392,606,409]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0633/d7f6295ea0ea19949cb9558454511fdf436d54a5c81395f98d681681c3538196.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { 2 } = 4 n - r a n k J _ { 2 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } , \\\\hat { \\\\bf x } _ { 3 } , \\\\hat { \\\\bf x } _ { 4 } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,410,545,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which is the third number of the deflation sequence. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,426,794,472]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Step 3. Let $n _ { 2 }$ and $( \\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } , \\\\hat { \\\\mathbf { x } } _ { 3 } , \\\\hat { \\\\mathbf { x } } _ { 4 } )$ be the number and solution in Step 2, respectively. We choose a random matrix $R _ { 3 } \\\\in \\\\mathbb { C } ^ { n _ { 2 } \\\\times 4 n }$ and a random vector $d _ { 3 } \\\\in \\\\mathbb { C } ^ { n _ { 2 } }$ . If we continue taking the deflation process on $F _ { 2 } ( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , { \\\\bf x } _ { 3 } , { \\\\bf x } _ { 4 } )$ , then by (3.15) we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[303,476,692,613]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0417/2facba96f6f4fdcdb3b250907558fd0c5886d4fc4cba3545c45f192d6cb0ff1d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { 3 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , . . . , \\\\mathbf { x } _ { 8 } ) = [ \\\\begin{array} { c } { F _ { 2 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , \\\\mathbf { x } _ { 3 } , \\\\mathbf { x } _ { 4 } ) } \\\\\\\\ { [ \\\\begin{array} { c } { \\\\mathbf { x } _ { 5 } } \\\\\\\\ { J _ { 2 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , \\\\mathbf { x } _ { 3 } , \\\\mathbf { x } _ { 4 } ) } \\\\\\\\ { \\\\mathbf { x } _ { 7 } } \\\\\\\\ { \\\\mathbf { x } _ { 8 } } \\\\end{array} ] } = [ { \\\\begin{array} { c } { \\\\mathbf { x } _ { 1 } } \\\\\\\\ { \\\\mathbf { x } _ { 6 } } \\\\\\\\ { \\\\mathbf { x } _ { 7 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\mathbf { x } _ { 1 5 } } \\\\end{array} } ] , \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,617,462,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and from (4.4), (4.5) and (4.6) we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[323,633,669,886]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0964/6a7e14aa1f21fdbedaf3567c8bff7b3876c18f3ad509d6426fcbd25f224c8da2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l } & { h _ { i } = \\\\delta _ { i } , \\\\quad \\\\mathrm { f o r } \\\\quad ( 1 - 1 , 2 , . . . , 2 , . } \\\\\\\\ & { h _ { i } = V _ { i } , V _ { i } ( \\\\mathbf { x } _ { 1 } ) , } \\\\\\\\ & { h _ { i } = V _ { i } , \\\\quad \\\\mathrm { f o r } \\\\quad ( 1 ) , } \\\\\\\\ & { h _ { i } = V _ { i } , \\\\quad \\\\mathrm { f o r } \\\\quad ( \\\\mathbf { x } _ { 1 } ) + \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) , } \\\\\\\\ & { h _ { i } = V _ { i } \\\\times \\\\nabla _ { x } , \\\\quad \\\\mathrm { f o r } \\\\quad ( 1 ) , } \\\\\\\\ & { h _ { i } = \\\\nabla _ { x } \\\\nabla _ { x } , \\\\quad \\\\mathrm { f o r } \\\\quad ( 1 ) + \\\\nabla _ { x } , \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) + \\\\nabla _ { x } , \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) , } \\\\\\\\ & { h _ { i } = \\\\nabla _ { x } , \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) + \\\\nabla _ { x } , \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) , } \\\\\\\\ & { \\\\qquad \\\\quad + \\\\nabla _ { x } \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) + \\\\nabla _ { x } , F ( \\\\mathbf { x } _ { 1 } ) , } \\\\\\\\ & { h _ { i } = R \\\\times \\\\nabla _ { x } , \\\\quad } \\\\\\\\ & { h _ { i } = R \\\\times \\\\left[ \\\\begin{array} { l } { \\\\mathbf { x } _ { 1 } } \\\\\\\\ { \\\\mathbf { x } _ { 2 } } \\\\\\\\ { \\\\mathbf { x } _ { 3 } } \\\\\\\\ { \\\\mathbf { x } _ { 4 } } \\\\end{array} \\\\right] } \\\\\\\\ & { h _ { i } = R \\\\times \\\\left[ \\\\begin{array} { l } { \\\\mathbf { x } _ { 1 } } \\\\\\\\ { \\\\mathbf { x } _ { 5 } } \\\\\\\\ { \\\\mathbf { x } _ { 5 } } \\\\\\\\ { \\\\mathbf { x } _ { 5 } } \\\\\\\\ { \\\\mathbf { x } _ { 6 } } \\\\end{array} \\\\right] - d _ { 3 } } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[295,118,700,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[779,119,792,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,146,795,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let $J _ { 3 } ( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , . . . , { \\\\bf x } _ { 8 } )$ be the Jacobian of $F _ { 3 } ( { \\\\bf x } _ { 1 } , { \\\\bf x } _ { 2 } , . . . , { \\\\bf x } _ { 8 } )$ . It consists of $1 5 \\\\times 8 = 1 2 0$ partial Jacobian blocks, which can be seen as follows \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[330,181,666,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0653/57062bdc5aa8f2f9dc836dad49b4d7f7cc5055085d2cc265d0c316eb175076bf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { J _ { 3 } ( \\\\mathbf { x } _ { 1 } , \\\\mathbf { x } _ { 2 } , . . . , \\\\mathbf { x } _ { 8 } ) = \\\\left[ { \\\\begin{array} { c c c } { J ( h _ { 1 } , \\\\mathbf { x } _ { 1 } ) } & { \\\\cdot \\\\cdot \\\\cdot } & { J ( h _ { 1 } , \\\\mathbf { x } _ { 8 } ) } \\\\\\\\ { J ( h _ { 2 } , \\\\mathbf { x } _ { 1 } ) } & { \\\\cdot \\\\cdot \\\\cdot } & { J ( h _ { 2 } , \\\\mathbf { x } _ { 8 } ) } \\\\\\\\ { \\\\vdots } & { } & { \\\\vdots } \\\\\\\\ { J ( h _ { 1 5 } , \\\\mathbf { x } _ { 1 } ) } & { \\\\cdot \\\\cdot \\\\cdot } & { J ( h _ { 1 5 } , \\\\mathbf { x } _ { 8 } ) } \\\\end{array} } \\\\right] . } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[209,261,794,290]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In (4.10), we only describe the partial Jacobians $J ( h _ { 1 2 } , { \\\\bf x } _ { 2 } )$ and $J ( h _ { 1 2 } , { \\\\bf x } _ { 3 } )$ . By Lemma 4.3 we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[310,292,687,332]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0466/70d9c1fc50fd8124a79269ff1020365afd39d43b1533085aa3213a4a79d12425.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l } & { J ( h _ { 1 2 } , { \\\\mathbf x } _ { 2 } ) = J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 5 } } \\\\nabla _ { { \\\\mathbf x } _ { 3 } } \\\\nabla _ { { \\\\mathbf x } _ { 2 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 2 } \\\\right) + J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 7 } } \\\\nabla _ { { \\\\mathbf x } _ { 2 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 2 } \\\\right) } \\\\\\\\ & { \\\\quad \\\\quad \\\\quad = J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 5 } } \\\\nabla _ { { \\\\mathbf x } _ { 3 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 1 } \\\\right) + J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 7 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 1 } \\\\right) , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,338,232,352]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[310,356,687,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0564/642d486600bfc59e6f3a678fe3f85f1bbf80b7e2d9517d83a910162590cfedad.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l } & { J ( h _ { 1 2 } , { \\\\mathbf x } _ { 3 } ) = J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 5 } } \\\\nabla _ { { \\\\mathbf x } _ { 3 } } \\\\nabla _ { { \\\\mathbf x } _ { 2 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 3 } \\\\right) + J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 6 } } \\\\nabla _ { { \\\\mathbf x } _ { 3 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 3 } \\\\right) } \\\\\\\\ & { \\\\quad \\\\quad \\\\quad = J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 5 } } \\\\nabla _ { { \\\\mathbf x } _ { 2 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 1 } \\\\right) + J \\\\left( \\\\nabla _ { { \\\\mathbf x } _ { 6 } } F ( { \\\\mathbf x } _ { 1 } ) , { \\\\mathbf x } _ { 1 } \\\\right) } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[223,400,700,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fixing $\\\\hat { \\\\mathbf { x } } _ { 1 } , \\\\hat { \\\\mathbf { x } } _ { 2 } , \\\\hat { \\\\mathbf { x } } _ { 3 } , \\\\hat { \\\\mathbf { x } } _ { 4 }$ , let $\\\\hat { \\\\mathbf { x } } _ { 5 } , \\\\hat { \\\\mathbf { x } } _ { 6 } , \\\\hat { \\\\mathbf { x } } _ { 7 } , \\\\hat { \\\\mathbf { x } } _ { 8 }$ be the solution of the linear system \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[383,424,612,440]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0971/be3a9b3f42a05c420d457ce981b20e3a3ebf288843610cca604486055b6af6ce.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nF _ { 3 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } , \\\\hat { \\\\bf x } _ { 3 } , \\\\hat { \\\\bf x } _ { 4 } , { \\\\bf x } _ { 5 } , { \\\\bf x } _ { 6 } , { \\\\bf x } _ { 7 } , { \\\\bf x } _ { 8 } ) = { \\\\bf 0 } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,448,299,462]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Then we have \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[392,465,604,482]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0531/51abc5b181aa09e6168a403e465dc53609f40bd4e1e6eb4609fabc062bfa6020.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nn _ { 3 } = 8 n - r a n k J _ { 3 } ( \\\\hat { \\\\bf x } _ { 1 } , \\\\hat { \\\\bf x } _ { 2 } , . . . , \\\\hat { \\\\bf x } _ { 8 } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,487,557,502]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which is the fourth number of the deflation sequence. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[218,502,718,518]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the polynomial system $F = [ f _ { 1 } , f _ { 2 } , . . . f _ { m } ] ^ { \\\\mathrm { T } }$ , the degree of $F$ is defined by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[382,525,614,541]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0215/6bbecf17a2046ff92832362535f445265d85e5ef6d532d243fe4a8d859706bc0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD e g F = \\\\operatorname* { m a x } \\\\{ D e g f _ { i } | i = 1 , 2 , . . . m \\\\} ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,549,794,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $D e g \\\\ f _ { i }$ are the degrees of the polynomials $f _ { i }$ . So from above analysis, we have the following proposition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,589,792,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Proposition 4.4. If Deg $F = 3$ , in the deflation process (3.15), the Jacobians $J _ { i } ( { \\\\pmb x } _ { 1 } , . . . , { \\\\pmb x } _ { 2 ^ { i } } )$ are builded up by $R _ { i }$ and the following partial Jacobians \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[379,628,617,643]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0915/a57f33c8c6de7d074ca85495c9c4becee4f626a1b6f7630579ea79cb7d0b514a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nJ ( x ) , J ( \\\\nabla _ { u } F ( x ) , x ) , J ( \\\\nabla _ { u } \\\\nabla _ { \\\\nu } F ( x ) , x ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,651,578,667]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\pmb { u }$ , v are (partial) solutions of the extended system. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[200,676,794,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Proof. Since Deg $F = 3$ , we can see that $J ( \\\\nabla _ { \\\\mathbf { u } } \\\\nabla _ { \\\\mathbf { v } } \\\\nabla _ { \\\\mathbf { w } } F ( \\\\mathbf { x } ) , \\\\mathbf { x } ) = \\\\mathbf { 0 }$ , for any solutions u, v, w of the extended system. \\u0003 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,719,795,750]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The degree of the polynomial systems obtained by tensor decompositions of tensors of order 3 are all of degree 3, such as the Brent equations in next section. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[346,770,653,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5. Numerical experiments on Brent equations \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,791,794,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Firstly, we recall the definition of Brent equations (see also [28]). Let $V _ { 1 } ~ = ~ \\\\mathbb { C } ^ { m \\\\times n }$ , $V _ { 2 } = \\\\mathbb { C } ^ { n \\\\times p }$ and $V _ { 3 } = \\\\mathbb { C } ^ { p \\\\times m }$ denote the set of complex $m \\\\times n , n \\\\times p$ and $p \\\\times m$ matrices, respectively. The matrix multiplication tensor is defined by (see e.g. [5, 24]) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[302,843,694,886]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0541/da3cbb4bfbfd3f30db7af38a6687a0e3b022152beafae7f10f983b948025f038.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\left. m , n , p \\\\right. = \\\\sum _ { i = 1 } ^ { m } \\\\sum _ { j = 1 } ^ { n } \\\\sum _ { k = 1 } ^ { p } e _ { i j } \\\\otimes e _ { j k } \\\\otimes e _ { k i } \\\\in \\\\mathbb { C } ^ { m \\\\times n } \\\\otimes \\\\mathbb { C } ^ { n \\\\times p } \\\\otimes \\\\mathbb { C } ^ { p \\\\times m } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[444,119,552,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,119,218,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[204,146,795,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $e _ { i j }$ denotes the matrix with a 1 in the ith row and jth column, and other entries are 0. Finding a tensor decomposition of $\\\\langle m , n , p \\\\rangle$ with rank $r$ is equivalent to find solutions of a system of polynomial equations called the Brent equations, which is given as follows: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[380,196,616,237]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0797/955b53ff5149277cd01b7d6fc483b675941b677d29c6bba2f1c84b662b84e1e2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\sum _ { i = 1 } ^ { r } \\\\alpha _ { i _ { 1 } , i _ { 2 } } ^ { ( i ) } \\\\beta _ { j _ { 1 } , j _ { 2 } } ^ { ( i ) } \\\\gamma _ { k _ { 1 } , k _ { 2 } } ^ { ( i ) } = \\\\delta _ { i _ { 2 } , j _ { 1 } } \\\\delta _ { j _ { 2 } , k _ { 1 } } \\\\delta _ { k _ { 2 } , i _ { 1 } } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[207,241,790,275]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $ \\\\mathbf { \\\\mu } _ { , i _ { 1 } } \\\\in \\\\{ 1 , 2 , . . . , m \\\\} , ~ i _ { 2 } , ~ j _ { 1 } \\\\in \\\\{ 1 , 2 , . . . , n \\\\} , ~ j _ { 2 } , k _ { 1 } \\\\in \\\\{ 1 , 2 , . . . , p \\\\} , ~ \\\\delta _ { i j } \\\\ : \\\\mathbf { i } _ { 1 }$ s the Kronecker symbol, $\\\\alpha _ { i _ { 1 } , i _ { 2 } } ^ { ( i ) } , \\\\beta _ { j _ { 1 } , j _ { 2 } } ^ { ( i ) }$ and $\\\\gamma _ { k _ { 1 } , k _ { 2 } } ^ { ( i ) }$ are unknown variables. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,275,794,335]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the following, the polynomial system in (5.2) is called the Brent equations of type $[ m , n , p | r ]$ , which is denoted by $B ( m , n , p | r )$ . We can see that the polynomial system $B ( m , n , p | r )$ has $( m n + n p + p m ) r$ variables and $( m n p ) ^ { 2 }$ equations. So $B ( m , n , p | r )$ can be considered as a polynomial mapping: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[377,340,620,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0345/8074a01783d2e81d166a4c352a4dcd694b76503a7b3de450ba124b28fce6cf96.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nB ( m , n , p | r ) \\\\colon \\\\mathbb { C } ^ { ( m n + n p + p m ) r } \\\\to \\\\mathbb { C } ^ { ( m n p ) ^ { 2 } } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[200,366,805,396]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Usually, $B ( m , n , p | r )$ is an overdetermined polynomial system. The solution set of $B ( m , n , p | r )$ over $\\\\mathbb { C }$ is denoted by $\\\\mathbf { V } ( m , n , p | r )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,397,795,505]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the convenience of coding, an order can be given for the variables in (5.2). For example, for $i = 1 , 2 , . . . r$ let $A _ { i } = \\\\bar { \\\\left( \\\\alpha _ { i _ { 1 } , i _ { 2 } } ^ { ( i ) } \\\\right) } \\\\in \\\\mathbb { C } ^ { m \\\\times n }$ , $B _ { i } = \\\\big ( \\\\beta _ { j _ { 1 } , j _ { 2 } } ^ { ( i ) } \\\\big ) \\\\in \\\\mathbb { C } ^ { n \\\\times p }$ \\u0011 ∈ Cn×p and Ci = \\u0010γ(i)k1 ,k2 \\u0011 $\\\\mathbb { C } ^ { n \\\\times p }$ . For any matrix in $\\\\mathbb { C } ^ { a \\\\times b }$ , define the columnwise vectorization map $C \\\\colon \\\\mathbb { C } ^ { a \\\\times b } \\\\mathbb { C } ^ { a b \\\\times 1 }$ by concatenating the columns of the matrix in $\\\\mathbb { C } ^ { a \\\\times b }$ as a column vector of $\\\\mathbb { C } ^ { a b \\\\times 1 }$ (or $\\\\mathbb { C } ^ { a b }$ ). For example, let $\\\\boldsymbol { a } = \\\\left[ \\\\begin{array} { l l } { a _ { 1 1 } } & { a _ { 1 2 } } \\\\\\\\ { a _ { 2 1 } } & { a _ { 2 2 } } \\\\end{array} \\\\right] \\\\in \\\\mathbb { C } ^ { 2 \\\\times 2 }$ , then $C ( { \\\\boldsymbol { a } } ) = [ a _ { 1 1 } , a _ { 2 1 } , a _ { 1 2 } , a _ { 2 2 } ] ^ { \\\\mathbf { T } } \\\\in \\\\mathbb { C } ^ { 4 }$ . For $i = 1 , 2 , . . . r$ , let \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[403,503,593,553]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0585/baecd1fda12865cd4b6ad460d0c4c6584c99ca8778f3c0bc727e2f8dede515c0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf { x } _ { i } = \\\\left[ \\\\begin{array} { c } { C ( A _ { i } ) } \\\\\\\\ { C ( B _ { i } ) } \\\\\\\\ { C ( C _ { i } ) } \\\\end{array} \\\\right] \\\\in \\\\mathbb { C } ^ { m n + n p + p m } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[205,555,488,569]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Then we can order the variables in (5.2) by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[410,577,588,631]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0733/1da1febf7a727083c6e76ddfb0d2b4236f22290ba0f5c4b2bf62a9c05bfc2d69.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\mathbf { x } = \\\\left[ \\\\begin{array} { c } { \\\\mathbf { x } _ { 1 } } \\\\\\\\ { \\\\vdots } \\\\\\\\ { \\\\mathbf { x } _ { r } } \\\\end{array} \\\\right] \\\\in \\\\mathbb { C } ^ { ( m n + n p + p m ) r } .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,637,794,683]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the following of this section, we report our experimental results. By Theorem 3.2 and Remark 3.3, the deflation sequence tells us the bound of the local dimension. We can see that the as $r$ in (5.2) decreases, singular solutions become more and more. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,694,633,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.1. Deflation test on $\\\\mathbf { V } ( 2 , 2 , 2 | 7 )$ : Strassen’s classical solution. \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,710,795,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For $B ( 2 , 2 , 2 | 7 )$ , it is an underdetermined system which has $m = 6 4$ equations and $n = 8 4$ variables. So from equation (3) of [36], we know that for any $p \\\\in \\\\mathbf { V } ( 2 , 2 , 2 | 7 )$ , its local dimension has a lower bound \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[357,762,638,779]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0256/f7d9f26527013ae1f1fd45f6b5aad5ec34d5c1fcc43ef02c3b0279caba7fed0f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n2 0 = 8 4 - 6 4 = n - m \\\\leq \\\\mathrm { d i m } _ { p } \\\\mathbf { V } ( 2 , 2 , 2 | 7 ) .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[204,784,797,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In particular, for the classical solution of $B ( 2 , 2 , 2 | 7 )$ given by Strassen [34] (see also [5, 24]), after doing deflation 3 times, the first 4 numbers of deflation sequence are \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,844,709,861]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"So its local dimension should be 23. Moreover, $\\\\mathrm { d i m } { \\\\bf V } ( 2 , 2 , 2 | 7 )$ should be 23. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,867,717,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Remark 5.1. It was proved in [10] that $\\\\mathbf { V } ( 2 , 2 , 2 | 7 )$ has projective dimension 9. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[297,118,702,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[779,119,792,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,147,442,161]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.2. Deflation test on $\\\\mathbf { V } ( 3 , 3 , 3 | 2 3 )$ . \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,162,812,252]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the website [17], using SAT solvers Heule et al. provided 17376 solutions in $\\\\mathbf { V } ( 3 , 3 , 3 | 2 3 )$ which are inequivalent under the de Groote group action [5, 9]. We take deflation test on these solutions. We found that most of these solutions are ultrasingular. Let $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ be the first 4 numbers of the deflation sequence. Overall, from the experimental result, we can see that $7 6 \\\\leq n _ { 0 } \\\\leq 9 5$ (see also [28, Sect. 3]). After doing deflation 3 times, we can see that $7 0 \\\\leq n _ { 3 } \\\\leq 8 6$ . The data can be found on [29]. The results are summarized below. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,260,795,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.2.1. The first step of deflation. Among the 17376 solutions, after doing the first step of deflation, there are 16511 solutions whose nullities of Jacobians are strictly decreased, that is, $n _ { 0 } > n _ { 1 }$ . Let $d _ { 1 } = n _ { 0 } - n _ { 1 }$ . Then the numerical experiment tells us that $0 \\\\leq d _ { 1 } \\\\leq 2 3$ . The distribution is as follows. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[227,332,769,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0889/8d953cce634d073654a6c6eda0a05c5887f126911062c6bf7669d823853ebea9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=1 colspan=1>d =no-n1</td><td rowspan=1 colspan=1>d1=0</td><td rowspan=1 colspan=1>d=01≤d≤3</td><td rowspan=1 colspan=1>4≤d≤10</td><td rowspan=1 colspan=1>11≤d ≤23</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>865</td><td rowspan=1 colspan=1>5495</td><td rowspan=1 colspan=1>9375</td><td rowspan=1 colspan=1>1641</td><td rowspan=1 colspan=1>17376</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[202,392,795,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.2.2. The second step of deflation. After doing the second step of deflation, there are 16206 solutions whose nullities of Jacobians are strictly decreased, that is, $n _ { 1 } > n _ { 2 }$ . Let $d _ { 2 } = n _ { 1 } - n _ { 2 }$ . Then the numerical experiment tells us that $0 \\\\leq d _ { 2 } \\\\leq 1 0$ . The distribution is as follows. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[276,464,718,498]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0959/dc8e859db3bcf62b99f2f92cf6e216c847478217227940949054db7a025c9f80.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=1 colspan=1>d =n1-n2</td><td rowspan=1 colspan=1>d=0</td><td rowspan=1 colspan=1>1≤d≤3</td><td rowspan=1 colspan=1>4≤d≤10</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>1168</td><td rowspan=1 colspan=1>14732</td><td rowspan=1 colspan=1>1476</td><td rowspan=1 colspan=1>17376</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[204,525,795,616]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.2.3. The third step of deflation. In this step, there are only 978 solutions whose nullities of Jacobians are strictly decreased, that is, $n _ { 2 } > n _ { 3 }$ . Let $d _ { 3 } = n _ { 2 } - n _ { 3 }$ . Then the numerical experiment tells us that $0 \\\\leq d _ { 3 } \\\\leq 5$ . By Theorem 3.2, we know that $n _ { 2 } \\\\geq n _ { 3 }$ . However, due to the test is numerical, some errors appear for 41 solutions, that is, $n _ { 2 } - n _ { 3 } < 0$ . On the other hand, if we restart the deflation process separately for these solutions, we can find that $n _ { 2 } \\\\geq n _ { 3 }$ . The distribution can be seen as follows. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[240,628,754,662]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0828/5b85a76ca6df5a58d485752c7998f81093d752dcdf553631532bb7cc4c3be6da.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=1 colspan=1>d =n-n3</td><td rowspan=1 colspan=1>d=0</td><td rowspan=1 colspan=1>d=1</td><td rowspan=1 colspan=1>d=12≤d≤5</td><td rowspan=1 colspan=1>Error (d <0)</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>16357</td><td rowspan=1 colspan=1>795</td><td rowspan=1 colspan=1>183</td><td rowspan=1 colspan=1>41</td><td rowspan=1 colspan=1>17376</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[205,679,795,724]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The first 4 numbers of deflation sequence of Laderman’s solution [23] are (76,76,76,76). The first 4 numbers of deflation sequence of Smirnov’s solution [33] in $\\\\mathbf { V } ( 3 , 3 , 3 | 2 3 )$ are (87,82,79,79). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,733,442,747]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.3. Deflation test on $\\\\mathbf { V } ( 4 , 4 , 4 | 4 9 )$ . \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,748,794,792]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In [13, 14], Fawzi et al. provided 14236 solutions in $\\\\mathbf { V } ( 4 , 4 , 4 | 4 9 )$ , which are inequivalent under the isotopy group action. We take deflation on these points and find that the ultrasingular solutions are relatively small among all the 14236 solutions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,794,794,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Note that $B ( 4 , 4 , 4 | 4 9 )$ has 2352 variables and 4096 equations. For each solution, it takes about 10 minutes for the computation of $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ . It will spend a lot of time if we take the first 3 steps of deflation for all 14236 solutions. On the other hand, the time for the computation of $( n _ { 0 } , n _ { 1 } )$ is relatively acceptable. So we firstly take the first step of deflation on Fawzi et al.’s solutions and obtain $( n _ { 0 } , n _ { 1 } )$ of the 14236 solutions, the data can be found on [29]. The distribution is summarized as follows. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[444,119,552,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,121,218,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[323,143,673,178]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0823/91a2a313f4d521082a62a17bbec4d9cd795a44da9cbab1f0031878cc1686421f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1>n=no=197</td><td rowspan=1 colspan=1>no >n1</td><td rowspan=1 colspan=1>Total number</td></tr><tr><td rowspan=1 colspan=1>Number</td><td rowspan=1 colspan=1>13530</td><td rowspan=1 colspan=1>706</td><td rowspan=1 colspan=1>14236</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[204,198,797,272]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Secondly, from above table, for the 13530 solutions whose $n _ { 0 } = n _ { 1 } = 1 9 7$ , we randomly choose 100 solutions and take the second and third deflation steps to obtain $( n _ { 2 } , n _ { 3 } )$ . For all the 100 solutions, we find that $n _ { 2 } = n _ { 3 } = 1 9 7$ , so the first 4 numbers of their deflation sequences are all equal to: (197,197,197,197). So this implies that for all 13530 solutions we should have $n _ { 0 } = n _ { 1 } = n _ { 2 } = n _ { 3 } = 1 9 7$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,273,813,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the remaining 706 solutions, their first 4 numbers of deflation sequences $( n _ { 0 } , n _ { 1 } , n _ { 2 } , n _ { 3 } )$ are computed. We found that: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[232,306,493,352]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(1) $1 5 1 \\\\leq n _ { 0 } \\\\leq 2 0 8$ ; \\n(2) $1 4 5 \\\\le n _ { 3 } \\\\le 1 8 2$ ; \\n(3) for most solutions we have $n _ { 2 } = n _ { 3 }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,361,547,375]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.4. Deflation test on other well-known solutions. \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,376,795,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Firstly, the first 4 numbers of deflation sequence Smirnov’s solution [33] that lies in $\\\\mathbf { V } ( 3 , 3 , 6 | 4 0 )$ are: (131, 131, 131, 131). So it seems that this solution is semiregular. Recently, Kauers and Moosbauer found many new solutions of $B ( m , n , p | r )$ and put them on Github [20, 21]. We take deflation process for some solutions that are suitable to the complex field. The first 4 numbers of deflation sequence are summarized in Table 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[383,464,614,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0058/56ac8a66a750f83f465453d0e7b0f9b6d643ef61dcf8d0ae0e6b187daa21a103.jpg\",\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=1 colspan=1>(m,n,plr)</td><td rowspan=1 colspan=1>(no,ni,n2,n3)</td></tr><tr><td rowspan=1 colspan=1>(3,4,5|47)</td><td rowspan=1 colspan=1>(152,149,148,148)</td></tr><tr><td rowspan=1 colspan=1>(4,4,5|62)</td><td rowspan=1 colspan=1>(201,194,193,193)</td></tr><tr><td rowspan=1 colspan=1>(4,5,5|76)</td><td rowspan=1 colspan=1>(251,251,251,251)</td></tr><tr><td rowspan=1 colspan=1>(5,5,5|97)</td><td rowspan=1 colspan=1>(395,344,339,339)</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[\\\"Table 1. Deflation sequences for some solutions in [20, 21] \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[205,569,823,614]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Table 1, $( m , n , p | r )$ means the solution lie in the set $\\\\mathbf { V } ( m , n , p | r )$ , which can be found in the Github database of the article [20, 21]. In particular, the computation of (395, 344, 339, 339) for (5, 5, 5|97) spends the time about 4.8 hours on our server. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,623,491,637]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.5. Deflation test on natural algorithms. \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,638,795,698]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When $r = m n p$ , the definition of $\\\\langle m , n , p \\\\rangle$ in (5.1) provides a solution of $B ( m , n , p | m n p )$ which is denoted by $N ( m , n , p )$ . Before Strassen’s algorithm [34], we usually use the algorithm induced in (5.1) for the computation of matrix multiplication. So we call $N ( m , n , p )$ the natural algorithm. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,699,794,758]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Intuitively, $N ( m , n , p )$ should be semiregular. So we should have $n _ { 0 } = n _ { 1 } = n _ { 2 } = n _ { 3 }$ for their deflation sequences. When $2 \\\\leq m , n , p \\\\leq 4$ , our experimental results are summarized in Table 2. In Table 2, it is interesting to see that there is a big drop between $n _ { 1 }$ and $n _ { 2 }$ . It tells us that the natural algorithms are geometric singular. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[379,772,617,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6. final remarks and open problems \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,792,794,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6.1. The deflation sequence as an invariant. In [28, Quest. 3.15], we observed that the rank of Jacobian of $B ( m , n , p | r )$ may be served as an invariant to decide the equivalent classes under the de Groote group action [5, 9]. Further discussions of de Groote group action can be seen from [18, 24, 35], etc. In this paper, from the numerical experiment, we also find that the deflation sequences are unchanged when the solutions are transformed by the de Groote group action. So we have the following question. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[299,119,704,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[779,121,792,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[390,143,607,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0477/e1842f38b4c3c7610040d77191bf3e489f754368b63e925fe435db0b5074f14b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1>(no,ni,n2,n3)</td></tr><tr><td rowspan=1 colspan=1>N(2,2,2)</td><td rowspan=1 colspan=1>(40,40,32,22)</td></tr><tr><td rowspan=1 colspan=1>N(2,2,3)</td><td rowspan=1 colspan=1>(72,72,48,34)</td></tr><tr><td rowspan=1 colspan=1>N(2,3,3)</td><td rowspan=1 colspan=1>(126,126,54,50)</td></tr><tr><td rowspan=1 colspan=1>N(3,3,3)</td><td rowspan=1 colspan=1>(216,216,72,72)</td></tr><tr><td rowspan=1 colspan=1>N(3,3,4)</td><td rowspan=1 colspan=1>(324,324,96,96)</td></tr><tr><td rowspan=1 colspan=1>N(3,4,4)</td><td rowspan=1 colspan=1>(480,480,126,126)</td></tr><tr><td rowspan=1 colspan=1>N(4,4,4)</td><td rowspan=1 colspan=1>(704,704,164,164)</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[\\\"Table 2. Deflation sequences for natural algorithms \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[204,300,795,329]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Question 6.1. For two points in $\\\\mathbf { V } ( m , n , p | r )$ , if their deflation sequences are different, do they also lie in different group orbits under the de Groote group action? \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,337,794,398]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the deflation sequence $( n _ { 0 } , n _ { 1 } , . . . ) , n _ { 0 }$ is the nullity of Jacobian. So the deflation sequence contains more information and is more useful to distinguish the equivalent classes. For the solutions in [17], in our numerical experiment, it is easy to find two deflation sequences $( n _ { 0 } , n _ { 1 } , . . . )$ and $( n _ { 0 } ^ { \\\\prime } , n _ { 1 } ^ { \\\\prime } , . . . )$ such that $n _ { 0 } = n _ { 0 } ^ { \\\\prime }$ but $n _ { 1 } \\\\neq n _ { 1 } ^ { \\\\prime }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,398,792,457]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However, for the solutions provied in [14], almost all solutions have the deflation sequence:(197,197,197,197). So in this case, distinguishing equivalent classes by deflation sequences is not so effective. On the other hand, this implies that the tensor rank of h4, 4, 4i should be less than 49. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,465,792,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6.2. Deciding the singularity of a solution. Given a polynomial system and a solution. Which type of the solution belongs to: numerical smooth/singular or geometric smooth/singular? The deflation sequence only tells us partial information about the type. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,518,794,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6.3. The real deflation process. By now, the deflation processes in [7, 8, 16, 26] are given for the complex algebraic set. In practical, the polynomial system we are interested is often of real coefficients and has real solutions. For example, the Brent equations are of this type. Is the results in [7, 8, 16, 26] also suitable to the real algebraic set? For example, it is not hard to see that Conjecture 1 also has a real counterpart. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,602,794,678]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6.4. On local real dimension and local complex dimension. From the relation between fast matrix algorithms and solutions of the Brent equations [5, 18], we can see that integer, rational and real solutions are more useful than complex solutions. For real solutions of the Brent equation, we want to know the difference between the local real dimension and local complex dimension. Related discussions are given in the paper [15]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,684,794,744]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6.5. On the numerical determination of local dimension. On how to determine the local dimension, Kuo and Li provided a numerical method in [22]. In addition, in the neighbourhood of the solution, the convergence behavior under the rank- $r$ projection iteration in [37] can also help us identify the local dimension of the solution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[436,756,560,770]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,777,815,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Xin Li is supported by National Natural Science Foundation of China (Grant No.11801506). Liping Zhang is supported by the Zhejiang Provincial Natural Science Foundation of China (Grant No. LY21A010015) and Grant 11601484, the National Natural Science Foundation, People’s Republic of China. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[202,839,794,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The discussion with Professor Zhonggang Zeng of Northeastern Illinois University inspired us a lot. We are grateful to him for so many valuable comments and suggestions. We are grateful to Yuan Feng, Xiaodong Ding, Liaoyuan Zeng, Changfeng Ma and Jinyan \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,121,218,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[444,119,552,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[205,147,794,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fan for their kind supports and suggestions. Many thanks to Professor Petr Tichavsk ´y for many helpful discussions when we prepare this paper. Xin Li show his appreciation to Yaqiong Zhang for her support and patience. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[460,220,535,233]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[204,234,794,886]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. D. J. Bates, Jonathan D. Hauenstein, C. Peterson, Andrew J. Sommese, A numerical local dimensions test for points on the solution set of a system of polynomial equations SIAM J. Numer. Anal. 47(2009), no.5, 3608-3623. \\n2. D.J. Bates, J.D. Hauenstein, C. Peterson, A.J. Sommese, Numerical decomposition of the rank-deficiency set of a matrix of multivariate polynomials, in: L. Robbiano, J. Abbott (Eds.), Approximate Commutative Algebra, Springer Vienna, Vienna, 2010, pp. 55-77. \\n3. D. J. Bates, J. D. Hauenstein, A. J. Sommese, and C. W. Wampler, Numerically solving polynomial systems with Bertini, Software, Environments, and Tools, vol. 25, Society for Industrial and Applied Mathematics (SIAM), Philadelphia, PA, 2013. \\n4. D. J. Bates, D. Eklund, J. D. Hauenstein, and C. Peterson. Excess intersections and numerical irreducible decompositions. In 2021 23rd International Symposium on Symbolic and Numeric Algorithms for Scientific Computing (SYNASC), pages 52-60, 2021. \\n5. Vladimir P. Burichenko, Symmetries of matrix multiplication algorithms I, arXiv:1508.01110, 2015. \\n6. David A. Cox, J. Little, D. O’Shea, Ideals, varieties, and algorithms. Fourth edition. Undergraduate Texts in Mathematics. Springer, 2015. \\n7. Barry H. Dayton, Zhonggang Zeng, Computing the multiplicity structure in solving polynomial systems. ISSAC’05, 116-123, ACM, New York, 2005. \\n8. Barry H. Dayton, Tien-Yien Li, Zhonggang Zeng, Multiple zeros of nonlinear systems. Math. Comp. 80(2011), no.276, 2143-2168. \\n9. H.F. de Groote, On varieties of optimal algorithms for the computation of bilinear mappings. I. The isotropy group of a bilinear mapping, Theor. Comput. Sci. 7(1978), 1-24. \\n10. H.F. de Groote, On varieties of optimal algorithms for the computation of bilinear mappings. II. Optimal algorithms for $2 \\\\times 2$ matrix multiplication, Theor. Comput. Sci. 7(1978), 127-148. \\n11. W. Decker, F. O. Schreyer, Varieties, Gr ¨obner Bases, and Algebraic Curves. To appear. 2007. \\n12. 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Safey El Din, Computing the dimension of real algebraic sets. ISSAC’21, 257-264, ACM, New York. \\n26. Anton Leykin, Jan Verschelde, Ailing Zhao, Newton’s method with deflation for isolated singularities of polynomial systems. Theoret. Comput. Sci. 359(2006), no.1-3, 111-122. \\n27. A. D. Lewis, Semicontinuity of rank and nullity and some consequences, https://mast.queensu.ca/˜andrew/notes/pdf/2009a.pdf, preprint 2009. \\n28. X. Li, Y. Bao, L. Zhang, On the local dimensions of solutions of Brent equations, arXiv:2303.09754. \\n29. X. Li, Github: https://github.com/Xinli-zjut. \\n30. T. Ojika, S. Watanabe, T. Mitsui, Deflation algorithm for the multiple roots of a system of nonlinear equations. J. Math. Anal. Appl. 96(1983), no.2, 463-479. \\n31. T. Ojika, Modified deflation algorithm for the solution of singular problems. I. A system of nonlinear algebraic equations. J. Math. Anal. Appl. 123(1987), no.1, 199-221. \\n32. A.J. Sommese, C.W. Wampler, The Numerical Solution of Systems of Polynomials Arising in Engineering and Science, World Scientific, Singapore, 2005. \\n33. A. V. Smirnov, The bilinear complexity and practical algorithms for matrix multiplication. Comput. Math. Math. Phys. 53(2013), no.12, 1781-1795. \\n34. V. Strassen, Gaussian elimination is not optimal, Numer. Math. 13(1969), 354-356. \\n35. Petr Tichavsk ´y, Characterization of Decomposition of Matrix Multiplication Tensors, arXiv:2104.05323v1, 2021. \\n36. C. W. Wampler, J. D. Hauenstein, A. J. Sommese, Mechanism mobility and a local dimension test, Mechanism and Machine Theory, 46(2011) 1193-1206. \\n37. Zhonggang Zeng, A Newton’s iteration converges quadratically to nonisolated solutions too, Math. Comp. 92(2023), no.344, 2795-2824. Department of Mathematics, Zhejiang University of Technology, Hangzhou 310023, P. R. China Email address: xinli1019@126.com (Xin Li) School of Mathematical Sciences, Qufu Normal University, Qufu 273165, P. R. China Email address: zhanglp06@gmail.com (Liping Zhang) School of Mathematics and Statistics, Fujian Normal University, 350117 Fuzhou, P.R. China Email address: keyifen@fjnu.edu.cn (Yifen Ke) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[299,119,702,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DEFLATION CONJECTURE AND LOCAL DIMENSIONS OF BRENT EQUATIONS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[781,121,792,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[202,147,795,541]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,121,218,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"18 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[444,121,552,130]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LI, ZHANG, AND KE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.48550/arxiv.2310.11686"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Mathematics and Computational Science"},"sha256":{"kind":"string","value":"76bc2bb93b839cd24f8786f7709052e315eae73298bfd1404c1a13b5c06e2fed"},"title":{"kind":"string","value":"Deflation conjecture and local dimensions of Brent equations"}}},{"rowIdx":172,"cells":{"abstract":{"kind":"string","value":"Elder abuse is currently a worldwide problem. The literature reports that one elderly person out of six is a potential victim. To analyse cases reported to the judicial authorities in the territory of Genoa in the period 2010–2019, to investigate the features of elder abuse, to assess the trend of this phenomenon and to propose preventive strategies. We analysed the data on reports of abuse passed by the Court of Genoa in the period 2015–2019 concerning physical and mental maltreatment, abandonment and financial exploitation of elderly subjects. These data were compared with those recorded in the previous 5-year period and in the literature. In the period 2015–2019, 156 cases of elder abuse were identified (versus 63 in the previous period): 18 cases of domestic violence, 5 cases of abuse of the means of correction, 18 cases of caregiver neglect, 76 cases of physical injury and 39 cases of financial exploitation. Abuse was seen to be perpetrated most frequently in the domestic setting and by the victims' relatives. The main risk factors were female gender and the victim’s dependence on others, the maltreating subject’s mental illness and substance abuse. We documented a progressive increase in the number of abuses reported to the judicial authority; this reflects greater awareness of the problem. However, our figures remained well below the incidence estimated in the literature. It is necessary to train healthcare personnel to identify and manage cases of suspected abuse, and to provide adequate support in situations at risk."},"author":{"kind":"string","value":"Martina Drommi|Andrea Molinelli|Francesco Ventura|Alessandra Ponte"},"content_list":{"kind":"list like","value":[{"bbox":"[80,130,811,200]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Elder abuse in Europe's \"most elderly\" city: an update of the phenomenon based on the cases reported to the Penal Court of Genoa from 2015 to 2019 and literature review ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,218,642,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Martina Drommi $^{1}$ · Alessandra Ponte $^{1}$ · Francesco Ventura $^{1}$ · Andrea Molinelli $^{1}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,256,386,282]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 2 December 2020 / Accepted: 8 January 2021 \n© The Author(s) 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,307,149,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,322,915,351]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background Elder abuse is currently a worldwide problem. The literature reports that one elderly person out of six is a potential victim. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,353,914,384]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aims To analyse cases reported to the judicial authorities in the territory of Genoa in the period 2010-2019, to investigate the features of elder abuse, to assess the trend of this phenomenon and to propose preventive strategies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,384,915,432]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods We analysed the data on reports of abuse passed by the Court of Genoa in the period 2015–2019 concerning physical and mental maltreatment, abandonment and financial exploitation of elderly subjects. These data were compared with those recorded in the previous 5-year period and in the literature. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,432,915,479]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results In the period 2015–2019, 156 cases of elder abuse were identified (versus 63 in the previous period): 18 cases of domestic violence, 5 cases of abuse of the means of correction, 18 cases of caregiver neglect, 76 cases of physical injury and 39 cases of financial exploitation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,479,915,526]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion Abuse was seen to be perpetrated most frequently in the domestic setting and by the victims' relatives. The main risk factors were female gender and the victim's dependence on others, the maltreating subject's mental illness and substance abuse. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,527,915,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions We documented a progressive increase in the number of abuses reported to the judicial authority; this reflects greater awareness of the problem. However, our figures remained well below the incidence estimated in the literature. It is necessary to train healthcare personnel to identify and manage cases of suspected abuse, and to provide adequate support in situations at risk. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,606,766,622]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords Elder abuse $\\cdot$ Domestic violence $\\cdot$ Ageism $\\cdot$ Personal injury $\\cdot$ Prosecutor's office $\\cdot$ Sentence ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,651,200,669]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,684,487,748]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The phenomenon of elder abuse is a highly topical and significant issue. Indeed, it is estimated that, worldwide, one elderly person out of six is a victim of some type of abuse (about 141 million victims per year) [1]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,749,485,812]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The WHO defines elder abuse as \"a single or repeated act, or the lack of appropriate action, occurring within any relationship where there is an expectation of trust which causes harm or distress to an older person\" [2]. The phenomenon ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,654,915,732]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is extremely serious in view of its possible impact on the life expectancy of elderly subjects; indeed, it gives rise to situations of mental and social distress and increases rates of mortality, hospitalisation and access to emergency departments [3, 4]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,732,915,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Given that the world's population is steadily ageing, the phenomenon of elder abuse is destined to become increasingly common. Data on World Population Ageing indicate that the number of persons aged more than 65 years will increase from 703 million in 2019 to 1.5 billion in 2050 [5]. Moreover, it is estimated that the number of persons aged over 80 years will increase even more markedly, reaching 426 million in 2050. This latter age-group is at greater risk of frailty, isolation and impaired personal autonomy—factors associated with the risk of abuse [6]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,334,67]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research https://doi.org/10.1007/s40520-021-01790-6 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,79,243,94]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORIGINAL ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,81,915,120]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,841,290,870]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Martina Drommi martina.drommi91@gmail.com ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[80,879,433,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Department of Forensic and Legal Medicine, University of Genova, Via De' Toni 12, 16132 Genova, Italy ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[80,929,284,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published online: 31 January 2021 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[840,927,915,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,69,485,227]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Italy, according to the National Statistics Institute (ISTAT), by 2019 life expectancy at birth had risen to 81 years for men and 85.3 years for women [7]. With regard to the metropolitan area of Genoa, one of Europe's \"most elderly\" cities and the focus of our investigation, elderly subjects (over 65 years of age) account for almost $29\\%$ of the total population of 841,180. Given the structure of the population and the high index of dependence $(47.3\\%)$ of the elderly, the territory under examination is one in which the risk of abuse is high. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,227,485,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With regard to the phenomenon of elder abuse, we can distinguish abuse in domestic/community settings [1] and abuse in institutional settings (care facilities, hospitals) [8]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,275,485,353]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Concerning abuse in the community setting [1], a recent meta-analysis reported that the phenomenon involved $15.7\\%$ of subjects aged over 65 years (11.6% psychological abuse, $6.8\\%$ financial abuse, $4.2\\%$ abandonment and neglect, $2.6\\%$ physical abuse, $0.9\\%$ sexual abuse). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,354,485,559]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With regard to abuse in institutional settings, the European Journal of Public Health [8] reported that almost two out of three $(64.2\\%)$ staff members had reported some form of maltreatment of elderly patients, mainly physical and psychological. Moreover, a survey conducted among the staff of residences for the elderly in the United States in 1993 revealed that about $40\\%$ had perpetrated psychological abuse, while $10\\%$ had committed acts of physical violence [9]. By contrast, a 2018 Chinese study of elderly people's residences reported a much lower incidence of the phenomenon: of the 681 elderly subjects recruited in two different facilities, $11.48\\%$ claimed to have suffered psychological abuse and $8.24\\%$ physical abuse [10]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,560,485,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition, a US study involving 2,713 elderly persons estimated the incidence of elder abuse in community settings to be about $8.8\\%$ ; the risk factors identified were: female gender, advanced age ( $>85$ years) and the presence of multiple physical pathologies. The type of abuse most frequently cited was psychological ( $4.8\\%$ ), followed by financial ( $2.9\\%$ ), caregiver neglect ( $1.1\\%$ ), physical ( $0.5\\%$ ) and sexual abuse ( $0.1\\%$ ) [11]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,686,485,748]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The term \"physical abuse\" refers to the use of force that may result in injury, pain or permanent damage; these actions include violent behaviours, corporal punishment and the improper administration of pharmaceutical drugs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,749,485,843]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Psychological maltreatment consists of causing anxiety and/or distress through the use of verbal or non-verbal language and includes threats, intimidation, molestation, and forced isolation of victims from their loved ones. The prolonged state of anguish that may ensue can result in changes of mood and even in full-blown depression [12]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,844,485,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Elderly people, who are often frail and dependent on others, are also vulnerable to theft, fraud or other types of economic exploitation. Financial abuse is defined as the illegal use of an elderly subject's funds, goods or property, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,69,912,100]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the unauthorised cashing of cheques and falsification of the person's signature. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,101,914,227]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Another aspect of elder abuse is that of neglect. For instance, a caregiver may fail to provide for the elderly person's primary necessities, in terms not only of hygiene, feeding and therapy but also of psychological and social needs [13]. This may be due to the caregiver's lack of professional training or to wilful neglect on the part of a caregiver who is only interested in being paid and/or obtaining free accommodation [14]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,227,914,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Risk factors for the maltreatment of elderly persons include: female sex, advanced age, cohabitation with the abuser, social isolation and a poor network of support [15]; dementia and other neurological disorders also facilitate abuse, in that caring for such patients places a burden on the caregiver, both physically and, especially, psychologically. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,322,912,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For what concerns the perpetrators of abuse, they are most often members of the elderly person's own family, who are compelled to act as caregivers; this is mainly the case in community settings. In institutional settings, it is the healthcare workers themselves who act as caregivers, and who are therefore at risk of enacting abusive behaviours [16]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,417,912,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The factors that place caregivers at risk of becoming abusers are substance abuse (alcohol or drugs), psychiatric disorders, physical problems, social isolation, a perception of being overburdened with responsibility, and financial or employment problems that may make the subject dependent on the victim [17-19]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,512,914,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Italy, the family is the mainstay of the care of elderly persons. Consequently, the phenomenon of \"informal caregiving\" is common; indeed, the elderly are frequently looked after by family members, who often lack the skills needed to carry out this task. Moreover, the commitment undertaken requires the caregiver to live in the same house as the elderly person and to make considerable sacrifices. Indeed, the burden of assistance is added to the ordinary duties of work and family; this may result in economic and social problems, while the elderly person's continual requests may give rise to stress, anxiety and depression [20, 21]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,702,914,859]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although the case-reports reveal that elder abuse is a serious problem and that its dimensions are inevitably destined to increase, the phenomenon remains underestimated. Indeed, it has been claimed that only 1 in every 24 cases is reported to the judicial authorities [22]. Although the institutions have devoted greater attention to elder abuse over the last decade (owing to media coverage of residential facilities for the elderly), the phenomenon has been only scantily investigated; this hinders the evaluation of its true magnitude and of the adoption of possible preventive measures [23]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,860,912,907]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Italy, there is still no specific law that safeguards elderly persons. Indeed, under Italian law, the elderly subject is equated with any subject who is in a state of need, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[684,37,915,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[84,927,154,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,69,485,256]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"poverty or abandonment [24]. In the Italian Penal Code, the articles that refer more specifically to violence against elderly persons are art. 570 (Violation of the obligations of family care), art. 571 (Abuse of the means of correction or discipline), art. 572 (Maltreatment of family members and cohabiting persons), art. 582 (Personal injuries), art. 591 (Abandonment of minors or incapable persons) and art. 643 (Circumvention of incapable persons). Owing to the intrinsic fragility of elderly persons, these subjects are vulnerable to the offences that we considered, the consequences of which, in prognostic terms, constitute a serious social and economic problem for society. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[84,305,290,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Materials and methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[82,337,485,431]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The aim of our study was to analyse cases of elder abuse covered by the above-mentioned articles of the Penal Code that came to the attention of the judicial authority in the metropolitan area of Genoa between 2010 and 2019, in order to examine the characteristics of this abuse and propose preventive strategies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,432,485,589]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The data from the period 2015-2019 were obtained with the help of the Public Prosecutor's Office. Subsequently, these data were compared both with those recorded in a previous study conducted by the Department of Legal Medicine of the University of Genoa, which analysed reports and sentences registered in the previous 5-year period (2010-2014) [25], and with the data reported in the literature. In this way, we were able to depict the present state of the phenomenon and to trace its evolution over the last 10 years. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,591,485,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Examination of the contents of the sentences handed down enabled us to pick out several features of elder abuse in the territory considered: profiles of both abusers and victims (sex, age, psychological profile and possible pathologies of both), the type of relationship between the two, the settings in which the abuse took place and, finally, the verdicts pronounced (conviction or acquittal). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,69,576,84]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,103,885,117]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The following data emerged from the reports (Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,118,912,149]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A total of 979 offences were reported in the period 2015-2019, as against 300 in the period 2010-2014. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,150,914,243]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With regard to the abuse of the means of correction or discipline, 7 reports were found; these involved offences of a strictly physical nature (beating, forced restraint, injury) that left visible signs on the victim's body; if such incidents are promptly reported, evidence of the offence can easily be gathered. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,245,912,339]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A large portion of the offences in our case-reports involved maltreatment in the family setting, which accounted for 165 reports. Art. 572 safeguards the person's physical safety, mental salubrity and dignity, and refers to unlawful conduct that is reiterated over time and enacted with the intention of engendering a state of permanent oppression. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,340,912,417]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Of the offences considered, those involving personal injuries were the most common (504 reports). The cases examined referred to situations in which there was a considerable difference in age between the victim and the abuser, who exploited the elderly person's frailty. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,418,912,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The abandonment of an incapable elderly person (38 reports) was seen to stem chiefly from disputes among the children of an infirm elderly subject, each of whom may, for various reasons, refuse to take on the responsibility of caring for a parent who is no longer self-sufficient. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,497,912,591]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, financial exploitation (240 reports) proved to be the second most frequent type of abuse, after physical and psychological maltreatment. Solitude, isolation and the presence of organic diseases that impair the individual's critical faculties and ability to distinguish between the good and bad intentions of others are the main risk factors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,593,912,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is very important to underline that there is a great difference between notifications of crimes and trial verdicts; indeed, while in the Italian legal system it is very simple to file a notification against someone, considerable evidence is needed to bring the person to trial. For this reason, there are many crime reports but few of them are judged worthy of prosecution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,762,915,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0167/00503dc459053c1be853e91fea92d0c83cb234b64b63b4d1827b9a232c5cf7aa.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>Penal code</td><td>2015</td><td>2016</td><td>2017</td><td>2018</td><td>2019</td><td>Total</td></tr><tr><td>Art 570 (violation of family care obligations)</td><td>7</td><td>9</td><td>6</td><td>1</td><td>2</td><td>25</td></tr><tr><td>Art 571 (abuse of the means of correction or discipline)</td><td>0</td><td>1</td><td>2</td><td>2</td><td>2</td><td>7</td></tr><tr><td>Art 572 (maltreatment of family members and cohabiting persons)</td><td>26</td><td>27</td><td>37</td><td>43</td><td>32</td><td>165</td></tr><tr><td>Art 582 (personal injury)</td><td>127</td><td>95</td><td>103</td><td>85</td><td>94</td><td>504</td></tr><tr><td>Art 591 (abandonment of minors or incapable persons)</td><td>8</td><td>5</td><td>8</td><td>9</td><td>8</td><td>38</td></tr><tr><td>Art 643 (circumvention of incapable persons)</td><td>43</td><td>56</td><td>41</td><td>46</td><td>54</td><td>240</td></tr><tr><td>Total</td><td>211</td><td>193</td><td>197</td><td>186</td><td>192</td><td>979</td></tr></table>","table_caption":"[\"Table 1 Analysis of the reports collected in Genoa during the period 2015-2019 \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[82,39,310,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[840,927,914,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,69,485,178]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Analysis of the judicial sentences enabled us to construct profiles of both abusers and abused elderly persons (sex, age, physical and/or mental disorders) and to identify the causes and settings of the abuses committed. We analysed a total of 4500 sentences, only 156 of which involved the abuse of an elderly person (3.5% of the total, versus 2.1% in the previous 5-year period). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,179,381,194]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The following figures emerged (Table 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,196,485,430]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For what concerns art. 571 (Abuse of the means of correction or discipline) the 5 cases examined occurred in residential facilities for the elderly, the maltreating subjects being nurses or care workers. The unlawful behaviour was seen to have been enacted during night shifts and involved the imposition of uncomfortable positions for long periods, forced immobilisation, and abuse of the means of constraint. Only in one case, however, was the perpetrator convicted; in the other cases, working conditions were acknowledged to be arduous, with few staff members having to deal with large numbers of patients, and constraint devices being applied for long periods to control bouts of psychomotor agitation or delirium. What emerges here is that lack of time and staff shortages exacerbate care-related stress and reduce the quality of the care provided. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,432,485,573]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Analysis of the sentences regarding art. 572 (Maltreatment of family members and cohabiting persons) turned up 18 cases of abuse perpetrated in the victim's own home, which was shared by the abuser. In $84\\%$ of cases, the perpetrator was a son/daughter of the victim; most perpetrators $(63\\%)$ were affected by problems of alcoholism, substance abuse or psychiatric disorders; moreover, 18 of the 21 maltreating subjects $(86\\%)$ were males, and 15 of the 21 $(71\\%)$ were aged over 40 years. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,575,485,713]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the case of informal caregivers, a lack of training and an overload of responsibility may lead to conflict, which may then trigger violent behaviour (damage to property) and physical or verbal aggression (insults, humiliation, death threats). Many authors have identified the following risk factors of abuse: parent-child relationship, male sex of the abuser, age over 40 years, substance abuse, alcoholism, psychiatric disorders, financial dependence on the victim, and forced cohabitation between the victim and the abuser. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,69,912,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Victims' children also proved to be the main offenders in cases involving art 582 (Personal injury), with the home again being the most frequent setting of maltreatment. Moreover, the crime of personal injury is often associated with that of maltreatment in the family (art. 572). Indeed, situations of ongoing daily conflict may explode in physical violence that causes fractures, bruises or lacerations, with the result that treatment in the Emergency Department is required and the incident is reported to the judicial authority. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,211,912,321]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Three cases of neglect came to light. In these cases, the offender was the victim's caregiver, a subject who is specifically responsible for the care and supervision of the elderly person, and the setting of the maltreatment was the home of an elderly person, who was not self-sufficient. The behaviour took the form of dereliction of duty: long absences from the home, neglect and failure to maintain proper hygiene. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,322,912,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Financial abuse figured in 39 sentences. The victims suffered from mental deficiency (Parkinson's disease, dementia, depression) and had a poor social network. Age proved to be a major risk factor; of the 43 victims, 26 $(60\\%)$ were over 80 years of age, while 8 $(19\\%)$ were aged between 75 and 84 years. The oldest old $(>85$ years) proved to be at the greatest risk of financial abuse, often being isolated and dependent on others. The offenders did not have a daily relationship with their victims, but gained their trust to defraud them; this occurred in 25 cases involving strangers, 7 cases involving caregivers, and 3 cases involving the staff of residential facilities. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,541,757,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion and conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,575,912,651]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Having analysed the results of the present study, and after comparing these with the data from the previous 5-year period [25] and those reported in the literature, we were able to draw several conclusions regarding the trend in the phenomenon of elder abuse over the past decade. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,654,912,713]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With regard to the sex of the victims of abuse, the literature indicates that women are at greater risk. Similarly, in our study, of the total of 249 elderly subjects who had suffered maltreatment, 134 were women and 115 were men. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,760,915,903]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0943/17ebed99f8a1bf5e7cf05d1c2323bb616176096b922ecb5fee447e8f2255f5b7.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Penal code</td><td>2015</td><td>2016</td><td>2017</td><td>2018</td><td>2019</td><td>Total</td><td>Conviction</td><td>Acquittal</td></tr><tr><td>Art 570—violation of family care obligations</td><td>0</td><td>3</td><td>5</td><td>6</td><td>1</td><td>15</td><td>7</td><td>8</td></tr><tr><td>Art 571—abuse of the means of correction...</td><td>2</td><td>2</td><td>0</td><td>1</td><td>0</td><td>5</td><td>1</td><td>4</td></tr><tr><td>Art 572—maltreatment of family members...</td><td>4</td><td>3</td><td>2</td><td>6</td><td>3</td><td>18</td><td>13</td><td>5</td></tr><tr><td>Art 582—personal injury</td><td>7</td><td>19</td><td>22</td><td>15</td><td>13</td><td>76</td><td>40</td><td>26</td></tr><tr><td>Art 591—abandonment of...incapable persons</td><td>1</td><td>1</td><td>0</td><td>0</td><td>1</td><td>3</td><td>0</td><td>3</td></tr><tr><td>Art 643—circumvention of incapable persons</td><td>8</td><td>3</td><td>7</td><td>10</td><td>11</td><td>39</td><td>19</td><td>20</td></tr><tr><td>Total</td><td>22</td><td>31</td><td>36</td><td>38</td><td>29</td><td>156</td><td>80</td><td>76</td></tr></table>","table_caption":"[\"Table 2 Analysis of the sentences passed in Genoa during the period 2015-2019 \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[685,39,915,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[82,927,154,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,69,484,100]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Moreover, women are at greater risk of reiterated abuse and physical and mental oppression. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,100,485,224]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Regarding the sex of abusers, there is no complete consensus in the literature. However, our study supported the conviction that a majority of cases of abuse are perpetrated by men. Indeed, on a total of 276 persons charged with abuse, 178 were men and 98 women; maltreatment perpetrated by males tended to be physical and violent (personal injury, abuse in the family), while females were more often involved in financial abuse. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,227,485,368]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although physical and psychological abuse was seen to be perpetrated most frequently by a single victims' relative, regarding the extra-family context our study has proved that abuses (especially financial abuse) were mainly perpetrated by a group of two or three people. In fact, acting as real criminal organizations, these strangers were able to gain the confidence of the elderly (pretending to be lawyers, bankers or investors) and to obtain money, cheques, goods or property illegally. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,370,485,588]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The most common setting of abuse was seen to be the elderly person's own home; about $47\\%$ of our cases took place in the domestic environment. This can be explained by the fact that in Italy, unlike the US or Northern European countries (where many of the other studies have been conducted), infirm elderly people tend to be looked after at home, and only exceptionally in residential facilities. In our study, only 5 cases $(8\\%)$ of abuse took place in institutional settings in the period 2010-2014, and only 14 $(9\\%)$ in the period 2015-2019. Although estimates of the incidence of abuse in residential facilities in Italy are not yet available, such institutions seem to be safer than the domestic environment, not least on account of the adoption of modern systems of staff surveillance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,589,485,763]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For what concerns the trend in the phenomenon of elder abuse over the decade considered, it must first be observed that the total number of cases notified differed markedly between the two 5-year periods; in the period 2015-2019, we recorded 979 reports and 156 sentences that met the criteria for inclusion in our analysis, as against 300 reports and 63 sentences in the previous 5-year period. This increase may have been due to the greater awareness of the problem on the part of the public and the judiciary, resulting in the emergence of cases that, in the past, would not have come to light. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,764,485,874]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present study confirmed that the most frequent perpetrators of abuse were the children of the victims, followed by spouses and caregivers; in the previous study, however, caregivers occupied the second position. This finding could suggest that owing to greater public awareness of the phenomenon, the families of elderly persons now exercise greater caution in choosing caregivers. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,875,485,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Comparison of the sentences handed down by the Court of Genoa during the two 5-year periods also yielded ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,68,914,178]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"interesting findings. The data that emerged from the two studies revealed that convictions had increased; during the second period, $51\\%$ of those charged with abuse were convicted, as against $35\\%$ in the first period. It can, therefore, be claimed that, during the period 2015-2019, more of the cases reported to the judiciary proved to be genuine cases of elder abuse, and that they were dealt with more strictly. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,179,914,336]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Given the progressive ageing of the global population, there is a need to increase our knowledge of the characteristics of maltreatment and its related mechanisms, to implement adequate prevention and to ensure prompt identification and effective management of the phenomenon. Doctors and the staff of emergency departments, hospitals and residential facilities play a fundamental role in the screening and identification of cases of abuse [26]; this implies the need to implement screening protocols that are agreed upon by the scientific community. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,337,914,510]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although the Comprehensive Geriatric Assessment (CGA) constitutes the \"gold standard\" for the thorough evaluation of the health and well-being of elderly subjects, it cannot be carried out in a short time (e.g. during visits by family doctors or non-geriatric specialists or in the emergency department) [15]. However, questionnaires like the BASE (Brief Abuse Screen for the Elderly) or the CASE (Caregiver Abuse Screen) can investigate suspected abuse during brief clinical examinations; these questionnaires differ in terms of their compilation time, ease of use and time required for personnel training [27]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,511,914,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The investigation of suspected abuse should include the history of the alleged maltreatment, the elderly person's recent and remote medical history, his/her dependence on others, assessment of the subject's functional capacity, identification of the use of physical or pharmacological means of constraint, psychiatric and cognitive evaluation, complete objective examination, and generic and toxicological laboratory tests [28]. Caution must always be exercised to avoid confusing age-related physiological modifications with signs of abuse; the five main pathological conditions that may cause confusion are skin lesions, anomalous bleeding, fractures, malnutrition and anogenital lesions [29, 30]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,701,914,858]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Interactions with healthcare personnel offer opportunities to recognise signs of abuse and enable suspected cases to be reported to the judicial authorities. Indeed, in the US, the percentage of accesses to the emergency department due to cases of ascertained elder abuse remains very low compared to the estimated prevalence [31]. This reveals the need to rectify the shortcomings in the identification and reporting of cases of abuse, which could be done by introducing training courses for healthcare personnel and implementing clear and appropriate screening protocols. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,859,912,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In particular, health-care professionals should receive adequate clinical-forensic training in order not only to recognize cases of abuse but also to gather evidence that may ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,39,310,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[840,927,914,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[78,68,485,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"be useful in criminal proceedings. If possible, after collecting the victim's details and story, consent shall be required for inspection, collection and correct storage of biological material for judicial purposes. After a general examination, the lesions on the victim's body must be located, accurately described and photographed, in order to ensure valuable evidence. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,179,485,226]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The ultimate objective, in fact, should be to improve knowledge of the phenomenon of elder abuse and to adopt a multidisciplinary approach to its management. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,227,485,320]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A further useful measure could be to introduce \"emergency refuges\", facilities where the elderly person can be temporarily assisted until such time as the problem can be properly dealt with. Moreover, systems of psychological and financial support should be made available to families who care for infirm elderly relatives. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,321,485,415]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With regard to cases of abuse by the staff of residential facilities, the causes appear to lie in the inadequate training of healthcare personnel and work-related stress. This implies that adequate training should be provided, workloads should be reduced and relationships between staff and inmates should be improved. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,417,485,541]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Elder abuse is an extremely complex and heterogeneous problem. Indeed, global prevention of the phenomenon, prompt identification of cases of maltreatment, the safeguard of victims and recognition of the difficulties facing caregivers are delicate issues that require adequate attention. Despite growing awareness of the phenomenon and the proposals mentioned above, elder abuse remains largely unrecognised and infrequently reported to the authorities. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,572,485,600]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author contributions All authors contributed to the study conception and design. All authors read and approved the final manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,613,485,639]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding Open Access funding provided by Università degli Studi di Genova. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,654,485,679]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Availability of data and materials This article does not involve clinical studies or contain patient data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,697,352,713]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Compliance with ethical standards ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,727,485,741]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflict of interest Authors declare that there is no conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,753,326,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Human and animal rights Not applicable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,777,282,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Informed consent Not applicable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,812,485,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,68,915,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,179,613,194]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[512,210,915,882]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Yon Y, Mikton CR, Gassoumis ZD et al (2017) Elder abuse prevalence in community settings: a systematic review and meta-analysis. Lancet Glob Health 5:147-156. https://doi.org/10.1016/S2214-109X(17)30006-2 \",\"2. World Health Organisation (2020) Elder abuse. https://www.who.int/news-room/fact-sheets/detail/elder-abuse. Accessed 15 June 2020 \",\"3. Dong XQ (2015) Elder abuse: systematic review and implications for pratie. 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Yon Y, Ramiro-Gonzales M, Mikton CR et al (2019) The prevalence of elder abuse in institutional settings: a systematic review and meta-analysis. Eur J Public Health 29:58-67. https://doi.org/10.1093/eurpub/cky093 \",\"9. Pillemer K, Hudson B (1993) A model abuse prevention program for nursing assistants. Gerontologist 33:128-131. https://doi.org/10.1093/geront/33.1.128 \",\"10. Wang F, Meng LR, Zhang Q et al (2018) Elder abuse and its impact on quality of life in nursing homes in China. Arch Gerontol Geriatr 78:155-159. https://doi.org/10.1016/j.archger.2018.06.011 \",\"11. Wang B, Dong X (2017) Incidence of Elder Abuse in a U.S. Chinese Population: findings from the longitudinal cohort PINE Study. J Gerontol A Biol Sci Med Sci 72:S95-S101. https://doi.org/10.1093/gerona/glx005 \",\"12. Fulmer T, Rodgers RF, Pelger A (2014) Verbal mistreatment of the elderly. J Elder Abuse Neglect 26:351-364. https://doi.org/10.1080/08946566.2013.801817 \",\"13. Ventura F, Caputo F, Molinelli A (2018) Medico-legal aspect of deaths related to neglect and abandonment in the elderly. Aging Clin Exp Res 30:1399-1402. https://doi.org/10.1007/s4052 0-018-0912-2 \",\"14. De Liema M, Homeier DC, Anglin D et al (2016) The forensic lens: bringing elder neglect into focus in the Emergency Department. Ann Emerg Med 68:371-377. https://doi.org/10.1016/j.annemergmed.2016.02.008 \",\"15. Burnett J, Achenbaum WA, Murphy KP (2014) Prevention and early identification of elder abuse. Clin Geriatr Med 30:743-759. https://doi.org/10.1016/j.cger.2014.08.013 \"]","page_idx":"5","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[684,37,915,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,927,100,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[102,930,154,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[82,68,485,449]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"16. Simone L, Wettstein A, Senn O et al (2016) Types of abuse and risk factors associated with elder abuse. Swiss Med Wkly 146:14273. https://doi.org/10.4414/smw.2016.14273 \",\"17. Lachs MS, Pillemer KA (2015) Elder abuse. New Engl J Med 373:1947-1956. https://doi.org/10.1056/NEJMra1404688 \",\"18. Jackson SL (2016) All elder abuse perpetrators are not alike: the heterogeneity of elder abuse perpetrators and implications for intervention. Int J Offender Ther Comp Criminol 60:265-285. https://doi.org/10.1177/0306624X14554063 \",\"19. Kepic M, Randolph A, Hermann-Turner KM (2019) Care for caregivers: understanding the need for caregiver support. Adultspan J. https://doi.org/10.1002/adsp.12068 \",\"20. Orfila F, Coma-Sole M, Cabanas M et al (2018) Family caregiver mistreatment of the elderly: Prevalence of risk and associated factors. BMC Public Health 18:1-14. https://doi.org/10.1186/s12889-018-5067-8 \",\"21. Kepic M, Randolph A, Hermann-Turner KM (2019) Care for caregivers: understanding the need for caregiver support. Adultspan J 18:40-51. https://doi.org/10.1002/adsp.12068 \",\"22. Lifespan of Greater Rochester Inc., Weill Cornell Medical Center of Cornell University, New York City Department for the Aging (2011) Under the Radar: New York State Elder Abuse Prevalence Study. https://www.ncjrs.gov/App/Publications/abstract.aspx?ID=258421. Accessed May 2011 \",\"23. Pillemer K, Burnes D, Riffin C et al (2016) Elder abuse: global situation, risk factors and prevention strategies. Gerontologis 56:S194-205. https://doi.org/10.1093/geront/gnw004 \",\"24. Molinelli A, Viale L, Landolfa MC et al (2011) Old age as an \\\"alternative\\\" to illness: gerontological and medico-legal aspects. Aging Clin Exp Res 23:148-152. https://doi.org/10.3275/7042 \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[510,68,914,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"25. Molinelli A, Ventura F, Lo Pinto S et al (2017) Elder abuse in Europe's \\\"most elderly\\\" city: an assessment of the phenomenon and an analysis of the data from the Penal Court of Genova from 2010 to 2015. Aging Clin Exp Res 29:1285-1290. https://doi.org/10.1007/s40520-017-0738-3 \",\"26. DeLiema M, Homeier DC, Anglin D et al (2016) The forensic lens: bringing elder neglect into focus in the emergency department. Ann Emerg Med 68:371-377. https://doi.org/10.1016/j.annemergmed.2016.02.008 \",\"27. Keller E, Santos C, Cusack D et al (2019) European council of legal medicine (ECLM) guidelines for the examination of suspected elder abuse. Int J Legal Med 133:317-322. https://doi.org/10.1007/s00414-018-1880-y \",\"28. Hoover RM, Polson M (2014) Detecting elder abuse and neglect: assessment and intervention. Am Fam Physician 89:453-460 \",\"29. LoFaso VM, Rosen T (2014) Medical and laboratory indicators of elder abuse and neglect. Clin Geriatr Med 30:713-728. https://doi.org/10.1016/j.cger.2014.09.003 \",\"30. Lachs MS, Pillemer K (2004) Elder abuse. Lancet 364:1263-1272. https://doi.org/10.1016/S0140-6736(04)17144-4 \",\"31. Evans CS, Hunold KM, Rosen T et al (2017) Diagnosis of elder abuse in U.S. Emergency Departments. J Am Geriatr Soc 65:91-91. https://doi.org/10.1111/jgs.14480 \"]","page_idx":"6","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[510,373,914,400]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,37,312,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aging Clinical and Experimental Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[840,927,914,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Springer ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[80,130,811,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Elder abuse in Europe's \\\"most elderly\\\" city: an update of the phenomenon based on the cases reported to the Penal Court of Genoa from 2015 to 2019 and literature review \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,218,642,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Martina Drommi $^{1}$ · Alessandra Ponte $^{1}$ · Francesco Ventura $^{1}$ · Andrea Molinelli $^{1}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,256,386,282]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 2 December 2020 / Accepted: 8 January 2021 \\n© The Author(s) 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,307,149,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,322,915,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background Elder abuse is currently a worldwide problem. The literature reports that one elderly person out of six is a potential victim. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,353,914,384]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aims To analyse cases reported to the judicial authorities in the territory of Genoa in the period 2010-2019, to investigate the features of elder abuse, to assess the trend of this phenomenon and to propose preventive strategies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,384,915,432]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods We analysed the data on reports of abuse passed by the Court of Genoa in the period 2015–2019 concerning physical and mental maltreatment, abandonment and financial exploitation of elderly subjects. These data were compared with those recorded in the previous 5-year period and in the literature. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,432,915,479]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results In the period 2015–2019, 156 cases of elder abuse were identified (versus 63 in the previous period): 18 cases of domestic violence, 5 cases of abuse of the means of correction, 18 cases of caregiver neglect, 76 cases of physical injury and 39 cases of financial exploitation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,479,915,526]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion Abuse was seen to be perpetrated most frequently in the domestic setting and by the victims' relatives. The main risk factors were female gender and the victim's dependence on others, the maltreating subject's mental illness and substance abuse. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,527,915,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions We documented a progressive increase in the number of abuses reported to the judicial authority; this reflects greater awareness of the problem. However, our figures remained well below the incidence estimated in the literature. It is necessary to train healthcare personnel to identify and manage cases of suspected abuse, and to provide adequate support in situations at risk. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,606,766,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords Elder abuse $\\\\cdot$ Domestic violence $\\\\cdot$ Ageism $\\\\cdot$ Personal injury $\\\\cdot$ Prosecutor's office $\\\\cdot$ Sentence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,651,200,669]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,684,487,748]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The phenomenon of elder abuse is a highly topical and significant issue. Indeed, it is estimated that, worldwide, one elderly person out of six is a victim of some type of abuse (about 141 million victims per year) [1]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,749,485,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The WHO defines elder abuse as \\\"a single or repeated act, or the lack of appropriate action, occurring within any relationship where there is an expectation of trust which causes harm or distress to an older person\\\" [2]. The phenomenon \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,654,915,732]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is extremely serious in view of its possible impact on the life expectancy of elderly subjects; indeed, it gives rise to situations of mental and social distress and increases rates of mortality, hospitalisation and access to emergency departments [3, 4]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,732,915,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Given that the world's population is steadily ageing, the phenomenon of elder abuse is destined to become increasingly common. Data on World Population Ageing indicate that the number of persons aged more than 65 years will increase from 703 million in 2019 to 1.5 billion in 2050 [5]. Moreover, it is estimated that the number of persons aged over 80 years will increase even more markedly, reaching 426 million in 2050. This latter age-group is at greater risk of frailty, isolation and impaired personal autonomy—factors associated with the risk of abuse [6]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,334,67]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research https://doi.org/10.1007/s40520-021-01790-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,79,243,94]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORIGINAL ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,81,915,120]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,841,290,870]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Martina Drommi martina.drommi91@gmail.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[80,879,433,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Department of Forensic and Legal Medicine, University of Genova, Via De' Toni 12, 16132 Genova, Italy \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[80,929,284,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published online: 31 January 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[840,927,915,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,69,485,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Italy, according to the National Statistics Institute (ISTAT), by 2019 life expectancy at birth had risen to 81 years for men and 85.3 years for women [7]. With regard to the metropolitan area of Genoa, one of Europe's \\\"most elderly\\\" cities and the focus of our investigation, elderly subjects (over 65 years of age) account for almost $29\\\\%$ of the total population of 841,180. Given the structure of the population and the high index of dependence $(47.3\\\\%)$ of the elderly, the territory under examination is one in which the risk of abuse is high. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,227,485,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With regard to the phenomenon of elder abuse, we can distinguish abuse in domestic/community settings [1] and abuse in institutional settings (care facilities, hospitals) [8]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,275,485,353]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Concerning abuse in the community setting [1], a recent meta-analysis reported that the phenomenon involved $15.7\\\\%$ of subjects aged over 65 years (11.6% psychological abuse, $6.8\\\\%$ financial abuse, $4.2\\\\%$ abandonment and neglect, $2.6\\\\%$ physical abuse, $0.9\\\\%$ sexual abuse). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,354,485,559]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With regard to abuse in institutional settings, the European Journal of Public Health [8] reported that almost two out of three $(64.2\\\\%)$ staff members had reported some form of maltreatment of elderly patients, mainly physical and psychological. Moreover, a survey conducted among the staff of residences for the elderly in the United States in 1993 revealed that about $40\\\\%$ had perpetrated psychological abuse, while $10\\\\%$ had committed acts of physical violence [9]. By contrast, a 2018 Chinese study of elderly people's residences reported a much lower incidence of the phenomenon: of the 681 elderly subjects recruited in two different facilities, $11.48\\\\%$ claimed to have suffered psychological abuse and $8.24\\\\%$ physical abuse [10]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,560,485,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition, a US study involving 2,713 elderly persons estimated the incidence of elder abuse in community settings to be about $8.8\\\\%$ ; the risk factors identified were: female gender, advanced age ( $>85$ years) and the presence of multiple physical pathologies. The type of abuse most frequently cited was psychological ( $4.8\\\\%$ ), followed by financial ( $2.9\\\\%$ ), caregiver neglect ( $1.1\\\\%$ ), physical ( $0.5\\\\%$ ) and sexual abuse ( $0.1\\\\%$ ) [11]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,686,485,748]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The term \\\"physical abuse\\\" refers to the use of force that may result in injury, pain or permanent damage; these actions include violent behaviours, corporal punishment and the improper administration of pharmaceutical drugs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,749,485,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Psychological maltreatment consists of causing anxiety and/or distress through the use of verbal or non-verbal language and includes threats, intimidation, molestation, and forced isolation of victims from their loved ones. The prolonged state of anguish that may ensue can result in changes of mood and even in full-blown depression [12]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,844,485,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Elderly people, who are often frail and dependent on others, are also vulnerable to theft, fraud or other types of economic exploitation. Financial abuse is defined as the illegal use of an elderly subject's funds, goods or property, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,69,912,100]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the unauthorised cashing of cheques and falsification of the person's signature. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,101,914,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Another aspect of elder abuse is that of neglect. For instance, a caregiver may fail to provide for the elderly person's primary necessities, in terms not only of hygiene, feeding and therapy but also of psychological and social needs [13]. This may be due to the caregiver's lack of professional training or to wilful neglect on the part of a caregiver who is only interested in being paid and/or obtaining free accommodation [14]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,227,914,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Risk factors for the maltreatment of elderly persons include: female sex, advanced age, cohabitation with the abuser, social isolation and a poor network of support [15]; dementia and other neurological disorders also facilitate abuse, in that caring for such patients places a burden on the caregiver, both physically and, especially, psychologically. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,322,912,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For what concerns the perpetrators of abuse, they are most often members of the elderly person's own family, who are compelled to act as caregivers; this is mainly the case in community settings. In institutional settings, it is the healthcare workers themselves who act as caregivers, and who are therefore at risk of enacting abusive behaviours [16]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,417,912,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The factors that place caregivers at risk of becoming abusers are substance abuse (alcohol or drugs), psychiatric disorders, physical problems, social isolation, a perception of being overburdened with responsibility, and financial or employment problems that may make the subject dependent on the victim [17-19]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,512,914,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Italy, the family is the mainstay of the care of elderly persons. Consequently, the phenomenon of \\\"informal caregiving\\\" is common; indeed, the elderly are frequently looked after by family members, who often lack the skills needed to carry out this task. Moreover, the commitment undertaken requires the caregiver to live in the same house as the elderly person and to make considerable sacrifices. Indeed, the burden of assistance is added to the ordinary duties of work and family; this may result in economic and social problems, while the elderly person's continual requests may give rise to stress, anxiety and depression [20, 21]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,702,914,859]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although the case-reports reveal that elder abuse is a serious problem and that its dimensions are inevitably destined to increase, the phenomenon remains underestimated. Indeed, it has been claimed that only 1 in every 24 cases is reported to the judicial authorities [22]. Although the institutions have devoted greater attention to elder abuse over the last decade (owing to media coverage of residential facilities for the elderly), the phenomenon has been only scantily investigated; this hinders the evaluation of its true magnitude and of the adoption of possible preventive measures [23]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,860,912,907]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Italy, there is still no specific law that safeguards elderly persons. Indeed, under Italian law, the elderly subject is equated with any subject who is in a state of need, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[684,37,915,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[84,927,154,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,69,485,256]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"poverty or abandonment [24]. In the Italian Penal Code, the articles that refer more specifically to violence against elderly persons are art. 570 (Violation of the obligations of family care), art. 571 (Abuse of the means of correction or discipline), art. 572 (Maltreatment of family members and cohabiting persons), art. 582 (Personal injuries), art. 591 (Abandonment of minors or incapable persons) and art. 643 (Circumvention of incapable persons). Owing to the intrinsic fragility of elderly persons, these subjects are vulnerable to the offences that we considered, the consequences of which, in prognostic terms, constitute a serious social and economic problem for society. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[84,305,290,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Materials and methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,337,485,431]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The aim of our study was to analyse cases of elder abuse covered by the above-mentioned articles of the Penal Code that came to the attention of the judicial authority in the metropolitan area of Genoa between 2010 and 2019, in order to examine the characteristics of this abuse and propose preventive strategies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,432,485,589]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The data from the period 2015-2019 were obtained with the help of the Public Prosecutor's Office. Subsequently, these data were compared both with those recorded in a previous study conducted by the Department of Legal Medicine of the University of Genoa, which analysed reports and sentences registered in the previous 5-year period (2010-2014) [25], and with the data reported in the literature. In this way, we were able to depict the present state of the phenomenon and to trace its evolution over the last 10 years. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,591,485,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Examination of the contents of the sentences handed down enabled us to pick out several features of elder abuse in the territory considered: profiles of both abusers and victims (sex, age, psychological profile and possible pathologies of both), the type of relationship between the two, the settings in which the abuse took place and, finally, the verdicts pronounced (conviction or acquittal). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,69,576,84]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,103,885,117]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The following data emerged from the reports (Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,118,912,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A total of 979 offences were reported in the period 2015-2019, as against 300 in the period 2010-2014. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,150,914,243]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With regard to the abuse of the means of correction or discipline, 7 reports were found; these involved offences of a strictly physical nature (beating, forced restraint, injury) that left visible signs on the victim's body; if such incidents are promptly reported, evidence of the offence can easily be gathered. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,245,912,339]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A large portion of the offences in our case-reports involved maltreatment in the family setting, which accounted for 165 reports. Art. 572 safeguards the person's physical safety, mental salubrity and dignity, and refers to unlawful conduct that is reiterated over time and enacted with the intention of engendering a state of permanent oppression. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,340,912,417]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Of the offences considered, those involving personal injuries were the most common (504 reports). The cases examined referred to situations in which there was a considerable difference in age between the victim and the abuser, who exploited the elderly person's frailty. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,418,912,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The abandonment of an incapable elderly person (38 reports) was seen to stem chiefly from disputes among the children of an infirm elderly subject, each of whom may, for various reasons, refuse to take on the responsibility of caring for a parent who is no longer self-sufficient. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,497,912,591]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, financial exploitation (240 reports) proved to be the second most frequent type of abuse, after physical and psychological maltreatment. Solitude, isolation and the presence of organic diseases that impair the individual's critical faculties and ability to distinguish between the good and bad intentions of others are the main risk factors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,593,912,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is very important to underline that there is a great difference between notifications of crimes and trial verdicts; indeed, while in the Italian legal system it is very simple to file a notification against someone, considerable evidence is needed to bring the person to trial. For this reason, there are many crime reports but few of them are judged worthy of prosecution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,762,915,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0167/00503dc459053c1be853e91fea92d0c83cb234b64b63b4d1827b9a232c5cf7aa.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Penal code</td><td>2015</td><td>2016</td><td>2017</td><td>2018</td><td>2019</td><td>Total</td></tr><tr><td>Art 570 (violation of family care obligations)</td><td>7</td><td>9</td><td>6</td><td>1</td><td>2</td><td>25</td></tr><tr><td>Art 571 (abuse of the means of correction or discipline)</td><td>0</td><td>1</td><td>2</td><td>2</td><td>2</td><td>7</td></tr><tr><td>Art 572 (maltreatment of family members and cohabiting persons)</td><td>26</td><td>27</td><td>37</td><td>43</td><td>32</td><td>165</td></tr><tr><td>Art 582 (personal injury)</td><td>127</td><td>95</td><td>103</td><td>85</td><td>94</td><td>504</td></tr><tr><td>Art 591 (abandonment of minors or incapable persons)</td><td>8</td><td>5</td><td>8</td><td>9</td><td>8</td><td>38</td></tr><tr><td>Art 643 (circumvention of incapable persons)</td><td>43</td><td>56</td><td>41</td><td>46</td><td>54</td><td>240</td></tr><tr><td>Total</td><td>211</td><td>193</td><td>197</td><td>186</td><td>192</td><td>979</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1 Analysis of the reports collected in Genoa during the period 2015-2019 \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[82,39,310,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[840,927,914,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,69,485,178]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Analysis of the judicial sentences enabled us to construct profiles of both abusers and abused elderly persons (sex, age, physical and/or mental disorders) and to identify the causes and settings of the abuses committed. We analysed a total of 4500 sentences, only 156 of which involved the abuse of an elderly person (3.5% of the total, versus 2.1% in the previous 5-year period). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,179,381,194]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The following figures emerged (Table 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,196,485,430]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For what concerns art. 571 (Abuse of the means of correction or discipline) the 5 cases examined occurred in residential facilities for the elderly, the maltreating subjects being nurses or care workers. The unlawful behaviour was seen to have been enacted during night shifts and involved the imposition of uncomfortable positions for long periods, forced immobilisation, and abuse of the means of constraint. Only in one case, however, was the perpetrator convicted; in the other cases, working conditions were acknowledged to be arduous, with few staff members having to deal with large numbers of patients, and constraint devices being applied for long periods to control bouts of psychomotor agitation or delirium. What emerges here is that lack of time and staff shortages exacerbate care-related stress and reduce the quality of the care provided. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,432,485,573]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Analysis of the sentences regarding art. 572 (Maltreatment of family members and cohabiting persons) turned up 18 cases of abuse perpetrated in the victim's own home, which was shared by the abuser. In $84\\\\%$ of cases, the perpetrator was a son/daughter of the victim; most perpetrators $(63\\\\%)$ were affected by problems of alcoholism, substance abuse or psychiatric disorders; moreover, 18 of the 21 maltreating subjects $(86\\\\%)$ were males, and 15 of the 21 $(71\\\\%)$ were aged over 40 years. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,575,485,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the case of informal caregivers, a lack of training and an overload of responsibility may lead to conflict, which may then trigger violent behaviour (damage to property) and physical or verbal aggression (insults, humiliation, death threats). Many authors have identified the following risk factors of abuse: parent-child relationship, male sex of the abuser, age over 40 years, substance abuse, alcoholism, psychiatric disorders, financial dependence on the victim, and forced cohabitation between the victim and the abuser. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,69,912,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Victims' children also proved to be the main offenders in cases involving art 582 (Personal injury), with the home again being the most frequent setting of maltreatment. Moreover, the crime of personal injury is often associated with that of maltreatment in the family (art. 572). Indeed, situations of ongoing daily conflict may explode in physical violence that causes fractures, bruises or lacerations, with the result that treatment in the Emergency Department is required and the incident is reported to the judicial authority. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,211,912,321]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Three cases of neglect came to light. In these cases, the offender was the victim's caregiver, a subject who is specifically responsible for the care and supervision of the elderly person, and the setting of the maltreatment was the home of an elderly person, who was not self-sufficient. The behaviour took the form of dereliction of duty: long absences from the home, neglect and failure to maintain proper hygiene. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,322,912,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Financial abuse figured in 39 sentences. The victims suffered from mental deficiency (Parkinson's disease, dementia, depression) and had a poor social network. Age proved to be a major risk factor; of the 43 victims, 26 $(60\\\\%)$ were over 80 years of age, while 8 $(19\\\\%)$ were aged between 75 and 84 years. The oldest old $(>85$ years) proved to be at the greatest risk of financial abuse, often being isolated and dependent on others. The offenders did not have a daily relationship with their victims, but gained their trust to defraud them; this occurred in 25 cases involving strangers, 7 cases involving caregivers, and 3 cases involving the staff of residential facilities. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,541,757,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion and conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,575,912,651]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Having analysed the results of the present study, and after comparing these with the data from the previous 5-year period [25] and those reported in the literature, we were able to draw several conclusions regarding the trend in the phenomenon of elder abuse over the past decade. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,654,912,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With regard to the sex of the victims of abuse, the literature indicates that women are at greater risk. Similarly, in our study, of the total of 249 elderly subjects who had suffered maltreatment, 134 were women and 115 were men. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,760,915,903]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0943/17ebed99f8a1bf5e7cf05d1c2323bb616176096b922ecb5fee447e8f2255f5b7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Penal code</td><td>2015</td><td>2016</td><td>2017</td><td>2018</td><td>2019</td><td>Total</td><td>Conviction</td><td>Acquittal</td></tr><tr><td>Art 570—violation of family care obligations</td><td>0</td><td>3</td><td>5</td><td>6</td><td>1</td><td>15</td><td>7</td><td>8</td></tr><tr><td>Art 571—abuse of the means of correction...</td><td>2</td><td>2</td><td>0</td><td>1</td><td>0</td><td>5</td><td>1</td><td>4</td></tr><tr><td>Art 572—maltreatment of family members...</td><td>4</td><td>3</td><td>2</td><td>6</td><td>3</td><td>18</td><td>13</td><td>5</td></tr><tr><td>Art 582—personal injury</td><td>7</td><td>19</td><td>22</td><td>15</td><td>13</td><td>76</td><td>40</td><td>26</td></tr><tr><td>Art 591—abandonment of...incapable persons</td><td>1</td><td>1</td><td>0</td><td>0</td><td>1</td><td>3</td><td>0</td><td>3</td></tr><tr><td>Art 643—circumvention of incapable persons</td><td>8</td><td>3</td><td>7</td><td>10</td><td>11</td><td>39</td><td>19</td><td>20</td></tr><tr><td>Total</td><td>22</td><td>31</td><td>36</td><td>38</td><td>29</td><td>156</td><td>80</td><td>76</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2 Analysis of the sentences passed in Genoa during the period 2015-2019 \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[685,39,915,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[82,927,154,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,69,484,100]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Moreover, women are at greater risk of reiterated abuse and physical and mental oppression. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,100,485,224]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Regarding the sex of abusers, there is no complete consensus in the literature. However, our study supported the conviction that a majority of cases of abuse are perpetrated by men. Indeed, on a total of 276 persons charged with abuse, 178 were men and 98 women; maltreatment perpetrated by males tended to be physical and violent (personal injury, abuse in the family), while females were more often involved in financial abuse. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,227,485,368]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although physical and psychological abuse was seen to be perpetrated most frequently by a single victims' relative, regarding the extra-family context our study has proved that abuses (especially financial abuse) were mainly perpetrated by a group of two or three people. In fact, acting as real criminal organizations, these strangers were able to gain the confidence of the elderly (pretending to be lawyers, bankers or investors) and to obtain money, cheques, goods or property illegally. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,370,485,588]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The most common setting of abuse was seen to be the elderly person's own home; about $47\\\\%$ of our cases took place in the domestic environment. This can be explained by the fact that in Italy, unlike the US or Northern European countries (where many of the other studies have been conducted), infirm elderly people tend to be looked after at home, and only exceptionally in residential facilities. In our study, only 5 cases $(8\\\\%)$ of abuse took place in institutional settings in the period 2010-2014, and only 14 $(9\\\\%)$ in the period 2015-2019. Although estimates of the incidence of abuse in residential facilities in Italy are not yet available, such institutions seem to be safer than the domestic environment, not least on account of the adoption of modern systems of staff surveillance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,589,485,763]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For what concerns the trend in the phenomenon of elder abuse over the decade considered, it must first be observed that the total number of cases notified differed markedly between the two 5-year periods; in the period 2015-2019, we recorded 979 reports and 156 sentences that met the criteria for inclusion in our analysis, as against 300 reports and 63 sentences in the previous 5-year period. This increase may have been due to the greater awareness of the problem on the part of the public and the judiciary, resulting in the emergence of cases that, in the past, would not have come to light. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,764,485,874]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The present study confirmed that the most frequent perpetrators of abuse were the children of the victims, followed by spouses and caregivers; in the previous study, however, caregivers occupied the second position. This finding could suggest that owing to greater public awareness of the phenomenon, the families of elderly persons now exercise greater caution in choosing caregivers. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,875,485,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Comparison of the sentences handed down by the Court of Genoa during the two 5-year periods also yielded \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,68,914,178]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"interesting findings. The data that emerged from the two studies revealed that convictions had increased; during the second period, $51\\\\%$ of those charged with abuse were convicted, as against $35\\\\%$ in the first period. It can, therefore, be claimed that, during the period 2015-2019, more of the cases reported to the judiciary proved to be genuine cases of elder abuse, and that they were dealt with more strictly. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,179,914,336]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Given the progressive ageing of the global population, there is a need to increase our knowledge of the characteristics of maltreatment and its related mechanisms, to implement adequate prevention and to ensure prompt identification and effective management of the phenomenon. Doctors and the staff of emergency departments, hospitals and residential facilities play a fundamental role in the screening and identification of cases of abuse [26]; this implies the need to implement screening protocols that are agreed upon by the scientific community. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,337,914,510]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although the Comprehensive Geriatric Assessment (CGA) constitutes the \\\"gold standard\\\" for the thorough evaluation of the health and well-being of elderly subjects, it cannot be carried out in a short time (e.g. during visits by family doctors or non-geriatric specialists or in the emergency department) [15]. However, questionnaires like the BASE (Brief Abuse Screen for the Elderly) or the CASE (Caregiver Abuse Screen) can investigate suspected abuse during brief clinical examinations; these questionnaires differ in terms of their compilation time, ease of use and time required for personnel training [27]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,511,914,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The investigation of suspected abuse should include the history of the alleged maltreatment, the elderly person's recent and remote medical history, his/her dependence on others, assessment of the subject's functional capacity, identification of the use of physical or pharmacological means of constraint, psychiatric and cognitive evaluation, complete objective examination, and generic and toxicological laboratory tests [28]. Caution must always be exercised to avoid confusing age-related physiological modifications with signs of abuse; the five main pathological conditions that may cause confusion are skin lesions, anomalous bleeding, fractures, malnutrition and anogenital lesions [29, 30]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,701,914,858]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Interactions with healthcare personnel offer opportunities to recognise signs of abuse and enable suspected cases to be reported to the judicial authorities. Indeed, in the US, the percentage of accesses to the emergency department due to cases of ascertained elder abuse remains very low compared to the estimated prevalence [31]. This reveals the need to rectify the shortcomings in the identification and reporting of cases of abuse, which could be done by introducing training courses for healthcare personnel and implementing clear and appropriate screening protocols. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,859,912,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In particular, health-care professionals should receive adequate clinical-forensic training in order not only to recognize cases of abuse but also to gather evidence that may \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,39,310,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[840,927,914,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[78,68,485,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"be useful in criminal proceedings. If possible, after collecting the victim's details and story, consent shall be required for inspection, collection and correct storage of biological material for judicial purposes. After a general examination, the lesions on the victim's body must be located, accurately described and photographed, in order to ensure valuable evidence. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,179,485,226]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The ultimate objective, in fact, should be to improve knowledge of the phenomenon of elder abuse and to adopt a multidisciplinary approach to its management. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,227,485,320]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A further useful measure could be to introduce \\\"emergency refuges\\\", facilities where the elderly person can be temporarily assisted until such time as the problem can be properly dealt with. Moreover, systems of psychological and financial support should be made available to families who care for infirm elderly relatives. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,321,485,415]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With regard to cases of abuse by the staff of residential facilities, the causes appear to lie in the inadequate training of healthcare personnel and work-related stress. This implies that adequate training should be provided, workloads should be reduced and relationships between staff and inmates should be improved. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,417,485,541]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Elder abuse is an extremely complex and heterogeneous problem. Indeed, global prevention of the phenomenon, prompt identification of cases of maltreatment, the safeguard of victims and recognition of the difficulties facing caregivers are delicate issues that require adequate attention. Despite growing awareness of the phenomenon and the proposals mentioned above, elder abuse remains largely unrecognised and infrequently reported to the authorities. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,572,485,600]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author contributions All authors contributed to the study conception and design. All authors read and approved the final manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,613,485,639]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding Open Access funding provided by Università degli Studi di Genova. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,654,485,679]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Availability of data and materials This article does not involve clinical studies or contain patient data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,697,352,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Compliance with ethical standards \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,727,485,741]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflict of interest Authors declare that there is no conflict of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,753,326,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Human and animal rights Not applicable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,777,282,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Informed consent Not applicable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,812,485,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,68,915,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,179,613,194]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,210,915,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Yon Y, Mikton CR, Gassoumis ZD et al (2017) Elder abuse prevalence in community settings: a systematic review and meta-analysis. Lancet Glob Health 5:147-156. https://doi.org/10.1016/S2214-109X(17)30006-2 \\\",\\\"2. World Health Organisation (2020) Elder abuse. https://www.who.int/news-room/fact-sheets/detail/elder-abuse. Accessed 15 June 2020 \\\",\\\"3. Dong XQ (2015) Elder abuse: systematic review and implications for pratie. J Am Geriatr Soc 63:1214-1238. https://doi.org/10.1111/jgs.13454 \\\",\\\"4. Burnett J, Jackson SL, Sinha A et al (2016) Five-year all-cause mortality rates across five categories of substantiated elder abuse occurring in the community. J Elder Abuse Negl 28:59-75. https://doi.org/10.1080/08946566.2016.1142920 \\\",\\\"5. United Nations, Department of Economic and Social Affairs, Population Division (2020). World Population Ageing 2019. https://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2019-Report.pdf. Accessed 14 Jan 2020 \\\",\\\"6. United Nations-Department of Economic and Social Affairs (2019) World Population Prospects 2019. https://population.un.org/wpp/. Accessed 17 June 2019 \\\",\\\"7. ISTAT. Inditori demografici. Stime per l'anno 2018 (2019) Statistiche Report 2019. https://www.istanit.it/it/files/2019/02/Report-Sttime-inditori-demografici.pdf. Accessed 7 Feb 2019 \\\",\\\"8. Yon Y, Ramiro-Gonzales M, Mikton CR et al (2019) The prevalence of elder abuse in institutional settings: a systematic review and meta-analysis. Eur J Public Health 29:58-67. https://doi.org/10.1093/eurpub/cky093 \\\",\\\"9. Pillemer K, Hudson B (1993) A model abuse prevention program for nursing assistants. Gerontologist 33:128-131. https://doi.org/10.1093/geront/33.1.128 \\\",\\\"10. Wang F, Meng LR, Zhang Q et al (2018) Elder abuse and its impact on quality of life in nursing homes in China. Arch Gerontol Geriatr 78:155-159. https://doi.org/10.1016/j.archger.2018.06.011 \\\",\\\"11. Wang B, Dong X (2017) Incidence of Elder Abuse in a U.S. Chinese Population: findings from the longitudinal cohort PINE Study. J Gerontol A Biol Sci Med Sci 72:S95-S101. https://doi.org/10.1093/gerona/glx005 \\\",\\\"12. Fulmer T, Rodgers RF, Pelger A (2014) Verbal mistreatment of the elderly. J Elder Abuse Neglect 26:351-364. https://doi.org/10.1080/08946566.2013.801817 \\\",\\\"13. Ventura F, Caputo F, Molinelli A (2018) Medico-legal aspect of deaths related to neglect and abandonment in the elderly. Aging Clin Exp Res 30:1399-1402. https://doi.org/10.1007/s4052 0-018-0912-2 \\\",\\\"14. De Liema M, Homeier DC, Anglin D et al (2016) The forensic lens: bringing elder neglect into focus in the Emergency Department. Ann Emerg Med 68:371-377. https://doi.org/10.1016/j.annemergmed.2016.02.008 \\\",\\\"15. Burnett J, Achenbaum WA, Murphy KP (2014) Prevention and early identification of elder abuse. Clin Geriatr Med 30:743-759. https://doi.org/10.1016/j.cger.2014.08.013 \\\"]\",\n \"page_idx\": \"5\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[684,37,915,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,927,100,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[102,930,154,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[82,68,485,449]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"16. Simone L, Wettstein A, Senn O et al (2016) Types of abuse and risk factors associated with elder abuse. Swiss Med Wkly 146:14273. https://doi.org/10.4414/smw.2016.14273 \\\",\\\"17. Lachs MS, Pillemer KA (2015) Elder abuse. New Engl J Med 373:1947-1956. https://doi.org/10.1056/NEJMra1404688 \\\",\\\"18. Jackson SL (2016) All elder abuse perpetrators are not alike: the heterogeneity of elder abuse perpetrators and implications for intervention. Int J Offender Ther Comp Criminol 60:265-285. https://doi.org/10.1177/0306624X14554063 \\\",\\\"19. Kepic M, Randolph A, Hermann-Turner KM (2019) Care for caregivers: understanding the need for caregiver support. Adultspan J. https://doi.org/10.1002/adsp.12068 \\\",\\\"20. Orfila F, Coma-Sole M, Cabanas M et al (2018) Family caregiver mistreatment of the elderly: Prevalence of risk and associated factors. BMC Public Health 18:1-14. https://doi.org/10.1186/s12889-018-5067-8 \\\",\\\"21. Kepic M, Randolph A, Hermann-Turner KM (2019) Care for caregivers: understanding the need for caregiver support. Adultspan J 18:40-51. https://doi.org/10.1002/adsp.12068 \\\",\\\"22. Lifespan of Greater Rochester Inc., Weill Cornell Medical Center of Cornell University, New York City Department for the Aging (2011) Under the Radar: New York State Elder Abuse Prevalence Study. https://www.ncjrs.gov/App/Publications/abstract.aspx?ID=258421. Accessed May 2011 \\\",\\\"23. Pillemer K, Burnes D, Riffin C et al (2016) Elder abuse: global situation, risk factors and prevention strategies. Gerontologis 56:S194-205. https://doi.org/10.1093/geront/gnw004 \\\",\\\"24. Molinelli A, Viale L, Landolfa MC et al (2011) Old age as an \\\\\\\"alternative\\\\\\\" to illness: gerontological and medico-legal aspects. Aging Clin Exp Res 23:148-152. https://doi.org/10.3275/7042 \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[510,68,914,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"25. Molinelli A, Ventura F, Lo Pinto S et al (2017) Elder abuse in Europe's \\\\\\\"most elderly\\\\\\\" city: an assessment of the phenomenon and an analysis of the data from the Penal Court of Genova from 2010 to 2015. Aging Clin Exp Res 29:1285-1290. https://doi.org/10.1007/s40520-017-0738-3 \\\",\\\"26. DeLiema M, Homeier DC, Anglin D et al (2016) The forensic lens: bringing elder neglect into focus in the emergency department. Ann Emerg Med 68:371-377. https://doi.org/10.1016/j.annemergmed.2016.02.008 \\\",\\\"27. Keller E, Santos C, Cusack D et al (2019) European council of legal medicine (ECLM) guidelines for the examination of suspected elder abuse. Int J Legal Med 133:317-322. https://doi.org/10.1007/s00414-018-1880-y \\\",\\\"28. Hoover RM, Polson M (2014) Detecting elder abuse and neglect: assessment and intervention. Am Fam Physician 89:453-460 \\\",\\\"29. LoFaso VM, Rosen T (2014) Medical and laboratory indicators of elder abuse and neglect. Clin Geriatr Med 30:713-728. https://doi.org/10.1016/j.cger.2014.09.003 \\\",\\\"30. Lachs MS, Pillemer K (2004) Elder abuse. Lancet 364:1263-1272. https://doi.org/10.1016/S0140-6736(04)17144-4 \\\",\\\"31. Evans CS, Hunold KM, Rosen T et al (2017) Diagnosis of elder abuse in U.S. Emergency Departments. J Am Geriatr Soc 65:91-91. https://doi.org/10.1111/jgs.14480 \\\"]\",\n \"page_idx\": \"6\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[510,373,914,400]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,37,312,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aging Clinical and Experimental Research \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[840,927,914,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Springer \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1007/s40520-021-01790-6"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"e2abe09a42607e549b206f818ea900526953729857c9779cad7e86d43f1bda80"},"title":{"kind":"string","value":"Elder abuse in Europe’s “most elderly” city: an update of the phenomenon based on the cases reported to the Penal Court of Genoa from 2015 to 2019 and literature review"}}},{"rowIdx":173,"cells":{"abstract":{"kind":"string","value":"\n \nIntegrated Sensing and Communication (ISAC) is a promising technology in 6G systems. The existing 3D Geometry-Based Stochastic Model (GBSM), as standardized for 5G systems, addresses solely communication channels and lacks consideration of the integration with sensing channel. Therefore, this letter extends 3D GBSM to support ISAC research, with a particular focus on capturing the sharing feature of both channels, including shared scatterers, clusters, paths, and similar propagation param-eters, which have been experimentally verified in the literature. The proposed approach can be summarized as follows: Firstly, an ISAC channel model is proposed, where shared and non-shared components are superimposed for both communication and sensing. Secondly, sensing channel is characterized as a cascade of TX-target, radar cross section, and target-RX, with the introduction of a novel parameter S for shared target extraction. Finally, an ISAC channel implementation framework is proposed, allowing flexible configuration of sharing feature and the joint generation of communication and sensing channels. The proposed ISAC channel model can be compatible with the 3GPP standards and offers promising support for ISAC technology evaluation.\n "},"author":{"kind":"string","value":"Tao Jiang|Yameng Liu|Jianhua Zhang|Guangyi Liu|Yuxiang Zhang|Huiwen Gong"},"content_list":{"kind":"list like","value":[{"bbox":"[83,70,911,137]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"How to Extend 3D GBSM to Integrated Sensing and Communication Channel with Sharing Feature? ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[179,147,812,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Yameng Liu, Jianhua Zhang, Yuxiang Zhang, Huiwen Gong, Tao Jiang, Guangyi Liu ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,222,488,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract—Integrated Sensing and Communication (ISAC) is a promising technology in 6G systems. The existing 3D Geometry-Based Stochastic Model (GBSM), as standardized for 5G systems, addresses solely communication channels and lacks consideration of the integration with sensing channel. Therefore, this letter extends 3D GBSM to support ISAC research, with a particular focus on capturing the sharing feature of both channels, including shared scatterers, clusters, paths, and similar propagation parameters, which have been experimentally verified in the literature. The proposed approach can be summarized as follows: Firstly, an ISAC channel model is proposed, where shared and nonshared components are superimposed for both communication and sensing. Secondly, sensing channel is characterized as a cascade of TX-target, radar cross section, and target-RX, with the introduction of a novel parameter S for shared target extraction. Finally, an ISAC channel implementation framework is proposed, allowing flexible configuration of sharing feature and the joint generation of communication and sensing channels. The proposed ISAC channel model can be compatible with the 3GPP standards and offers promising support for ISAC technology evaluation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[76,479,488,505]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Index Terms—ISAC, channel modeling, GBSM, sharing feature, shared cluster. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[220,530,348,545]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,553,488,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HE sixth generation (6G) systems envision intelligently connecting everything, which requires a high transmission rate and precise sensing accuracy [1]. Integrated sensing and communication (ISAC) has been identified as a typical usage scenario for 6G [2]. Different from conventional systems with separate functions, ISAC technology allows the base stations or terminals to communicate with each other and sense their surroundings. By sharing the same frequency and hardware resources, ISAC systems offer advantages in improving spectrum utilization and reducing costs [3], [4]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,704,490,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Realistic channel modeling is the prerequisite for the design of every generation of systems. The mainstream channel model, Geometry-Based Stochastic channel Model (GBSM), is the standardized modeling method adopted by ITU and 3GPP. It is two-dimensions (2D) in 4G systems and introduced the vertical angles and expanded to 3D in 5G systems [5]. GBSM is a clustered structure model, grouping multipaths into stochastic clusters. However, this channel model focuses on communication channel, lacking considering the integration with sensing channel. On the one hand, stochastic clusters in 3D GBSM cannot accurately represent the identified locations and attributes of the targets, which are crucial for sensing applications such as positioning and environment reconstruction. On the other hand, due to the multiplexing of hardware resources and the same propagation environment, some targets might serve as shared scatterers for both the communication and sensing channels. This sharing feature, including shared scatterers, clusters, paths, and similar propagation parameters, should be included in ISAC channel model to evaluate the integrated functions and algorithm design of ISAC systems. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,220,919,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,282,919,536]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"With the development of the integrated systems, some existing ISAC studies have operated under the assumption of the sharing feature/correlation between communication and sensing channels [6]–[8]. In [9], [10], the similarity of the azimuth power spectrum of communication and sensing are investigated using Ray-tracing simulations. To validate the existence of the sharing feature, we conduct indoor ISAC channel measurements at $2 8 \\ : \\mathrm { G H z }$ in [3], intuitively observing the shared scatterers from the power-angular-delay profiles of communication and sensing channels. To further extend GBSM to ISAC channels, the work in [11] analyzes the correlation between communication and sensing channels under realization of GBSM. In [3], we propose a shared cluster-based stochastic ISAC channel model according to the measured observation. However, a practical ISAC channel model that extends 3D GBSM with consideration for the sharing feature is still missing in the literature. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,539,919,703]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To bridge these gaps, this letter proposes a 3D GBSM principle based ISAC channel model with sharing feature. In this model, communication and sensing Channel Impulse Responses (CIRs) are composed of shared and non-shared components. A novel parameter S is introduced for shared target/cluster extraction and parametric modeling of the sensing channel is presented. Then, we propose an ISAC channel implementation framework, which is compatible with the 3GPP standards. The sensing cluster/path positions, the relationship between shared parameters, and the statistical sharing degree (SD) are analyzed to validate the model performance. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[602,726,825,739]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"II. ISAC CHANNEL MODELING ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,748,919,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This letter considers a wideband ISAC channel under a frequency selective fading channel. Fig. 1 provides an illustration of the proposed ISAC channel model. The Base Station (BS) and User Terminal (UT) are respectively equipped with $P$ and $Q$ antennas, serving as the transmitter (TX) and receiver (RX) for communication. The sensing TX and RX are equipped with $E$ and $W$ antennas. As shown in Fig. 1, assuming that BS serves as sensing TX $( E = P _ { , }$ ), mono-static sensing means the sensing signals are received as the echo, i.e., $W = P$ . When the UT or other terminal serve as the sensing RX, i.e., $W = Q$ or else, it represents bi-static sensing mode. Communication and sensing signals will contribute some shared clusters, also non-shared communication or sensing clusters. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,30,415,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[26,261,60,717]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"arXiv:2310.16765v1 [eess.SP] 25 Oct 2023 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[911,31,919,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[83,71,482,251]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. The illustration of ISAC channel model. The blue lines denote communication paths, and the red solid and dashed lines respectively denote sensing target- and environment- paths. \"]","image_footnote":"[]","img_path":"images/0703/734745ff84c45437a0d80a4dd0a2331a8c740c65897723f764522de702545d6b.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[78,327,238,342]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. ISAC channel model ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,348,490,468]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the proposed model, We designate the sensing targets of interest are indexed as $l = 1 , 2 , . . . , L$ . The cluster number as $n = 1 , 2 , . . . , N$ , and ray number within each cluster as $m =$ $1 , 2 , . . . , M$ . To capture the sharing feature in ISAC channel model, we express the communication and sensing CIRs as the superposition of shared and non-shared components. The CIRs at time $t$ between TX antenna $p / e$ and RX antenna $q / w$ for communication/sensing are respectively formulated as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[137,484,429,503]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0806/5bb245bc861ed6f771284c5624dc3489ebc95663852d00050863627ea118da7d.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nH _ { c , q , p } ( t , \\tau _ { c } ) = H _ { c , q , p } ^ { \\mathrm { s c } } ( t , \\tau _ { c } ) + H _ { c , q , p } ^ { \\mathrm { n s c } } ( t , \\tau _ { c } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[133,520,433,585]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0703/f35e9aa9484c1c098e49d837a09ac44b2a560028e9ccb8f62392b8ce3abacbe1.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l r } { { H _ { s , w , e } ( t , \\tau _ { s } ) = \\sum _ { l } ^ { L } H _ { s , w , l , e } ( t , \\tau _ { s } ) } } \\\\ & { } & { \\quad = H _ { s , w , e } ^ { \\mathrm { s c } } ( t , \\tau _ { s } ) + H _ { s , w , e } ^ { \\mathrm { n s c } } ( t , \\tau _ { s } ) , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[78,590,490,681]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $H _ { s , w , l , e } ( t , \\tau _ { s } )$ denotes the propagation from $\\mathrm { T X } _ { c }$ experience the $l ^ { t h }$ target to $\\mathrm { R X } _ { c }$ . $H _ { c , q , p } ^ { \\mathrm { s c } } ( t , \\tau _ { c } )$ and $H _ { c , q , p } ^ { \\mathrm { n s c } } ( t , \\tau _ { c } )$ denote the shared and non-shared components in communication channel. $H _ { s , w , e } ^ { \\mathrm { s c } } ( t , \\tau _ { s } )$ and $H _ { s , w , e } ^ { \\mathrm { n s c } } ( t , \\tau _ { s } )$ denote the corresponding components in sensing channel. The expanded expressions have been given as (3). In these formulas, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[93,684,490,946]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"• $( \\cdot ) _ { c }$ and $( \\cdot ) _ { s }$ denote the communication and sensing channels, respectively. \n• $( \\cdot ) ^ { T }$ stands for matrix transposition. \n• $\\lambda _ { 0 }$ is the wavelength of the carrier frequency. \n• $^ { a _ { c , n , m } }$ , $a _ { s , l , n , m } ^ { t a r , w }$ , and $a _ { s , l , n , m } ^ { e , t a r }$ are the amplitudes of cluster $n ^ { t h }$ path $\\dot { m } ^ { t h }$ in communication channel, targetl- ${ \\bf \\cal R } { \\bf X } _ { s }$ and $\\mathrm { T X } _ { s }$ -targetl sub-channels. $\\theta _ { c , n , m } ^ { \\mathrm { z o a } }$ , $\\phi _ { c , n , m } ^ { \\mathrm { a o a } }$ , $\\theta _ { c , n , m } ^ { \\mathrm { z o d } }$ , and $\\phi _ { c , n , m } ^ { \\mathrm { a o d } }$ represent the Zenith Angle of Arrival (ZAoA), the Azimuth Angle of Arrival (AAoA), the ZAoD, and the AAoD of the cluster $n ^ { t h }$ path θzoa $\\theta _ { s , l , n , m } ^ { \\mathrm { z o a } }$ $m ^ { t h }$ , $\\phi _ { s , l , n , m } ^ { \\mathrm { a o a } }$ at communication RX and TX, respectively. , $\\theta _ { s , l , n , m } ^ { \\mathrm { z o d } }$ , and $\\phi _ { s , l , n , m } ^ { \\mathrm { a o d } }$ represent the ZAoA, AAoA, ZAoD, and AAoD of the target cluster $n ^ { t h }$ path $m ^ { t h }$ at sensing RX and TX, respectively. \n• $\\theta _ { s , l , n , m } ^ { \\mathrm { o u t } }$ and $\\phi _ { s , l , n , m } ^ { \\mathrm { o u t } }$ are the zenith and azimuth angle of the cluster $n ^ { t h }$ path outgoing the sensing target in the targetl- ${ \\bf R X } _ { s }$ sub-channel. $\\theta _ { s , l , n , m } ^ { \\mathrm { i n } }$ and $\\phi _ { s , l , n , m } ^ { \\mathrm { i n } }$ are the zenith and azimuth angle of the cluster $n ^ { t h }$ path $m ^ { t h }$ get in, and $\\mathrm { T X } _ { s }$ -targetl sub-channel.ndicate the radiation F θc,rx,q , $F _ { c , r x , q } ^ { \\theta } , F _ { c , r x , q } ^ { \\phi } , F _ { c , t x , p } ^ { \\bar { \\theta } }$ $F _ { c , t x , p } ^ { \\phi }$ pattern of the communication RX antenna $q$ and TX antenna $p$ , in the $\\theta$ and $\\phi$ polarization. $F _ { s , r x , w } ^ { \\theta }$ , $F _ { s , r x , w } ^ { \\phi }$ , $F _ { s , t x , e } ^ { \\theta }$ F s,tx,e, and F ϕ $F _ { s , t x , e } ^ { \\phi }$ indicate the radiation pattern of the sensing RX antenna $w$ and TX antenna $e$ , in the $\\theta$ and $\\phi$ $\\psi _ { c , n , m } ^ { i j }$ ation.and $\\psi _ { s , l , n , m } ^ { i j }$ , $i , j ~ \\in ~ \\{ \\theta , \\phi \\}$ , respectively denote the random phase of the cluster path that originate in the $i$ direction and arrive in the $j$ direction in communication CIR and sensing CIR of target ${ { l } ^ { t h } }$ . \n• $\\kappa _ { c , n , m }$ and $\\kappa _ { s , l , n , m }$ represent the cross polarization power ratio (XPR) of the communication and sensing (target ${ { l } ^ { t h } }$ ) cluster $n ^ { t h }$ path $m ^ { t h }$ in the linear scale. \n• $\\sigma ^ { i j }$ , $i , j \\in \\{ \\theta , \\phi \\}$ denotes the RCS complex coefficient that originate in $i$ direction and arrive in $j$ direction. \n• $\\widehat { r } _ { c , r x , n , m }$ , $\\widehat { r } _ { c , t x , n , m }$ , $\\widehat { r } _ { s , r x , l , n , m }$ , and $\\widehat { r } _ { s , t x , l , n , m }$ are the b b b bspherical unit vector of communication and sensing (target ${ l ^ { t h } } ^ { \\prime }$ ) cluster $n ^ { t h }$ path $m ^ { t h }$ at RX and TX sides. $\\bar { \\overline { { d } } } _ { c , q }$ , $\\overline { { d } } _ { c , p }$ , $\\overline { { d } } _ { s , w }$ , and $\\overline { { d } } _ { s , e }$ are the location vectors of antennas $q$ and $p$ at communication sensing RX and TX sides, respectively. \n• $f _ { d , c , n , m }$ and $f _ { d , s , l , n , m }$ denote the Doppler shift of communication and sensing (target ${ { l } ^ { t h } }$ ) cluster $n ^ { t h }$ path $m ^ { t h }$ . \n• τc,n,m is the delay of cluster nth path $m ^ { t h }$ in com \nmunication channel. $\\tau _ { s , l , n , m } ^ { t a r , w }$ and $\\tau _ { s , l , n , m } ^ { p , t a r }$ indicate the delay of cluster s,path $\\dot { m } ^ { t h }$ s,l,n,m in sensing targetl- ${ \\bf R X } _ { s }$ and $\\mathrm { T X } _ { s }$ -targetl sub-channels. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,66,921,510]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,513,919,604]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In (3), the shared target, clusters, and paths are indexed by $l _ { c 0 }$ $, n _ { c 0 } / n _ { s 0 }$ and $m _ { c 0 } / m _ { s 0 }$ , and the non-shared components of communication and sensing CIRs are represented as cluster $n _ { 1 }$ path $m _ { 1 }$ and target $l _ { 2 }$ cluster $n _ { 2 }$ path $m _ { 2 }$ , respectively. The total number of communication and sensing clusters can be given as $N _ { c } = N _ { c 0 } + N _ { 1 }$ and $N _ { s } = L _ { s 0 } \\times N _ { s 0 } + L _ { 2 } \\times N _ { 2 }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,626,732,640]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. ISAC Model Parameterization ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,645,919,751]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This subsection elaborates on how the parameters in the proposed model, which deviate from the traditional 3D GBSM, are depicted. To account for the influence of targets, the sensing channel is modeled by a $\\mathrm { T X } _ { s }$ -targetl- ${ \\bf R X } _ { s }$ cascade channel, which is composed of the $\\mathrm { T X } _ { s }$ -targetl sub-channel, targetl-$\\mathrm { R X } _ { s }$ sub-channel, and the target response. The calculation can be expressed as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[549,758,875,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0095/5634ef44b8388264905b85dde7cc5e67c9bb5809a11abafe01f612af3ad6fb19.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nH _ { s , w , l , e } ( t , \\tau _ { s } ) = H _ { s , w , l } ( t , \\tau _ { s } ) * \\sigma _ { l } * H _ { s , l , e } ( t , \\tau _ { s } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[506,784,919,829]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $H _ { s , w , l } ( t , \\tau _ { s } )$ and $H _ { s , l , e } ( t , \\tau _ { s } )$ represent the channel coefficient for targetl- ${ \\mathrm { R X } } _ { s }$ and $\\mathrm { T X } _ { s }$ -targetl sub-channels. $\\sigma _ { l }$ is a composite RCS model of $l ^ { t h }$ target, expressed as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,835,903,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0893/26010d741381808fbc325bec7ca0bea9b8e0c4780d4a68c6f089718a8ceba08a.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\sigma _ { l } = \\left[ \\begin{array} { l } { \\sigma _ { l } ^ { \\theta \\theta } ( \\theta ^ { \\mathrm { o u t } } , \\phi ^ { \\mathrm { o u t } } , \\theta ^ { \\mathrm { i n } } , \\phi ^ { \\mathrm { i n } } ) \\sigma _ { l } ^ { \\theta \\phi } ( \\theta ^ { \\mathrm { o u t } } , \\phi ^ { \\mathrm { o u t } } , \\theta ^ { \\mathrm { i n } } , \\phi ^ { \\mathrm { i n } } ) } \\\\ { \\sigma _ { l } ^ { \\phi \\theta } ( \\theta ^ { \\mathrm { o u t } } , \\phi ^ { \\mathrm { o u t } } , \\theta ^ { \\mathrm { i n } } , \\phi ^ { \\mathrm { i n } } ) \\sigma _ { l } ^ { \\phi \\phi } ( \\theta ^ { \\mathrm { o u t } } , \\phi ^ { \\mathrm { o u t } } , \\theta ^ { \\mathrm { i n } } , \\phi ^ { \\mathrm { i n } } ) } \\end{array} \\right]\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[506,883,919,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in (3b) to accurately characterize the target response. In this letter, $\\sigma _ { l }$ is modeled as a $2 \\times 2$ array with different polarization directions. The $\\sigma ^ { i j }$ values are the function of angles that outgoing $\\theta ^ { \\mathrm { o u t } }$ and $\\phi ^ { \\mathrm { o u t } } .$ ) and incident $\\theta ^ { \\mathrm { i n } }$ and $\\phi ^ { \\mathrm { i n } }$ ) the targets. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,30,413,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[911,31,919,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[116,75,772,353]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0009/bdcd2edeeb4cc6a9be30639bca289d495b8715c1395e11d6974a2c351d3c13e8.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l } { H _ { \\mathrm { e m e s } } ^ { \\mathrm { i } } ( R _ { \\mathrm { e m e } } ^ { \\mathrm { i } } , R _ { \\mathrm { e m e } } ^ { \\mathrm { i } } \\ell , \\tau ) } & { = \\underbrace { \\nu _ { \\mathrm { s o l } } \\nu _ { \\mathrm { s t } } \\mu _ { \\mathrm { s t } } ^ { \\mathrm { i n } } \\mathcal { L } _ { \\mathrm { e m } } ^ { \\mathrm { i } } } _ { \\mathrm { c \\nu { e } } } } \\\\ & { = \\underbrace { \\nu _ { \\mathrm { s o l } } \\nu _ { \\mathrm { s t } } ^ { \\mathrm { i n } } \\mu _ { \\mathrm { s t } } ^ { \\mathrm { i n } } } _ { \\mathrm { c \\nu { e } } } } \\\\ & { \\cdot [ \\begin{array} { l l l } { R _ { \\mathrm { e m e } } ^ { \\mathrm { i } } \\nu _ { \\mathrm { s t } } ^ { \\mathrm { o } } ( R _ { \\mathrm { e m e } } ^ { \\mathrm { i n } } , \\omega _ { \\mathrm { n } } ^ { \\mathrm { ~ \\ \\ \\ } } ) } & { \\frac { \\nu _ { \\mathrm { s t } } ^ { \\mathrm { i n } } } { 2 } \\omega _ { \\mathrm { c } } } \\\\ { R _ { \\mathrm { e m e } } ^ { \\mathrm { i n } } \\nu _ { \\mathrm { s t } } ^ { \\mathrm { i n } } \\mu _ { \\mathrm { s t } } ^ { \\mathrm { i n } } } & { \\frac { \\nu _ { \\mathrm { s t } } ^ { \\mathrm { o } } } { 2 } \\omega _ { \\mathrm { c } } } \\end{array} ] ^ { \\tau } \\frac { \\Gamma _ { \\mathrm { e m } } ^ { \\mathrm { i } } ( R _ { \\mathrm { e m e } } ^ { \\mathrm { i n } } , \\omega _ { \\mathrm { n } } ^ { \\mathrm { ~ \\ \\ } } ) ^ { 2 } } { \\Gamma _ { \\mathrm { e m } } ^ { \\mathrm { i } } \\omega _ { \\mathrm { c } } ^ { 2 } } } \\\\ & \\cdot [ \\begin{array} { l l l } R _ { \\mathrm { e m e } } ^ { \\mathrm { i } } \\nu _ { \\mathrm { s t } } ^ { \\mathrm { o } } ( R _ { \\mathrm { e m e } } ^ { \\mathrm { i n } } , \\omega _ { \\mathrm { n } } ^ \\end{array} \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[78,387,490,496]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Due to the cascading nature of the sensing channel, the amplitudes (atar,ws,l,n,m and $a _ { s , l , n , m } ^ { e , t a r } )$ and delays $( \\tau _ { s , l , n , m } ^ { t a r , w }$ and $\\tau _ { s , l , n , m } ^ { e , t a r } )$ of thphase (3b) exhibit a two- and Doppler shift rn. The in (3b) $( \\psi _ { s , l , n , m } ^ { i , j } )$ $( f _ { d , s , l , n , m } )$ with known coordinates $( [ x _ { l } , y _ { l } , z _ { l } ] )$ , the 3D distances of $\\mathrm { T X } _ { s }$ - targetl or targetl- ${ \\mathrm { R X } } _ { s }$ sub-channels are calculated as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[120,503,446,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0013/5bb6bcb6c67a93956859f00b8acce1d722085123db69565525f2ecbb90840d67.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nd _ { e , t a r / t a r , w } ^ { \\mathrm { 3 D } } = \\left. ( x _ { e / w } , y _ { e / w } , z _ { e / w } ) - x _ { l } , y _ { l } , z _ { l } \\right. _ { 2 } ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[78,531,490,651]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $[ x _ { e / w } , y _ { e / w } , z _ { e / w } ]$ denotes the coordinate of TX/RX 2ZAoA, AAoA, ZAoD antenna represents the Euclidean norm. The LoS $( \\theta _ { s , l , \\mathrm { l o s } } ^ { \\mathrm { z o d } } )$ , and AAoD $( \\phi _ { s , l , \\mathrm { l o s } } ^ { \\mathrm { a o d } } )$ can be calculated under the global coordinate system. When the LoS clusters propagating through the targets are considered in sensing channel, these geometric LoS angles can be employed directly as the cluster angles. In this context, the LoS delay of cascade sensing channel are calculated by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[122,659,444,680]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0591/f015274dcbd3e074abfaab3909a866c93a2b4a710ef634a274ca042f244ab058.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\tau _ { s , l , \\mathrm { l o s } } = \\tau _ { s , l , \\mathrm { l o s } } ^ { e , t a r } + \\tau _ { s , l , \\mathrm { l o s } } ^ { t a r , w } = ( d _ { e , t a r } ^ { \\mathrm { 3 D } } + d _ { t a r , w } ^ { \\mathrm { 3 D } } ) / c ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[78,688,437,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $c$ denotes the speed of electromagnetic waves. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,703,490,914]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Given that the targets are known, the sensing parameters generated by these targets can be feedback to the communication channel to enhance modeling accuracy. The $l ^ { t h }$ target, as a potential communication scatterer, contributes to the communication propagation paths as $H _ { c , q , l , p } ( t , \\tau _ { c } )$ . Case 1: when communication TX is integrated with monostatic sensing, $H _ { c , q , l , p } ( t , \\tau _ { c } )$ can reuse the path departure angles of $H _ { s , w , l , e } ( t , \\tau _ { s } )$ . Case 2: when communication RX is integrated, the path arrival angles can reuse. Case 3: when communication TX/RX are integrated with bi-static sensing, propagation parameters of $H _ { c , q , l , p } ( t , \\tau _ { c } )$ and $H _ { s , w , l , e } ( t , \\tau _ { s } )$ can be considered equivalent. Note that the model expression and other propagation parameters in $H _ { c , q , l , p } ( t , \\tau _ { c } )$ still adhere to 3GPP standards, as denoted in (3a). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[76,915,488,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To model the sharing feature of ISAC channel, this letter proposes a novel parameter S with dimensions $1 \\times L$ for the shared cluster extraction from these targets. The calculations based on (1) and (2) are expressed as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,387,918,416]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[598,422,826,452]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0606/db56d12f0e9aa4d5154ec984f120e7083e552d5779b46227035a042053e452a5.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nH _ { c , q , p } ^ { \\mathrm { s c } } ( t , \\tau _ { c } ) = \\mathbf { et { } { ' } { \\bf { S } } } _ { 1 \\times L } \\cdot \\mathbf { H } _ { c , q , p } ^ { \\mathrm { t a r } } ( t , \\tau _ { c } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[591,457,830,486]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0192/d9075042befbfdb6af87362498f357671ae7dcca17586e50d16341c64f55bcaf.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nH _ { s , w , e } ^ { \\mathrm { s c } } ( t , \\tau _ { s } ) = \\mathbf { et { } { ' } { \\mathbf { S } } } _ { 1 \\times L } \\cdot \\mathbf { H } _ { s , w , p } ^ { \\mathrm { t a r } } ( t , \\tau _ { s } ) ,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[583,491,841,520]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0590/c6ac14ea28a41b8ebe513c66aced5bfe32ccf6f089ef1503c0d7b97e353703d6.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { H _ { s , w , p } ^ { \\mathrm { n s c } } ( t , \\tau _ { s } ) = ( \\mathbf { I } - \\mathbf { S } ) \\cdot \\mathbf { H } _ { s , w , e } ^ { \\mathrm { t a r } } ( t , \\tau _ { s } ) , } \\\\ { 1 \\times L \\qquad L \\times 1 } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,526,919,571]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\mathbf { H } _ { c , q , p } ^ { \\mathrm { t a r } } ( t , \\tau _ { c } ) = [ H _ { c , q , l , p } ( t , \\tau _ { c } ) ] _ { L \\times 1 }$ and $\\mathbf { H } _ { s , w , e } ^ { \\mathrm { t a r } } ( t , \\tau _ { s } ) =$ $[ H _ { s , w , l , e } ( \\dot { t } , \\hat { \\tau } _ { s } ) ] _ { L \\times 1 }$ . ${ \\bf I } = [ 1 , 1 , \\cdots , 1 , 1 ] _ { L \\times 1 }$ denote the unit vector. S contains $L$ nonnegative real-values, i.e., ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[583,579,844,597]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0098/ad546724868ded8bcacc645980788992b137ca0472b7a406fd03617e546c4ba6.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n{ \\bf S } = [ s _ { 1 } , \\cdots , s _ { l } , \\cdots , s _ { L } ] , s _ { l } = 0 \\mathrm { ~ o r ~ } 1 .\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,603,919,694]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$s _ { l } = 1$ means that the $l ^ { t h }$ target acts in both communication and sensing channels, $H _ { s , w , l , e } ( t , \\tau _ { s } )$ belongs to $H _ { s , w , p } ^ { \\mathrm { s c } } ( t , \\tau _ { s } )$ and communication clusters/paths contributed by this target are generated. On the contrary, $s _ { l } = 0$ represents the $l ^ { t h }$ target only serves as sensing scatterer, resulting in $H _ { s , w , l , e } ( t , \\tau _ { s } )$ belonging to $H _ { s , w , p } ^ { \\mathrm { n s c } } ( t , \\tau _ { s } )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,695,919,799]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In (3), the relationship of shared cluster number can be expressed as $N _ { c 0 } = L _ { s 0 } \\times N _ { s 0 }$ $( { \\cal L } _ { s 0 } = \\sum { \\bf s } )$ . In sensing channel, the LoS cluster has the highest power and provides more effective position information. $N _ { c 0 } ~ = ~ L _ { s 0 }$ when the sensing channel only characterizes cascaded LoS clusters $( N _ { s 0 } = 1 )$ . Moreover, $H _ { c , q , p } ^ { \\mathrm { n s c } } ( t , \\tau _ { c } )$ in (1) is stochastically modeled according to the traditional way. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[531,816,895,844]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"III. MODELING IMPLEMENTATION AND NUMERICAL ANALYSIS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,849,741,864]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. ISAC Modeling Implementation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,869,918,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the proposed ISAC channel model, this letter extends the 3D GBSM and proposes an ISAC channel implementation framework, as illustrated in Fig. 2. This framework, built upon the traditional communication modeling flow in accordance with 3GPP [12], incorporates the generation of sensing channels and the modeling of shared feature. Parameters generation steps that deviate from standard specifications are highlighted in red in the diagram. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,30,413,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[911,30,919,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[78,69,490,113]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[83,161,482,407]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2. ISAC channel model implementation framework. \"]","image_footnote":"[]","img_path":"images/0890/b797315f69e3b25ffa23370891e386f999c4fd2e519255860a8b380a75059d8d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[78,481,490,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1) Sensing channel realization: As illustrated by the blue flowcharts in Fig. 2, the position $( [ x _ { l } , y _ { l } , z _ { l } ] )$ and velocity $( \\overline { { v } } )$ of sensing targets are preset in step S2. Then, the distances and LoS angles of sub-channels are calculated. The path loss in step S3 can be generated as the multiplication of two independent sub-channels according to [12] or calculated based on free space radar equation. In step S5, traditional channel methodologies apply to both sub-channels, with cluster delays, powers, and angles generated. The RCS coefficient in step S6 can be initially implemented as fixed/stochastic values in the preset range depending on the typical object at a specific frequency. The generation of environment/clutter serves as an optional module in step S7, which this letter doesn’t discuss in detail. Step S10 generates cascade channel coefficient based on (4). The other sensing parameters are realized in the stochastic way according to the traditional 3D GBSM. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,733,490,944]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2) Communication channel realization: As illustrated by the gray flowcharts in Fig. 2, the primary parameters of the communication channel, such as large-scale delay spread (DS), angle spread (AS), shadow fading (SF), Ricean K-factor, etc., are generated in accordance with the 3GPP standards. Additionally, to model the sharing feature in the ISAC channel, the expected shared scatterer ratio $( \\sum \\mathbf { S } / L )$ is set in step C&S4. Focusing on the cascade LoS clusters in sensing channel (i.e., $N _ { s 0 } ~ = ~ 1 )$ , this letter provides a method for selecting $N _ { c 0 }$ shared cluster pairs and determining S by comparing specific parameters (such as AAoD and ZAoD) of sensing clusters $( H _ { s , w , l , e } )$ generated in step S5 and stochastic communication clusters $( H _ { c , q , p } ^ { \\mathrm { n s c } } )$ generated in steps $C 5 { \\cdot } C 7$ . Taking integrated case 1 defined in Section II-B as an example, the selection criteria are shown as formulas (12)-(14). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,69,781,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[540,89,857,169]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0504/a803fa9a29dbde8b5415d25a9b856c6098b56d6622d5b51148b424970813e936.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r l r } & { } & { \\mathrm { g a p } ^ { \\mathrm { a o d } } ( l , n ) = \\left| \\phi _ { s , l , \\mathrm { l o s } } ^ { \\mathrm { a o d } } - \\phi _ { c , n } ^ { \\mathrm { a o d } } \\right| \\in [ 0 , 2 \\pi ] , } \\\\ & { } & { \\mathrm { g a p } ^ { \\mathrm { z o d } } ( l , n ) = \\left| \\theta _ { s , l , \\mathrm { l o s } } ^ { \\mathrm { z o d } } - \\theta _ { c , n } ^ { \\mathrm { z o d } } \\right| \\in [ 0 , \\pi ] , } \\\\ & { } & { ( l , n ) ^ { n _ { \\mathrm { c o } } } = \\underset { l , n } { \\mathrm { a r g m i n } } \\left\\{ \\frac { 1 } { 2 } \\left( \\frac { \\mathrm { g a p } ^ { \\mathrm { a o d } } } { 2 \\pi } + \\frac { \\mathrm { g a p } ^ { \\mathrm { z o d } } } { \\pi } \\right) \\right\\} , } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[508,175,919,281]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\mathrm { g a p ^ { a o d } }$ and $\\mathrm { g a p } ^ { \\mathrm { z o d } }$ denote the AAoD and ZAoD gap between $l ^ { t h }$ sensing target and $n ^ { t h }$ communication stochastic cluster. $\\phi _ { c , n } ^ { \\mathrm { a o d } }$ and $\\theta _ { c , n } ^ { \\mathrm { z o d } }$ represent cluster AAoD and ZAoD of $n ^ { t h }$ communication cluster. $( l , n ) ^ { n _ { c 0 } }$ represent ${ n _ { c 0 } } ^ { t h }$ shared cluster pair. According to (14), the $N _ { c 0 }$ pairs of shared cluster labels $( l , n )$ are selected sequentially without repetition, and $s _ { l } = 1$ in (11) are set accordingly. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,284,919,477]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To balance the statistical nature of the communication channel and the deterministic features of the sensing channel, the AAoD and ZAoD of sensing clusters in $( l , n ) ^ { n _ { c 0 } }$ feedback and replace corresponding parameters of communication clusters, i.e., $\\phi _ { c , n } ^ { \\mathrm { a o d } } ~ = ~ \\phi _ { s , l , \\mathrm { l o s } } ^ { \\mathrm { a o d } }$ and $\\theta _ { c , n } ^ { \\mathrm { z o d } } ~ = ~ \\theta _ { s , l , \\mathrm { l o s } } ^ { \\mathrm { z o d } }$ . The remaining parameters of shared communication clusters $( H _ { c , q , p } ^ { \\mathrm { s c } } )$ are generated in reverse according to 3GPP standards and combined with $H _ { c , q , p } ^ { \\mathrm { n s c } }$ . Finally, the communication channel coefficients are generated according to the flowchart. Note that when the shared parameter in step C&S4 is set to 0, the communication and sensing channels will be independent. This configuration is compatible with traditional communication channel implementations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,501,661,515]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. Numerical Analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,521,919,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This letter performs simulations to valide the proposed modeling framework for ISAC channel. In step C&S1 of simulations (as shown in Fig. 2), the coordinate of the BS (sensing TX/RX and communication TX) is set as $( 0 , 0 , 1 . 5 ) \\textrm { m }$ , and the UT (communication RX) is set as $( 1 0 , 0 , 1 . 5 ) \\textrm { m }$ . The Indoor Hotspot (InH) scenario is configured as the baseline scenario. In step S2, we set up 12 targets $( L = 1 2$ ) around the origin. These targets are $5 \\textrm { m }$ from the origin, $1 . 5 \\mathrm { ~ m ~ }$ in height and spaced with $3 0 ^ { \\circ }$ horizontally. Only LoS clusters are set for each target, i.e., $N _ { s 0 } = 1$ . Fig. 3(a) shows the 2D simulation positions, where the blue lines denote the area of communication sectors. Fig. 3(b) presents the 3D positions of mono-static sensing paths, each belonging to one of the 12 target clusters. The simulation results demonstrate that the sensing clusters and paths obtained using the proposed modeling framework accurately correspond to the target positions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[524,777,905,912]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3. Simulation positions of (a) TX, RX, and targets and (b) sensing paths \"]","image_footnote":"[]","img_path":"images/0266/6926db96ba9646468a515e163262e212051d49ed2bd126e1cd4e330ed83b5fe0.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[81,30,415,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[911,31,919,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[78,69,490,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To reflect the parameter relationship between communication and sensing shared clusters, we set shared scatterer ratio to $1 / 6$ in step C&S4 and the shared clusters amount to 2. As an example, we consider the communication LoS scenario in one of our simulations. To ensure consistency with the 3GPP guidelines [12], we remove clusters with power levels more than $2 5 \\ \\mathrm { d B }$ below the maximum cluster power. This process results in 13 effective communication clusters in one simulation. The simulation clusters/paths of sensing and communication channels in the AAoD and ZAoD dimensions are shown in Fig. 3. In this simulation result, sensing cluster 1 and communication LoS cluster 1 are shared, as well as sensing cluster 11 and communication NLoS cluster 4. These shared clusters have the same cluster centroid departure angles. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[83,297,485,443]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4. Simulation clusters/paths of (a) sensing and (b) communication channels in dimensions of $\\\\mathbf { A A o D } ( ^ { \\\\circ } )$ and $\\\\mathbf { Z } \\\\mathbf { A o D ( ^ { \\\\circ } ) }$ . \"]","image_footnote":"[]","img_path":"images/0133/4ac642e257c53c8b3b95d67d429f45b29bee8c5d2db213267892522896a15fbb.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[78,500,490,724]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To further capture shared statistical characteristics, we simulate the shared degree (SD) metric, which has been defined in [3]. The SD represents the ratio of shared cluster power to the total cluster power. While keeping remaining simulation parameters constant, we conduct 200 simulations with varying shared cluster numbers of 4, 6, 8, and 10, respectively. The statistical Cumulative Distribution Functions (CDFs) of sensing and communication SD, respectively denoted as $\\mathrm { S D } _ { s }$ and $\\mathrm { S D } _ { c }$ , are illustrated in Fig. 5. It is evident that an increasing shared cluster number leads to higher SD values. Since the distances between the preset targets and the BS are uniformly consistent in this letter, the LoS cluster power for each target is also similar. Therefore, Under identical shared cluster settings, the sensing SD values exhibit greater concentration, which is reflected in steeper CDF curves in Fig. 5(a). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,756,493,898]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5. Simulation CDFs of SD in (a) sensing and (b) communication channels. \"]","image_footnote":"[]","img_path":"images/0165/5dc17c01ea091862e384f7c8b17aa56fa77fc13f3c438ad080f341484b935633.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[650,69,776,83]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IV. CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,88,919,390]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This letter extends the 3D GBSM and proposes an ISAC channel model that incorporates the sharing feature. This model smoothly aligns with the 3GPP standardization approach. Different from the existing ISAC model, communication and sensing channels are modeled as the shared and non-shared components superimposed in the proposed channel model. For targets of interest, the sensing channel is depicted as a cascade of TX-target, RCS, and target-RX, with RCS modeled as a $2 \\times 2$ array with different polarization directions. To capture the sharing feature of ISAC channel, this letter introduces a novel parameter S for the shared targets/clusters extraction. Based on the proposed model, we present an ISAC channel implementation framework that facilitates the joint generation of communication and sensing channels. To validate the model performance, this letter conducts simulations to examine the positions of sensing channel clusters/paths, the relationship between shared parameters such as cluster angles, and the statistical SD. The results demonstrate that the proposed channel model effectively portrays the practical sharing feature and can support the design of ISAC systems. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[666,407,759,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[514,426,919,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"[1] J. Zhang, P. Tang, L. Yu, T. Jiang, and L. Tian, “Channel measurements and models for 6G: current status and future outlook,” Frontiers of information technology & electronic engineering, vol. 21, no. 1, pp. 39–61, 2020. \n[2] “Framework and overall objectives of the future development of IMT for 2030 and beyond,” ITU-R, 2023. \n[3] Y. Liu, J. Zhang, Y. Zhang, Z. Yuan, and G. Liu, “A shared clusterbased stochastic channel model for joint communication and sensing systems,” IEEE Transactions on Vehicular Technology, Accepted, 2022. (arXiv: 2211.06615). \n[4] C. Ouyang, Y. Liu, and H. Yang, “Performance of downlink and uplink integrated sensing and communications (isac) systems,” IEEE Wireless Communications Letters, vol. 11, no. 9, pp. 1850–1854, 2022. \n[5] J. Zhang, Y. Zhang, Y. Yu, R. Xu, Q. Zheng, and P. Zhang, “3-D MIMO: How much does it meet our expectations observed from channel measurements?” IEEE Journal on Selected Areas in Communications, vol. 35, no. 8, pp. 1887–1903, 2017. \n[6] F. Liu, C. Masouros, A. P. Petropulu, H. Griffiths, and L. Hanzo, “Joint radar and communication design: Applications, state-of-the-art, and the road ahead,” IEEE Trans. Commun., vol. 68, no. 6, pp. 3834–3862, 2020. \n[7] A. Liu, Z. Huang, M. Li, Y. Wan, W. Li, T. X. Han, C. Liu, R. Du, D. K. P. Tan, J. Lu et al., “A survey on fundamental limits of integrated sensing and communication,” IEEE Communications Surveys & Tutorials, vol. 24, no. 2, pp. 994–1034, 2022. \n[8] Y. Fan, S. Gao, D. Duan, X. Cheng, and L. Yang, “Radar integrated mimo communications for multi-hop v2v networking,” IEEE Wireless Communications Letters, vol. 12, no. 2, pp. 307–311, 2022. \n[9] A. Ali, N. Gonzalez-Prelcic, and A. Ghosh, “Passive radar at the roadside ´ unit to configure millimeter wave vehicle-to-infrastructure links,” IEEE Trans. Veh. Technol., vol. 69, no. 12, pp. 14 903–14 917, 2020. \n[10] N. Gonzalez-Prelcic, R. Mendez-Rial, and R. W. Heath, “Radar aided ´ beam alignment in mmWave V2I communications supporting antenna diversity,” in 2016 Information Theory and Applications Workshop (ITA). IEEE, 2016, pp. 1–7. \n[11] A. Lopez-Reche, D. Prado-Alvarez, A. Ramos, S. Inca, J. F. Monserrat, ´ Y. Zhang, Z. Yu, and Y. Chen, “Considering correlation between sensed and communication channels in gbsm for $6 \\mathrm { g }$ isac applications,” in 2022 IEEE Globecom Workshops (GC Wkshps). IEEE, 2022, pp. 1317–1322. \n[12] “Channel model(s) for 0.5-100 GHz,” 3GPP, Sophia Antipolis Cedex, France, TR 38.901., Jun. 2018. [Online]. Available: www.3gpp.org. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,30,413,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[911,31,919,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"discarded"}],"string":"[\n {\n \"bbox\": \"[83,70,911,137]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"How to Extend 3D GBSM to Integrated Sensing and Communication Channel with Sharing Feature? \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[179,147,812,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Yameng Liu, Jianhua Zhang, Yuxiang Zhang, Huiwen Gong, Tao Jiang, Guangyi Liu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,222,488,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract—Integrated Sensing and Communication (ISAC) is a promising technology in 6G systems. The existing 3D Geometry-Based Stochastic Model (GBSM), as standardized for 5G systems, addresses solely communication channels and lacks consideration of the integration with sensing channel. Therefore, this letter extends 3D GBSM to support ISAC research, with a particular focus on capturing the sharing feature of both channels, including shared scatterers, clusters, paths, and similar propagation parameters, which have been experimentally verified in the literature. The proposed approach can be summarized as follows: Firstly, an ISAC channel model is proposed, where shared and nonshared components are superimposed for both communication and sensing. Secondly, sensing channel is characterized as a cascade of TX-target, radar cross section, and target-RX, with the introduction of a novel parameter S for shared target extraction. Finally, an ISAC channel implementation framework is proposed, allowing flexible configuration of sharing feature and the joint generation of communication and sensing channels. The proposed ISAC channel model can be compatible with the 3GPP standards and offers promising support for ISAC technology evaluation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[76,479,488,505]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Index Terms—ISAC, channel modeling, GBSM, sharing feature, shared cluster. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[220,530,348,545]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,553,488,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HE sixth generation (6G) systems envision intelligently connecting everything, which requires a high transmission rate and precise sensing accuracy [1]. Integrated sensing and communication (ISAC) has been identified as a typical usage scenario for 6G [2]. Different from conventional systems with separate functions, ISAC technology allows the base stations or terminals to communicate with each other and sense their surroundings. By sharing the same frequency and hardware resources, ISAC systems offer advantages in improving spectrum utilization and reducing costs [3], [4]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,704,490,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Realistic channel modeling is the prerequisite for the design of every generation of systems. The mainstream channel model, Geometry-Based Stochastic channel Model (GBSM), is the standardized modeling method adopted by ITU and 3GPP. It is two-dimensions (2D) in 4G systems and introduced the vertical angles and expanded to 3D in 5G systems [5]. GBSM is a clustered structure model, grouping multipaths into stochastic clusters. However, this channel model focuses on communication channel, lacking considering the integration with sensing channel. On the one hand, stochastic clusters in 3D GBSM cannot accurately represent the identified locations and attributes of the targets, which are crucial for sensing applications such as positioning and environment reconstruction. On the other hand, due to the multiplexing of hardware resources and the same propagation environment, some targets might serve as shared scatterers for both the communication and sensing channels. This sharing feature, including shared scatterers, clusters, paths, and similar propagation parameters, should be included in ISAC channel model to evaluate the integrated functions and algorithm design of ISAC systems. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,220,919,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,282,919,536]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"With the development of the integrated systems, some existing ISAC studies have operated under the assumption of the sharing feature/correlation between communication and sensing channels [6]–[8]. In [9], [10], the similarity of the azimuth power spectrum of communication and sensing are investigated using Ray-tracing simulations. To validate the existence of the sharing feature, we conduct indoor ISAC channel measurements at $2 8 \\\\ : \\\\mathrm { G H z }$ in [3], intuitively observing the shared scatterers from the power-angular-delay profiles of communication and sensing channels. To further extend GBSM to ISAC channels, the work in [11] analyzes the correlation between communication and sensing channels under realization of GBSM. In [3], we propose a shared cluster-based stochastic ISAC channel model according to the measured observation. However, a practical ISAC channel model that extends 3D GBSM with consideration for the sharing feature is still missing in the literature. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,539,919,703]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To bridge these gaps, this letter proposes a 3D GBSM principle based ISAC channel model with sharing feature. In this model, communication and sensing Channel Impulse Responses (CIRs) are composed of shared and non-shared components. A novel parameter S is introduced for shared target/cluster extraction and parametric modeling of the sensing channel is presented. Then, we propose an ISAC channel implementation framework, which is compatible with the 3GPP standards. The sensing cluster/path positions, the relationship between shared parameters, and the statistical sharing degree (SD) are analyzed to validate the model performance. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[602,726,825,739]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"II. ISAC CHANNEL MODELING \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,748,919,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This letter considers a wideband ISAC channel under a frequency selective fading channel. Fig. 1 provides an illustration of the proposed ISAC channel model. The Base Station (BS) and User Terminal (UT) are respectively equipped with $P$ and $Q$ antennas, serving as the transmitter (TX) and receiver (RX) for communication. The sensing TX and RX are equipped with $E$ and $W$ antennas. As shown in Fig. 1, assuming that BS serves as sensing TX $( E = P _ { , }$ ), mono-static sensing means the sensing signals are received as the echo, i.e., $W = P$ . When the UT or other terminal serve as the sensing RX, i.e., $W = Q$ or else, it represents bi-static sensing mode. Communication and sensing signals will contribute some shared clusters, also non-shared communication or sensing clusters. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,30,415,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[26,261,60,717]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"arXiv:2310.16765v1 [eess.SP] 25 Oct 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[911,31,919,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[83,71,482,251]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. The illustration of ISAC channel model. The blue lines denote communication paths, and the red solid and dashed lines respectively denote sensing target- and environment- paths. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0703/734745ff84c45437a0d80a4dd0a2331a8c740c65897723f764522de702545d6b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[78,327,238,342]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. ISAC channel model \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,348,490,468]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the proposed model, We designate the sensing targets of interest are indexed as $l = 1 , 2 , . . . , L$ . The cluster number as $n = 1 , 2 , . . . , N$ , and ray number within each cluster as $m =$ $1 , 2 , . . . , M$ . To capture the sharing feature in ISAC channel model, we express the communication and sensing CIRs as the superposition of shared and non-shared components. The CIRs at time $t$ between TX antenna $p / e$ and RX antenna $q / w$ for communication/sensing are respectively formulated as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[137,484,429,503]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0806/5bb245bc861ed6f771284c5624dc3489ebc95663852d00050863627ea118da7d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nH _ { c , q , p } ( t , \\\\tau _ { c } ) = H _ { c , q , p } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { c } ) + H _ { c , q , p } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { c } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[133,520,433,585]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0703/f35e9aa9484c1c098e49d837a09ac44b2a560028e9ccb8f62392b8ce3abacbe1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l r } { { H _ { s , w , e } ( t , \\\\tau _ { s } ) = \\\\sum _ { l } ^ { L } H _ { s , w , l , e } ( t , \\\\tau _ { s } ) } } \\\\\\\\ & { } & { \\\\quad = H _ { s , w , e } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { s } ) + H _ { s , w , e } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { s } ) , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[78,590,490,681]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $H _ { s , w , l , e } ( t , \\\\tau _ { s } )$ denotes the propagation from $\\\\mathrm { T X } _ { c }$ experience the $l ^ { t h }$ target to $\\\\mathrm { R X } _ { c }$ . $H _ { c , q , p } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { c } )$ and $H _ { c , q , p } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { c } )$ denote the shared and non-shared components in communication channel. $H _ { s , w , e } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { s } )$ and $H _ { s , w , e } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { s } )$ denote the corresponding components in sensing channel. The expanded expressions have been given as (3). In these formulas, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[93,684,490,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"• $( \\\\cdot ) _ { c }$ and $( \\\\cdot ) _ { s }$ denote the communication and sensing channels, respectively. \\n• $( \\\\cdot ) ^ { T }$ stands for matrix transposition. \\n• $\\\\lambda _ { 0 }$ is the wavelength of the carrier frequency. \\n• $^ { a _ { c , n , m } }$ , $a _ { s , l , n , m } ^ { t a r , w }$ , and $a _ { s , l , n , m } ^ { e , t a r }$ are the amplitudes of cluster $n ^ { t h }$ path $\\\\dot { m } ^ { t h }$ in communication channel, targetl- ${ \\\\bf \\\\cal R } { \\\\bf X } _ { s }$ and $\\\\mathrm { T X } _ { s }$ -targetl sub-channels. $\\\\theta _ { c , n , m } ^ { \\\\mathrm { z o a } }$ , $\\\\phi _ { c , n , m } ^ { \\\\mathrm { a o a } }$ , $\\\\theta _ { c , n , m } ^ { \\\\mathrm { z o d } }$ , and $\\\\phi _ { c , n , m } ^ { \\\\mathrm { a o d } }$ represent the Zenith Angle of Arrival (ZAoA), the Azimuth Angle of Arrival (AAoA), the ZAoD, and the AAoD of the cluster $n ^ { t h }$ path θzoa $\\\\theta _ { s , l , n , m } ^ { \\\\mathrm { z o a } }$ $m ^ { t h }$ , $\\\\phi _ { s , l , n , m } ^ { \\\\mathrm { a o a } }$ at communication RX and TX, respectively. , $\\\\theta _ { s , l , n , m } ^ { \\\\mathrm { z o d } }$ , and $\\\\phi _ { s , l , n , m } ^ { \\\\mathrm { a o d } }$ represent the ZAoA, AAoA, ZAoD, and AAoD of the target cluster $n ^ { t h }$ path $m ^ { t h }$ at sensing RX and TX, respectively. \\n• $\\\\theta _ { s , l , n , m } ^ { \\\\mathrm { o u t } }$ and $\\\\phi _ { s , l , n , m } ^ { \\\\mathrm { o u t } }$ are the zenith and azimuth angle of the cluster $n ^ { t h }$ path outgoing the sensing target in the targetl- ${ \\\\bf R X } _ { s }$ sub-channel. $\\\\theta _ { s , l , n , m } ^ { \\\\mathrm { i n } }$ and $\\\\phi _ { s , l , n , m } ^ { \\\\mathrm { i n } }$ are the zenith and azimuth angle of the cluster $n ^ { t h }$ path $m ^ { t h }$ get in, and $\\\\mathrm { T X } _ { s }$ -targetl sub-channel.ndicate the radiation F θc,rx,q , $F _ { c , r x , q } ^ { \\\\theta } , F _ { c , r x , q } ^ { \\\\phi } , F _ { c , t x , p } ^ { \\\\bar { \\\\theta } }$ $F _ { c , t x , p } ^ { \\\\phi }$ pattern of the communication RX antenna $q$ and TX antenna $p$ , in the $\\\\theta$ and $\\\\phi$ polarization. $F _ { s , r x , w } ^ { \\\\theta }$ , $F _ { s , r x , w } ^ { \\\\phi }$ , $F _ { s , t x , e } ^ { \\\\theta }$ F s,tx,e, and F ϕ $F _ { s , t x , e } ^ { \\\\phi }$ indicate the radiation pattern of the sensing RX antenna $w$ and TX antenna $e$ , in the $\\\\theta$ and $\\\\phi$ $\\\\psi _ { c , n , m } ^ { i j }$ ation.and $\\\\psi _ { s , l , n , m } ^ { i j }$ , $i , j ~ \\\\in ~ \\\\{ \\\\theta , \\\\phi \\\\}$ , respectively denote the random phase of the cluster path that originate in the $i$ direction and arrive in the $j$ direction in communication CIR and sensing CIR of target ${ { l } ^ { t h } }$ . \\n• $\\\\kappa _ { c , n , m }$ and $\\\\kappa _ { s , l , n , m }$ represent the cross polarization power ratio (XPR) of the communication and sensing (target ${ { l } ^ { t h } }$ ) cluster $n ^ { t h }$ path $m ^ { t h }$ in the linear scale. \\n• $\\\\sigma ^ { i j }$ , $i , j \\\\in \\\\{ \\\\theta , \\\\phi \\\\}$ denotes the RCS complex coefficient that originate in $i$ direction and arrive in $j$ direction. \\n• $\\\\widehat { r } _ { c , r x , n , m }$ , $\\\\widehat { r } _ { c , t x , n , m }$ , $\\\\widehat { r } _ { s , r x , l , n , m }$ , and $\\\\widehat { r } _ { s , t x , l , n , m }$ are the b b b bspherical unit vector of communication and sensing (target ${ l ^ { t h } } ^ { \\\\prime }$ ) cluster $n ^ { t h }$ path $m ^ { t h }$ at RX and TX sides. $\\\\bar { \\\\overline { { d } } } _ { c , q }$ , $\\\\overline { { d } } _ { c , p }$ , $\\\\overline { { d } } _ { s , w }$ , and $\\\\overline { { d } } _ { s , e }$ are the location vectors of antennas $q$ and $p$ at communication sensing RX and TX sides, respectively. \\n• $f _ { d , c , n , m }$ and $f _ { d , s , l , n , m }$ denote the Doppler shift of communication and sensing (target ${ { l } ^ { t h } }$ ) cluster $n ^ { t h }$ path $m ^ { t h }$ . \\n• τc,n,m is the delay of cluster nth path $m ^ { t h }$ in com \\nmunication channel. $\\\\tau _ { s , l , n , m } ^ { t a r , w }$ and $\\\\tau _ { s , l , n , m } ^ { p , t a r }$ indicate the delay of cluster s,path $\\\\dot { m } ^ { t h }$ s,l,n,m in sensing targetl- ${ \\\\bf R X } _ { s }$ and $\\\\mathrm { T X } _ { s }$ -targetl sub-channels. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,66,921,510]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,513,919,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In (3), the shared target, clusters, and paths are indexed by $l _ { c 0 }$ $, n _ { c 0 } / n _ { s 0 }$ and $m _ { c 0 } / m _ { s 0 }$ , and the non-shared components of communication and sensing CIRs are represented as cluster $n _ { 1 }$ path $m _ { 1 }$ and target $l _ { 2 }$ cluster $n _ { 2 }$ path $m _ { 2 }$ , respectively. The total number of communication and sensing clusters can be given as $N _ { c } = N _ { c 0 } + N _ { 1 }$ and $N _ { s } = L _ { s 0 } \\\\times N _ { s 0 } + L _ { 2 } \\\\times N _ { 2 }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,626,732,640]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. ISAC Model Parameterization \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,645,919,751]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This subsection elaborates on how the parameters in the proposed model, which deviate from the traditional 3D GBSM, are depicted. To account for the influence of targets, the sensing channel is modeled by a $\\\\mathrm { T X } _ { s }$ -targetl- ${ \\\\bf R X } _ { s }$ cascade channel, which is composed of the $\\\\mathrm { T X } _ { s }$ -targetl sub-channel, targetl-$\\\\mathrm { R X } _ { s }$ sub-channel, and the target response. The calculation can be expressed as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[549,758,875,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0095/5634ef44b8388264905b85dde7cc5e67c9bb5809a11abafe01f612af3ad6fb19.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nH _ { s , w , l , e } ( t , \\\\tau _ { s } ) = H _ { s , w , l } ( t , \\\\tau _ { s } ) * \\\\sigma _ { l } * H _ { s , l , e } ( t , \\\\tau _ { s } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[506,784,919,829]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $H _ { s , w , l } ( t , \\\\tau _ { s } )$ and $H _ { s , l , e } ( t , \\\\tau _ { s } )$ represent the channel coefficient for targetl- ${ \\\\mathrm { R X } } _ { s }$ and $\\\\mathrm { T X } _ { s }$ -targetl sub-channels. $\\\\sigma _ { l }$ is a composite RCS model of $l ^ { t h }$ target, expressed as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,835,903,873]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0893/26010d741381808fbc325bec7ca0bea9b8e0c4780d4a68c6f089718a8ceba08a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\sigma _ { l } = \\\\left[ \\\\begin{array} { l } { \\\\sigma _ { l } ^ { \\\\theta \\\\theta } ( \\\\theta ^ { \\\\mathrm { o u t } } , \\\\phi ^ { \\\\mathrm { o u t } } , \\\\theta ^ { \\\\mathrm { i n } } , \\\\phi ^ { \\\\mathrm { i n } } ) \\\\sigma _ { l } ^ { \\\\theta \\\\phi } ( \\\\theta ^ { \\\\mathrm { o u t } } , \\\\phi ^ { \\\\mathrm { o u t } } , \\\\theta ^ { \\\\mathrm { i n } } , \\\\phi ^ { \\\\mathrm { i n } } ) } \\\\\\\\ { \\\\sigma _ { l } ^ { \\\\phi \\\\theta } ( \\\\theta ^ { \\\\mathrm { o u t } } , \\\\phi ^ { \\\\mathrm { o u t } } , \\\\theta ^ { \\\\mathrm { i n } } , \\\\phi ^ { \\\\mathrm { i n } } ) \\\\sigma _ { l } ^ { \\\\phi \\\\phi } ( \\\\theta ^ { \\\\mathrm { o u t } } , \\\\phi ^ { \\\\mathrm { o u t } } , \\\\theta ^ { \\\\mathrm { i n } } , \\\\phi ^ { \\\\mathrm { i n } } ) } \\\\end{array} \\\\right]\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[506,883,919,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in (3b) to accurately characterize the target response. In this letter, $\\\\sigma _ { l }$ is modeled as a $2 \\\\times 2$ array with different polarization directions. The $\\\\sigma ^ { i j }$ values are the function of angles that outgoing $\\\\theta ^ { \\\\mathrm { o u t } }$ and $\\\\phi ^ { \\\\mathrm { o u t } } .$ ) and incident $\\\\theta ^ { \\\\mathrm { i n } }$ and $\\\\phi ^ { \\\\mathrm { i n } }$ ) the targets. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,30,413,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[911,31,919,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[116,75,772,353]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0009/bdcd2edeeb4cc6a9be30639bca289d495b8715c1395e11d6974a2c351d3c13e8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l } { H _ { \\\\mathrm { e m e s } } ^ { \\\\mathrm { i } } ( R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i } } , R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i } } \\\\ell , \\\\tau ) } & { = \\\\underbrace { \\\\nu _ { \\\\mathrm { s o l } } \\\\nu _ { \\\\mathrm { s t } } \\\\mu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { i n } } \\\\mathcal { L } _ { \\\\mathrm { e m } } ^ { \\\\mathrm { i } } } _ { \\\\mathrm { c \\\\nu { e } } } } \\\\\\\\ & { = \\\\underbrace { \\\\nu _ { \\\\mathrm { s o l } } \\\\nu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { i n } } \\\\mu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { i n } } } _ { \\\\mathrm { c \\\\nu { e } } } } \\\\\\\\ & { \\\\cdot [ \\\\begin{array} { l l l } { R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i } } \\\\nu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { o } } ( R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i n } } , \\\\omega _ { \\\\mathrm { n } } ^ { \\\\mathrm { ~ \\\\ \\\\ \\\\ } } ) } & { \\\\frac { \\\\nu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { i n } } } { 2 } \\\\omega _ { \\\\mathrm { c } } } \\\\\\\\ { R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i n } } \\\\nu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { i n } } \\\\mu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { i n } } } & { \\\\frac { \\\\nu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { o } } } { 2 } \\\\omega _ { \\\\mathrm { c } } } \\\\end{array} ] ^ { \\\\tau } \\\\frac { \\\\Gamma _ { \\\\mathrm { e m } } ^ { \\\\mathrm { i } } ( R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i n } } , \\\\omega _ { \\\\mathrm { n } } ^ { \\\\mathrm { ~ \\\\ \\\\ } } ) ^ { 2 } } { \\\\Gamma _ { \\\\mathrm { e m } } ^ { \\\\mathrm { i } } \\\\omega _ { \\\\mathrm { c } } ^ { 2 } } } \\\\\\\\ & \\\\cdot [ \\\\begin{array} { l l l } R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i } } \\\\nu _ { \\\\mathrm { s t } } ^ { \\\\mathrm { o } } ( R _ { \\\\mathrm { e m e } } ^ { \\\\mathrm { i n } } , \\\\omega _ { \\\\mathrm { n } } ^ \\\\end{array} \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[78,387,490,496]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Due to the cascading nature of the sensing channel, the amplitudes (atar,ws,l,n,m and $a _ { s , l , n , m } ^ { e , t a r } )$ and delays $( \\\\tau _ { s , l , n , m } ^ { t a r , w }$ and $\\\\tau _ { s , l , n , m } ^ { e , t a r } )$ of thphase (3b) exhibit a two- and Doppler shift rn. The in (3b) $( \\\\psi _ { s , l , n , m } ^ { i , j } )$ $( f _ { d , s , l , n , m } )$ with known coordinates $( [ x _ { l } , y _ { l } , z _ { l } ] )$ , the 3D distances of $\\\\mathrm { T X } _ { s }$ - targetl or targetl- ${ \\\\mathrm { R X } } _ { s }$ sub-channels are calculated as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[120,503,446,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0013/5bb6bcb6c67a93956859f00b8acce1d722085123db69565525f2ecbb90840d67.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nd _ { e , t a r / t a r , w } ^ { \\\\mathrm { 3 D } } = \\\\left. ( x _ { e / w } , y _ { e / w } , z _ { e / w } ) - x _ { l } , y _ { l } , z _ { l } \\\\right. _ { 2 } ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[78,531,490,651]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $[ x _ { e / w } , y _ { e / w } , z _ { e / w } ]$ denotes the coordinate of TX/RX 2ZAoA, AAoA, ZAoD antenna represents the Euclidean norm. The LoS $( \\\\theta _ { s , l , \\\\mathrm { l o s } } ^ { \\\\mathrm { z o d } } )$ , and AAoD $( \\\\phi _ { s , l , \\\\mathrm { l o s } } ^ { \\\\mathrm { a o d } } )$ can be calculated under the global coordinate system. When the LoS clusters propagating through the targets are considered in sensing channel, these geometric LoS angles can be employed directly as the cluster angles. In this context, the LoS delay of cascade sensing channel are calculated by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,659,444,680]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0591/f015274dcbd3e074abfaab3909a866c93a2b4a710ef634a274ca042f244ab058.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\tau _ { s , l , \\\\mathrm { l o s } } = \\\\tau _ { s , l , \\\\mathrm { l o s } } ^ { e , t a r } + \\\\tau _ { s , l , \\\\mathrm { l o s } } ^ { t a r , w } = ( d _ { e , t a r } ^ { \\\\mathrm { 3 D } } + d _ { t a r , w } ^ { \\\\mathrm { 3 D } } ) / c ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[78,688,437,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $c$ denotes the speed of electromagnetic waves. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,703,490,914]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Given that the targets are known, the sensing parameters generated by these targets can be feedback to the communication channel to enhance modeling accuracy. The $l ^ { t h }$ target, as a potential communication scatterer, contributes to the communication propagation paths as $H _ { c , q , l , p } ( t , \\\\tau _ { c } )$ . Case 1: when communication TX is integrated with monostatic sensing, $H _ { c , q , l , p } ( t , \\\\tau _ { c } )$ can reuse the path departure angles of $H _ { s , w , l , e } ( t , \\\\tau _ { s } )$ . Case 2: when communication RX is integrated, the path arrival angles can reuse. Case 3: when communication TX/RX are integrated with bi-static sensing, propagation parameters of $H _ { c , q , l , p } ( t , \\\\tau _ { c } )$ and $H _ { s , w , l , e } ( t , \\\\tau _ { s } )$ can be considered equivalent. Note that the model expression and other propagation parameters in $H _ { c , q , l , p } ( t , \\\\tau _ { c } )$ still adhere to 3GPP standards, as denoted in (3a). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[76,915,488,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To model the sharing feature of ISAC channel, this letter proposes a novel parameter S with dimensions $1 \\\\times L$ for the shared cluster extraction from these targets. The calculations based on (1) and (2) are expressed as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,387,918,416]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[598,422,826,452]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0606/db56d12f0e9aa4d5154ec984f120e7083e552d5779b46227035a042053e452a5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nH _ { c , q , p } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { c } ) = \\\\mathbf { et { } { ' } { \\\\bf { S } } } _ { 1 \\\\times L } \\\\cdot \\\\mathbf { H } _ { c , q , p } ^ { \\\\mathrm { t a r } } ( t , \\\\tau _ { c } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[591,457,830,486]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0192/d9075042befbfdb6af87362498f357671ae7dcca17586e50d16341c64f55bcaf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nH _ { s , w , e } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { s } ) = \\\\mathbf { et { } { ' } { \\\\mathbf { S } } } _ { 1 \\\\times L } \\\\cdot \\\\mathbf { H } _ { s , w , p } ^ { \\\\mathrm { t a r } } ( t , \\\\tau _ { s } ) ,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[583,491,841,520]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0590/c6ac14ea28a41b8ebe513c66aced5bfe32ccf6f089ef1503c0d7b97e353703d6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { H _ { s , w , p } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { s } ) = ( \\\\mathbf { I } - \\\\mathbf { S } ) \\\\cdot \\\\mathbf { H } _ { s , w , e } ^ { \\\\mathrm { t a r } } ( t , \\\\tau _ { s } ) , } \\\\\\\\ { 1 \\\\times L \\\\qquad L \\\\times 1 } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,526,919,571]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\mathbf { H } _ { c , q , p } ^ { \\\\mathrm { t a r } } ( t , \\\\tau _ { c } ) = [ H _ { c , q , l , p } ( t , \\\\tau _ { c } ) ] _ { L \\\\times 1 }$ and $\\\\mathbf { H } _ { s , w , e } ^ { \\\\mathrm { t a r } } ( t , \\\\tau _ { s } ) =$ $[ H _ { s , w , l , e } ( \\\\dot { t } , \\\\hat { \\\\tau } _ { s } ) ] _ { L \\\\times 1 }$ . ${ \\\\bf I } = [ 1 , 1 , \\\\cdots , 1 , 1 ] _ { L \\\\times 1 }$ denote the unit vector. S contains $L$ nonnegative real-values, i.e., \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[583,579,844,597]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0098/ad546724868ded8bcacc645980788992b137ca0472b7a406fd03617e546c4ba6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n{ \\\\bf S } = [ s _ { 1 } , \\\\cdots , s _ { l } , \\\\cdots , s _ { L } ] , s _ { l } = 0 \\\\mathrm { ~ o r ~ } 1 .\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,603,919,694]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$s _ { l } = 1$ means that the $l ^ { t h }$ target acts in both communication and sensing channels, $H _ { s , w , l , e } ( t , \\\\tau _ { s } )$ belongs to $H _ { s , w , p } ^ { \\\\mathrm { s c } } ( t , \\\\tau _ { s } )$ and communication clusters/paths contributed by this target are generated. On the contrary, $s _ { l } = 0$ represents the $l ^ { t h }$ target only serves as sensing scatterer, resulting in $H _ { s , w , l , e } ( t , \\\\tau _ { s } )$ belonging to $H _ { s , w , p } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { s } )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,695,919,799]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In (3), the relationship of shared cluster number can be expressed as $N _ { c 0 } = L _ { s 0 } \\\\times N _ { s 0 }$ $( { \\\\cal L } _ { s 0 } = \\\\sum { \\\\bf s } )$ . In sensing channel, the LoS cluster has the highest power and provides more effective position information. $N _ { c 0 } ~ = ~ L _ { s 0 }$ when the sensing channel only characterizes cascaded LoS clusters $( N _ { s 0 } = 1 )$ . Moreover, $H _ { c , q , p } ^ { \\\\mathrm { n s c } } ( t , \\\\tau _ { c } )$ in (1) is stochastically modeled according to the traditional way. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[531,816,895,844]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"III. MODELING IMPLEMENTATION AND NUMERICAL ANALYSIS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,849,741,864]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. ISAC Modeling Implementation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,869,918,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the proposed ISAC channel model, this letter extends the 3D GBSM and proposes an ISAC channel implementation framework, as illustrated in Fig. 2. This framework, built upon the traditional communication modeling flow in accordance with 3GPP [12], incorporates the generation of sensing channels and the modeling of shared feature. Parameters generation steps that deviate from standard specifications are highlighted in red in the diagram. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,30,413,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[911,30,919,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[78,69,490,113]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[83,161,482,407]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2. ISAC channel model implementation framework. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0890/b797315f69e3b25ffa23370891e386f999c4fd2e519255860a8b380a75059d8d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[78,481,490,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1) Sensing channel realization: As illustrated by the blue flowcharts in Fig. 2, the position $( [ x _ { l } , y _ { l } , z _ { l } ] )$ and velocity $( \\\\overline { { v } } )$ of sensing targets are preset in step S2. Then, the distances and LoS angles of sub-channels are calculated. The path loss in step S3 can be generated as the multiplication of two independent sub-channels according to [12] or calculated based on free space radar equation. In step S5, traditional channel methodologies apply to both sub-channels, with cluster delays, powers, and angles generated. The RCS coefficient in step S6 can be initially implemented as fixed/stochastic values in the preset range depending on the typical object at a specific frequency. The generation of environment/clutter serves as an optional module in step S7, which this letter doesn’t discuss in detail. Step S10 generates cascade channel coefficient based on (4). The other sensing parameters are realized in the stochastic way according to the traditional 3D GBSM. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,733,490,944]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2) Communication channel realization: As illustrated by the gray flowcharts in Fig. 2, the primary parameters of the communication channel, such as large-scale delay spread (DS), angle spread (AS), shadow fading (SF), Ricean K-factor, etc., are generated in accordance with the 3GPP standards. Additionally, to model the sharing feature in the ISAC channel, the expected shared scatterer ratio $( \\\\sum \\\\mathbf { S } / L )$ is set in step C&S4. Focusing on the cascade LoS clusters in sensing channel (i.e., $N _ { s 0 } ~ = ~ 1 )$ , this letter provides a method for selecting $N _ { c 0 }$ shared cluster pairs and determining S by comparing specific parameters (such as AAoD and ZAoD) of sensing clusters $( H _ { s , w , l , e } )$ generated in step S5 and stochastic communication clusters $( H _ { c , q , p } ^ { \\\\mathrm { n s c } } )$ generated in steps $C 5 { \\\\cdot } C 7$ . Taking integrated case 1 defined in Section II-B as an example, the selection criteria are shown as formulas (12)-(14). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,69,781,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[540,89,857,169]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0504/a803fa9a29dbde8b5415d25a9b856c6098b56d6622d5b51148b424970813e936.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r l r } & { } & { \\\\mathrm { g a p } ^ { \\\\mathrm { a o d } } ( l , n ) = \\\\left| \\\\phi _ { s , l , \\\\mathrm { l o s } } ^ { \\\\mathrm { a o d } } - \\\\phi _ { c , n } ^ { \\\\mathrm { a o d } } \\\\right| \\\\in [ 0 , 2 \\\\pi ] , } \\\\\\\\ & { } & { \\\\mathrm { g a p } ^ { \\\\mathrm { z o d } } ( l , n ) = \\\\left| \\\\theta _ { s , l , \\\\mathrm { l o s } } ^ { \\\\mathrm { z o d } } - \\\\theta _ { c , n } ^ { \\\\mathrm { z o d } } \\\\right| \\\\in [ 0 , \\\\pi ] , } \\\\\\\\ & { } & { ( l , n ) ^ { n _ { \\\\mathrm { c o } } } = \\\\underset { l , n } { \\\\mathrm { a r g m i n } } \\\\left\\\\{ \\\\frac { 1 } { 2 } \\\\left( \\\\frac { \\\\mathrm { g a p } ^ { \\\\mathrm { a o d } } } { 2 \\\\pi } + \\\\frac { \\\\mathrm { g a p } ^ { \\\\mathrm { z o d } } } { \\\\pi } \\\\right) \\\\right\\\\} , } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[508,175,919,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\mathrm { g a p ^ { a o d } }$ and $\\\\mathrm { g a p } ^ { \\\\mathrm { z o d } }$ denote the AAoD and ZAoD gap between $l ^ { t h }$ sensing target and $n ^ { t h }$ communication stochastic cluster. $\\\\phi _ { c , n } ^ { \\\\mathrm { a o d } }$ and $\\\\theta _ { c , n } ^ { \\\\mathrm { z o d } }$ represent cluster AAoD and ZAoD of $n ^ { t h }$ communication cluster. $( l , n ) ^ { n _ { c 0 } }$ represent ${ n _ { c 0 } } ^ { t h }$ shared cluster pair. According to (14), the $N _ { c 0 }$ pairs of shared cluster labels $( l , n )$ are selected sequentially without repetition, and $s _ { l } = 1$ in (11) are set accordingly. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,284,919,477]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To balance the statistical nature of the communication channel and the deterministic features of the sensing channel, the AAoD and ZAoD of sensing clusters in $( l , n ) ^ { n _ { c 0 } }$ feedback and replace corresponding parameters of communication clusters, i.e., $\\\\phi _ { c , n } ^ { \\\\mathrm { a o d } } ~ = ~ \\\\phi _ { s , l , \\\\mathrm { l o s } } ^ { \\\\mathrm { a o d } }$ and $\\\\theta _ { c , n } ^ { \\\\mathrm { z o d } } ~ = ~ \\\\theta _ { s , l , \\\\mathrm { l o s } } ^ { \\\\mathrm { z o d } }$ . The remaining parameters of shared communication clusters $( H _ { c , q , p } ^ { \\\\mathrm { s c } } )$ are generated in reverse according to 3GPP standards and combined with $H _ { c , q , p } ^ { \\\\mathrm { n s c } }$ . Finally, the communication channel coefficients are generated according to the flowchart. Note that when the shared parameter in step C&S4 is set to 0, the communication and sensing channels will be independent. This configuration is compatible with traditional communication channel implementations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,501,661,515]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. Numerical Analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,521,919,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This letter performs simulations to valide the proposed modeling framework for ISAC channel. In step C&S1 of simulations (as shown in Fig. 2), the coordinate of the BS (sensing TX/RX and communication TX) is set as $( 0 , 0 , 1 . 5 ) \\\\textrm { m }$ , and the UT (communication RX) is set as $( 1 0 , 0 , 1 . 5 ) \\\\textrm { m }$ . The Indoor Hotspot (InH) scenario is configured as the baseline scenario. In step S2, we set up 12 targets $( L = 1 2$ ) around the origin. These targets are $5 \\\\textrm { m }$ from the origin, $1 . 5 \\\\mathrm { ~ m ~ }$ in height and spaced with $3 0 ^ { \\\\circ }$ horizontally. Only LoS clusters are set for each target, i.e., $N _ { s 0 } = 1$ . Fig. 3(a) shows the 2D simulation positions, where the blue lines denote the area of communication sectors. Fig. 3(b) presents the 3D positions of mono-static sensing paths, each belonging to one of the 12 target clusters. The simulation results demonstrate that the sensing clusters and paths obtained using the proposed modeling framework accurately correspond to the target positions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[524,777,905,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3. Simulation positions of (a) TX, RX, and targets and (b) sensing paths \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0266/6926db96ba9646468a515e163262e212051d49ed2bd126e1cd4e330ed83b5fe0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[81,30,415,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[911,31,919,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[78,69,490,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To reflect the parameter relationship between communication and sensing shared clusters, we set shared scatterer ratio to $1 / 6$ in step C&S4 and the shared clusters amount to 2. As an example, we consider the communication LoS scenario in one of our simulations. To ensure consistency with the 3GPP guidelines [12], we remove clusters with power levels more than $2 5 \\\\ \\\\mathrm { d B }$ below the maximum cluster power. This process results in 13 effective communication clusters in one simulation. The simulation clusters/paths of sensing and communication channels in the AAoD and ZAoD dimensions are shown in Fig. 3. In this simulation result, sensing cluster 1 and communication LoS cluster 1 are shared, as well as sensing cluster 11 and communication NLoS cluster 4. These shared clusters have the same cluster centroid departure angles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[83,297,485,443]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4. Simulation clusters/paths of (a) sensing and (b) communication channels in dimensions of $\\\\\\\\mathbf { A A o D } ( ^ { \\\\\\\\circ } )$ and $\\\\\\\\mathbf { Z } \\\\\\\\mathbf { A o D ( ^ { \\\\\\\\circ } ) }$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0133/4ac642e257c53c8b3b95d67d429f45b29bee8c5d2db213267892522896a15fbb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[78,500,490,724]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To further capture shared statistical characteristics, we simulate the shared degree (SD) metric, which has been defined in [3]. The SD represents the ratio of shared cluster power to the total cluster power. While keeping remaining simulation parameters constant, we conduct 200 simulations with varying shared cluster numbers of 4, 6, 8, and 10, respectively. The statistical Cumulative Distribution Functions (CDFs) of sensing and communication SD, respectively denoted as $\\\\mathrm { S D } _ { s }$ and $\\\\mathrm { S D } _ { c }$ , are illustrated in Fig. 5. It is evident that an increasing shared cluster number leads to higher SD values. Since the distances between the preset targets and the BS are uniformly consistent in this letter, the LoS cluster power for each target is also similar. Therefore, Under identical shared cluster settings, the sensing SD values exhibit greater concentration, which is reflected in steeper CDF curves in Fig. 5(a). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,756,493,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5. Simulation CDFs of SD in (a) sensing and (b) communication channels. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0165/5dc17c01ea091862e384f7c8b17aa56fa77fc13f3c438ad080f341484b935633.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[650,69,776,83]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IV. CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,88,919,390]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This letter extends the 3D GBSM and proposes an ISAC channel model that incorporates the sharing feature. This model smoothly aligns with the 3GPP standardization approach. Different from the existing ISAC model, communication and sensing channels are modeled as the shared and non-shared components superimposed in the proposed channel model. For targets of interest, the sensing channel is depicted as a cascade of TX-target, RCS, and target-RX, with RCS modeled as a $2 \\\\times 2$ array with different polarization directions. To capture the sharing feature of ISAC channel, this letter introduces a novel parameter S for the shared targets/clusters extraction. Based on the proposed model, we present an ISAC channel implementation framework that facilitates the joint generation of communication and sensing channels. To validate the model performance, this letter conducts simulations to examine the positions of sensing channel clusters/paths, the relationship between shared parameters such as cluster angles, and the statistical SD. The results demonstrate that the proposed channel model effectively portrays the practical sharing feature and can support the design of ISAC systems. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[666,407,759,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[514,426,919,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"[1] J. Zhang, P. Tang, L. Yu, T. Jiang, and L. Tian, “Channel measurements and models for 6G: current status and future outlook,” Frontiers of information technology & electronic engineering, vol. 21, no. 1, pp. 39–61, 2020. \\n[2] “Framework and overall objectives of the future development of IMT for 2030 and beyond,” ITU-R, 2023. \\n[3] Y. Liu, J. Zhang, Y. Zhang, Z. Yuan, and G. Liu, “A shared clusterbased stochastic channel model for joint communication and sensing systems,” IEEE Transactions on Vehicular Technology, Accepted, 2022. (arXiv: 2211.06615). \\n[4] C. Ouyang, Y. Liu, and H. Yang, “Performance of downlink and uplink integrated sensing and communications (isac) systems,” IEEE Wireless Communications Letters, vol. 11, no. 9, pp. 1850–1854, 2022. \\n[5] J. Zhang, Y. Zhang, Y. Yu, R. Xu, Q. Zheng, and P. Zhang, “3-D MIMO: How much does it meet our expectations observed from channel measurements?” IEEE Journal on Selected Areas in Communications, vol. 35, no. 8, pp. 1887–1903, 2017. \\n[6] F. Liu, C. Masouros, A. P. Petropulu, H. Griffiths, and L. Hanzo, “Joint radar and communication design: Applications, state-of-the-art, and the road ahead,” IEEE Trans. Commun., vol. 68, no. 6, pp. 3834–3862, 2020. \\n[7] A. Liu, Z. Huang, M. Li, Y. Wan, W. Li, T. X. Han, C. Liu, R. Du, D. K. P. Tan, J. Lu et al., “A survey on fundamental limits of integrated sensing and communication,” IEEE Communications Surveys & Tutorials, vol. 24, no. 2, pp. 994–1034, 2022. \\n[8] Y. Fan, S. Gao, D. Duan, X. Cheng, and L. Yang, “Radar integrated mimo communications for multi-hop v2v networking,” IEEE Wireless Communications Letters, vol. 12, no. 2, pp. 307–311, 2022. \\n[9] A. Ali, N. Gonzalez-Prelcic, and A. Ghosh, “Passive radar at the roadside ´ unit to configure millimeter wave vehicle-to-infrastructure links,” IEEE Trans. Veh. Technol., vol. 69, no. 12, pp. 14 903–14 917, 2020. \\n[10] N. Gonzalez-Prelcic, R. Mendez-Rial, and R. W. Heath, “Radar aided ´ beam alignment in mmWave V2I communications supporting antenna diversity,” in 2016 Information Theory and Applications Workshop (ITA). IEEE, 2016, pp. 1–7. \\n[11] A. Lopez-Reche, D. Prado-Alvarez, A. Ramos, S. Inca, J. F. Monserrat, ´ Y. Zhang, Z. Yu, and Y. Chen, “Considering correlation between sensed and communication channels in gbsm for $6 \\\\mathrm { g }$ isac applications,” in 2022 IEEE Globecom Workshops (GC Wkshps). IEEE, 2022, pp. 1317–1322. \\n[12] “Channel model(s) for 0.5-100 GHz,” 3GPP, Sophia Antipolis Cedex, France, TR 38.901., Jun. 2018. [Online]. Available: www.3gpp.org. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,30,413,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JOURNAL OF LATEX CLASS FILES, VOL. 14, NO. 8, AUGUST 2021 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[911,31,919,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.48550/arxiv.2310.16765"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"76400b09de960c11a87dd1e5f770a37e16af59fadae993c4f1ce8b28f61c8e70"},"title":{"kind":"string","value":"How to Extend 3D GBSM to Integrated Sensing and Communication Channel with Sharing Feature?"}}},{"rowIdx":174,"cells":{"abstract":{"kind":"string","value":"Although theory identifies coextinctions as a main driver of biodiversity loss, their role at the planetary scale has yet to be estimated. We subjected a global model of interconnected terrestrial vertebrate food webs to future (2020-2100) climate and land-use changes. We predict a 17.6% (± 0.16% SE) average reduction of local vertebrate diversity globally by 2100, with coextinctions increasing the effect of primary extinctions by 184.2% (± 10.9% SE) on average under an intermediate emissions scenario. Communities will lose up to a half of ecological interactions, thus reducing trophic complexity, network connectance, and community resilience. The model reveals that the extreme toll of global change for vertebrate diversity might be of secondary importance compared to the damages to ecological network structure."},"author":{"kind":"string","value":"Giovanni Strona|Corey J. A. Bradshaw"},"content_list":{"kind":"list like","value":[{"bbox":"[59,75,139,89]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ECOLOGY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,99,768,150]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Coextinctions dominate future vertebrate losses from climate and land use change ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,161,409,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Giovanni Strona1,2\\* and Corey J. A. Bradshaw3 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[816,78,942,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright @ 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Distributed under a Creative Commons Attribution License 4.0 (CC BY). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,190,789,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although theoryidentifies coextinctionsas amaindriverof biodiversityloss,their role atthe planetary scale has yet to be estimated.We subjected a global model of interconnected terrestrial vertebrate food webs to future (2020-21oo) climate and land-use changes.We predict a $1 7 . 6 \\%$ $( \\pm 0 . 1 6 \\%$ SE) average reduction of local vertebrate diversity globally by 21o0,with coextinctions increasing the efect of primary extinctions by $1 8 4 . 2 \\%$ $[ \\pm$ $10 . 9 \\%$ SE)on average under an intermediate emissions scenario.Communities willose up to a half of ecological interactions,thus reducing trophic complexity, network connectance,and community resilience.The model reveals that the extreme tollof globalchange for vertebrate diversity might be of secondary importance com-pared to the damages to ecological network structure. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,342,166,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,355,490,632]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The planet has entered the sixth mass extinction (1-5). There are multiple causes underlying the rapid increase in observed and modeled extinction rates in recent times,of which land-use change,overharvesting,pollution,climate change,and biological invasions figure as dominant processes (6). However,assessing the relative importance and the realistic impact of such drivers at the global scale remains a challenge.Another aspect rendering assessment difficult are the synergies between drivers-a species might go extinct for multiple, simultaneous reasons,and in such contexts,ecological interactions play a fundamental role in predicting its fate (7). Growing recognition of the importance of species interactions in promoting the emergence of biodiversity in complex natural communities implies that an additional, fundamental component of biodiversity loss is represented by the amplification of primary extinctions acrossecological networks. Coextinction—the loss of species caused by direct or indirect effects stemming from other extinctions—is now recognized as a major contributor to global biodiversity loss, strongly amplifying the effect of primary (e.g.,climate-driven) extinctions (8-11). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,633,490,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Networks of ecological interactions are central to global patterns of diversity loss not only because coextinctions can be triggered by other extinction drivers,but also because network structure and dynamics might modulate several processes that can either reduce or increase extinction rate.For example,it is intuitive that a species' success in colonizing a new area depends strongly on its ability to exploit local resources while simultaneously escaping enemies (predators and parasites). The addition of the new species might also initiate substantial changes to and have important cascading effects in the local network. Ignoring the structure of ecological networks and how they reconfigure as their constituent diversity changes therefore gives a possibly misleading view of the future of global diversity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,342,940,675]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Previous attempts to predict the future of global diversity in the face of climate change and habitat modification have only considered the direct effects of these drivers on species (typically on single taxonomic groups), without explicitly accounting for ecological interactions.For instance,Thomas et al.(12) used projections of species'distributions and species-area relationships to predict extinction rates for $2 0 \\%$ of Earth's surface,and Malcolm et al.(13) applied both species-area and endemic-area relationships to predictions of biome shift under climate change in Biodiversity Hotspots. van Vuuren et al. (14) also applied species-area relationships to vascular plants to project extinctions under different land-use and climate-change scenarios within the Millennium Ecosystem Assessment,and Jetz et al.(15) used a similar approach for birds.Others have applied analogous techniques to many other taxa, including lizards (16),crop wild relatives (17),chelonians (18),bird,amphibians,and corals (19).Later,Warren et al. (20) applied point-process and global circulation models to predict climate change-induced shifts in species' distributions,and Urban (21) did a meta-analysis (including many of the studies cited above) to predict extinction rates of various taxa under several climate-change scenarios. Despite this extensive research foundation, future inferences of biodiversity's fate over the coming century are likely to underestimate extinctions arising from global change (11). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,677,940,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Apart from the obvious modeling and computational challenges to incorporate interactions among species,the main reason why there are few studies accounting for interactions is that obtaining sufficient data in most communities is intractable.Therefore, global-scale modeling of entire ecosystems appears to be the only viable solution, even if a challenging one (11,22). Recent developments in network approaches have shown that potential ecological interactions can be derived by applying different techniques (e.g., machine learning) to available datasets on species distribution and ecology (23,24). In previous work $( I I )$ ,we built on that idea to generate global-scale models of biodiversity by including species interactions using virtual species constructed to follow real-world archetypes.In such synthetic approaches,a virtual species is a plausible ecological entity that has a combination of ecological traits consistent with real-world species despite not corresponding exactly to them. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,865,490,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1European Commission,Joint Research Centre (JRC),Ispra,Italy.2Facultyof Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, Biocentre 3, 00790 Helsinki, Finland.'Global Ecology, College of Science and Engineering and ARC Centre of Excellence for Australian Biodiversity and Heritage, Flinders University,GPO Box 2100,Adelaide, South Australia 50oi,Australia. \\*Corresponding author. Email: giovanni.strona@ec.europa.eu ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[902,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[59,76,490,306]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There are several advantages in using virtual species in this manner. The first is that once the rules have been set to generate virtual species, current gaps and biases in biodiversity sampling cease to be a limitation; we can use virtual species to populate the entire Earth and generate plausible ecological communities,even in areas where data on local diversity are scarce or missing. Second, virtual species avoid preconceptions (and biases) about current biodiversity patterns,permitting instead a focus on the processes involved in change.Here,we can populate an entire virtual planet with species,let them develop communities based on a modest set of realistic ecological rules and assumptions,and then explore the emerging patterns.With such an approach,real-world data serve as a template for generating the virtual species and for identifying the basic ecological rules controlling community dynamics and as a benchmark with which to validate the realism of modeled predictions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,309,490,555]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We previously demonstrated how coextinctions increase the pace of annihilation of life on Earth by up to 10 times relative to primary extinctions,but only in the face of catastrophic,noreturn environmental change modeled as either extreme planetary heating or cooling (11).Although an instructive proof of concept, that model contained many simplifications and was applied to (hopefully） unrealistic scenarios of global change.Building on that original approach,here we developed a more complex,and ecologically realistic dynamic model to represent all terrestrial vertebrate communities with which we project future biodiversity trends.By accounting for both primary extinctions and their resulting coextinctions,the model predicts the cumulative toll on global biodiversity of different climate and land-use change projections up to 2100 at a spatial scale of $1 ^ { \\circ } \\times 1 ^ { \\circ }$ and at a monthly temporal resolution.In addition to providing estimates of potential global diversity loss,the model quantifies the relative contribution of the different extinction drivers at the global scale for the first time. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,585,119,597]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,600,490,846]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A limited set of assumptions regarding species' ecology (niche $^ +$ interactions) in the model generates a realistic map of initial (i.e., 2015) terrestrial vertebrate diversity that matches contemporary diversity patterns at the global scale(Fig.1 and figs. S1 to S3;in all climate-projection scenarios,Pearson's $r > 0 . 6$ and a slope $\\approx 1$ when regressing species richness in the model in each $1 ^ { \\circ } \\times 1 ^ { \\circ }$ cell in the global grid against a proxy for \"true\" diversity obtained by overlaying distributional ranges of 21,l43 real-world vertebrate species; see Materials and Methods for details). The consistency in observed versus simulated global diversity patterns provides support for the ecological realism of our network model, showing that it can reproduce plausible, broad-scale patterns of diversity. Notably,our modeled diversity map shows a finer-grained variation in diversity patterns derived from the interplay of climate,land use, and ecological interactions compared to maps of range overlap. The model also produced realistically structured networks and a plausible regional distribution of species body masses (figs.S4 and S5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,847,490,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our model predicted global biodiversity to experience local losses by 2050 ranging [across different CMIP6 carbon-emissions scenarios (25)] from $6 . 0 \\%$ $ { \\left( \\pm \\ \\mathrm { S E } = 0 . 1 \\% \\right. }$ ,SSP2-4.5) to $1 0 . 8 \\%$ （ $\\dot { \\underline { + } }$ $0 . 1 \\%$ ， SSP5-8.5） on average compared to initial diversity (and from $1 3 . 0 \\pm 0 . 1 \\%$ to $2 7 . 0 \\pm 0 . 2 \\%$ by 2100; Fig. 2,left column). In all climate scenarios,climate change was directly responsible (see also Discussion) for the most substantial fraction of local extinction events ( $6 2 . 1 \\pm 7 . 2 \\%$ SD in the intermediate SSP4-6.0 scenario), followed by secondary extinctions $( 2 0 . 3 \\pm 5 . 4 \\%$ ),local extirpations due to overcompetition by colonizers $( 1 3 . 9 \\pm 4 . 1 \\%$ ),and land-use change $( 3 . 7 \\pm 3 . 1 \\%$ see fig. S8 and table S1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,75,940,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,149,940,380]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tracking network structure as it varied through time,we could also quantify how the loss of species resulted in the loss of network interactions (edges). This loss of edges was substantial, averaging $2 3 . 6 \\pm 0 . 2 \\%$ by 2050 in the worst-case scenario ( $( 4 7 . 0 \\pm 0 . 3 \\%$ by 2100; Fig.2,middle column).The high rate of loss of network edges resulted in an overall strong reduction in network connectance (computed as number of edges $\\div$ squared number of nodes, because we are not preventing any interaction from occurring a priori, including cannibalistic interactions). Specifically,connectance declined $1 8 . 2 \\pm 0 . 2 \\%$ by 2050 on average in the worst-case climate-change scenario $( 2 6 . 7 ~ \\pm ~ 0 . 2 \\%$ by 2100；Fig.2,right column).This result is consistent with the expectation that the vulnerability of species to climate change will be insensitive to their position and role in local networks,making the observed trajectories of network disassembly worse than those expected under stable conditions (see fig. S9). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,382,940,701]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Networks also became \"shorter\" in diameter (the longest of all the shortest paths connecting any two nodes in a network),with a reduction of $1 1 . 7 \\pm 0 . 1 \\%$ by 2050 and $2 6 . 0 \\pm 0 . 2 \\%$ by 2100 in the worst-case scenario (fig. S1oA),and increasingly fragmented, with a loss of $1 2 . 8 \\pm 0 . 1 \\%$ by2050 ( $2 3 . 5 \\pm 0 . 1 \\%$ by 2100) of the fraction of nodes in the largest, weakly connected component of the network (i.e., the largest cluster of nodes having at least one path to one of the nodes in the same cluster) in the worst-case climatechange scenario (fig. S1oB). In terms of community structure and composition,we observed a moderate reduction in the average and maximum trophic level in local communities ( $( 1 2 . 0 \\pm 0 . 1 \\%$ and $1 3 . 2 \\ \\pm \\ 0 . 1 \\%$ ，respectively,by 21oo in the worst-case climatechange scenario),and a large reduction in the average and maximum body mass of local (vertebrate） species $( 2 6 . 0 \\pm 0 . 2 \\%$ and $3 8 . 3 \\pm 0 . 2 \\%$ ,respectively; fig. S8).As expected, larger species in high trophic levels will be the most threatened by future climate and land use changes.The reduction in body size and trophic level will be mainly driven by coextinction processes,with weaker patterns in the control simulations where we modeled primary extinctions only (i.e., those occurring due to climate and land-use change,and biological invasions), but not their cascading effects through trophic links (fig. S11). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,703,940,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When we compared the simulations including coextinction events to the controls that only accounted for primary extinctions, the average effects of coextinctions (measured as the percentage decrease in biodiversity between the coextinction and control simulations）were $2 7 . 5 \\pm 1 . 5 \\%$ ， $3 9 . 2 \\pm 2 . 5 \\%$ ，and $2 1 . 8 \\pm 0 . 6 \\%$ by 2050 $( 2 7 . 1 \\pm 2 . 0 \\%$ ， $3 4 . 0 \\pm 4 . 0 \\%$ ,and $1 8 . 1 \\pm 0 . 7 \\%$ by 2100) in the three climate-change scenarios SSP2-4.5,SSP4-6.0,and SSP5-8.5,respectively (Fig.3,left column).However,a potentially overoptimistic assumption of the model is that herbivores and invertebrate feeders never run out of plant and insect biomass.Our model treats insects and plants as nondepletable resources,despite growing evidence for invertebrate declines globally (26). This implies that both consumers capable of only using vertebrates and those also using invertebrates (insectivores and omnivores） are \"invulnerable\" to bottom-up coextinctions—extinctions of consumers triggered by resource depletion,which is the most common expectation for the mechanism underlying secondary extinctions (8-11)—and could therefore go extinct \"only\" due to climate and land-use change,as well as top-down network effects and outcompetition by new colonizers. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[64,78,485,519]","code_body":null,"code_caption":null,"image_caption":"[\"Fig.1.Observed versus modeled vertebrate diversity in 2020 in the CMIP6 SSP4-6.0 scenario.Observed diversity (A) is calculated by overlaying distributional ranges of all vertebrates used as an ecological mold for the virtual species (see Materials and Methods).Modeled diversity (B) corresponds to the ${ \\\\mathsf { l o g } } _ { e }$ -transformed number of virtual species per locality (averaged across 10o model replicates).The distribution of the virtual species does not result directly from the distribution of real-world vertebrates.Instead, the modeled diversity is an emergent property of the simulated system,stemming from the interaction between virtual species and the local virtual community/food web and environment. Map resolution is $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ .Maps for initial diversity in the other climate scenarios (CMIP6 SSP2-4.5 and SSP5-8.5),consistent with this one,are provided in figs.S2 and S3. \"]","image_footnote":"[]","img_path":"images/0963/897a0f1a77e6cd1d37e56826db659fe2eafdb48f355075bb7700f758dad8c33c.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,707,490,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,765,490,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Focusing instead on \"vulnerable\" species only—those at a trophic level higher than strict herbivores and insectivores—to avoid potentially underestimating the effectof coextinctions,diversity loss and the differences between the coextinction and control scenarios rise substantially (Fig.3,right column).Here, the effect of coextinctions amplified biodiversity loss relative to the primary-extinction scenario by $1 1 5 . 3 \\pm 3 . 9 \\%$ ， $1 4 8 . 0 \\pm 6 . 3 \\%$ ，and $1 0 7 . 8 ~ \\pm ~ 4 . 3 \\%$ by 2050 ( $1 7 3 . 7 ~ \\pm ~ 9 . 4 \\%$ ， $1 8 4 . 2 ~ \\pm ~ 1 0 . 9 \\%$ ，and $1 4 4 . 4 \\pm 6 . 1 \\%$ by 210o) in the three climate-change scenarios,with $9 0 ^ { \\mathrm { t h } }$ percentiles of 191.2, 223.7,and $1 7 2 . 4 \\%$ by 2050 (250.0,237.3, and $2 2 3 . 2 \\%$ by 2100),respectively.In all climate change scenarios (and in both the simulations accounting for coextinctions and those not),the average rate of diversity loss was higher from 2020 to 2050 than from 2051 to 2100 (Fig.2,bottom left panel,and fig. S12).Consequently, the greatest changes in diversity and network structure are already appreciable before 2050 (fig.S13), highlighting how the bleakest time for natural communities might be imminent and that the next few decades will be decisive for the future of global biodiversity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,76,935,357]","code_body":null,"code_caption":null,"image_caption":"[\"Fig.2.Simulated,relative local loss of terrestrial vertebrate diversity, interactions,and connectance by 21oo compared to 2o20 under different climatic projections.Maps show local lossin 21oo relative to initial conditions,while plots show the average loss across all Earth localities per year from 2020 to 210o.In both maps and plots,results are the average of 1oo replicates (for the plots,first, we averaged local loss in the 1oo replicates and then averaged local loss values across all localities. Shaded areas are $9 5 \\\\%$ confidence intervals, showing the variation across localities in the average map obtained with 10o simulations). \"]","image_footnote":"[]","img_path":"images/0829/10846bd463b29020a44082adf8a5ca2432af2a52f151f303756f48501775fa34.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[509,492,942,608]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,609,940,724]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Intriguingly,the strongest coextinction effect is predicted in the intermediate-severity SSP4-6.0 scenario.These relatively lower predicted losses in the worst-case SSP5-8.5 climate change projection are explained by the greater number of species in that scenario that are wiped out by primary extinctions arising directly from intolerance to climate change compared to milder climate-change projections,a characteristic that slightly reduces the relative importance of coextinctions therein (Fig.3,right column). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,726,940,871]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When we examine network diversity and structure among biomes,most of the expected losses are predicted to occur in areas with the highest species richness.This shows that Biodiversity Hotspots not only have more species under threat and hence will lose more species (27,28) but that they will also experience the highest rates of loss due to coextinctions over the coming decades (Fig. 4).In general,and regardless of biogeographical region, diversity loss tended to increase with initial diversity (fig. S14). Consistent patterns were also predicted in the decline of network interactions (fig. S15) and connectance (fig. S16). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[60,76,482,351]","code_body":null,"code_caption":null,"image_caption":"[\"Fig.3.Coextinction effect by 2o5o.This is quantified as the percentage increase in diversity loss in the coextinction scenario compared to the reference (primary extinctions only) scenario.To ease visualization and comparisons,we set the maximum value of the color bar to 2 (i.e., $2 0 0 \\\\%$ increase), but black pixels indicate all values $\\\\geq 2 0 0 \\\\%$ \"]","image_footnote":"[]","img_path":"images/0755/166a61193fb2812d88989ae87602aa1d5ccf50acb75a8841b33a41ab04bb82be.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[59,447,145,458]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,460,490,560]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our virtual-Earth model reveals the magnitude of and mechanisms driving biodiversity loss expected from climate change and land conversion this coming century. These results not only suggest a much greater loss than previously anticipated (21), they also demonstrate that biodiversity loss will be accompanied by an additional weakening of community resilience via erosion of the connectance of ecological networks. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,562,490,706]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An important caveat is that while our virtual species are functionally realistic,they do not have taxonomic or phylogenetic meaning. Hence,our results reveallocal changes in species diversity but do not provide information on global species extinctions per se. Neither does the model claim to produce an Earth replica, but instead aims to build an ecologically plausible Earth.Hence, the model cannot forecast Earth's future but instead projects relative potential scenarios based on different assumptions (mainly carbon emissions) and reveals the underlying processes leading to those outcomes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,708,490,924]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Examining the different drivers of extinction,our model reveals that the effect of climate change at the global scale is dominant, while land-use change played a comparatively minor role （fig. S8).However,in no way does that result refute the conclusion that land-use change is a major element of biodiversity loss; rather, it emphasizes that climate change is becoming more important. This emerges from two aspects of the model.First,we only considered relative land-use change from 2020 onward, meaning that the results reflect the relative future impact of land-use change,and not its dominant historical impact on biodiversity loss (3). Second,a strength of our model is that it can map extinctions everywhere on Earth.Even considering the extent of current human impacts,human presence and land-use change still directly affect only a small fraction of the total land inhabited by species. The area of primary and secondary cumulative land projected to be lost from 2020 to the end of the century for the worst-case climate change scenario (SSP5-8.5） is $8 , 0 0 \\dot { 0 } , 0 0 0 ~ \\mathrm { k m } ^ { 2 }$ in total; however, this value represents only $6 . 5 \\%$ of the global area in the simulation inhabited by at least one species in 2020 $\\mathrm { ~ ( \\sim ~ 1 3 0 , 0 0 0 , 0 0 0 ~ k m ^ { 2 } ) }$ (fig. S17). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,75,940,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,149,940,337]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It is also important to consider that the climatic projections take into account land-use change as one of the inputs to derive climatic variables.Therefore,the contribution of climate change to diversity loss also includes,in principle,the indirect effect ofland-use change on climate. Our model does take this into account,as well as other potential indirect, detrimental effects of land-use change,such as increasing fragmentation and then possible alterations to species dispersal and colonization patterns.However,our analysis of the relative importance of extinction drivers focuses exclusively on the direct effects of climate change,land-use change,coextinctions, and biological invasions.Under these caveats,the direct contribution of habitat loss to global extinction is still high,albeit relatively lower than what climate change will occasion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,338,940,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"These results are also robust to different assumptions regarding the local impact of land-use change on diversity; these different choices do not change our overall conclusions (figs. S6, S7,and S18).The main results presented here refer to a model where we assumed a linear relationship between the fraction of primary and secondary land lost at each step in a given locality and the resulting loss of local diversity. More pessimistic scenarios assuming high diversity loss following moderate changes in land use led to more extinctions globally (with a threshold effect observed for $S _ { \\mathrm { L U C } } > 0 . 2 $ see Materials and Methods and fig. S27),but did not change our conclusions on the relative disproportionate importance of climate change. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,513,940,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"By modeling food webs explicitly, our approach reveals synergies among extinction drivers (7),thereby confirming that overexploitation of resources by novel colonizers combined with climate change (i.e.,biological invasions) will become a major cause of diversity loss worldwide (29,30). Our model therefore provides the first global quantitative assessment of the impacts of biological invasions on planetary diversity over the coming century. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,615,940,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An interesting outcome from the sensitivity analyses is that increasing the frequency and intensity of acclimation events in local populations can counterintuitively lead to a higher global extinction rate.The \"adaptation\" mechanism implemented in our model (see Materials and Methods) assumes that species can shift their niches to match the climate of the preceding year. Such a mechanism一although reducing the risk of extinction for species capable of adapting under a stable climatic regime-does not necessarily ensure protection against future changes.When we assume a high probability of adaptation (e.g., $0 . 5 \\%$ of species shift their niche in all localities every year),the net effect is a reduction in average persistence of global diversity.This suggests that a strong and widespread adaptation to local conditions might both increase robustness toward steady conditions while simultaneously increasing vulnerability to change.This outcome is consistent with predictions based on a completely different approach (artificial life evolution simulations) showing that as ecological networks become more resilient to stable environmental conditions,they also become increasingly susceptible to change (31). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,891,940,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our results confirm that coextinctions are fundamental drivers of mass extinctions (5-11) and suggest that previous large extinction events revealed from the fossil record would likely have been exacerbated beyond their primary environmental drivers via the negative feedbacks arising from ecological dependencies.Unless conservation practitioners rapidly start to incorporate the complexity of ecological interactions and their role in extinction processes in their planning,averting the ongoing biodiversity crisis will become an unachievable target. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[99,74,888,369]","code_body":null,"code_caption":null,"image_caption":"[\"Fig.4.DiversitylosspredictedtobehigherinhighlydiversebiomesandlowerinthePalearcticandNearctic.Diversitylos is the $\\\\%$ loss in species number per oli average values,while shaded areas indicate $9 5 \\\\%$ confidence intervals,showing the variationacross localities within a region in the average map obtained with 100 simulations.Equivalent maps forloss of interactions and connectanceare provided in the Supplementary Materials. \"]","image_footnote":"[]","img_path":"images/0895/0ae3901dc846654dddf3cbd03998a3aacc02c5eb590ad655786729f7572882c2.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[59,452,490,538]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,567,247,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MATERIALSAND METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,583,172,596]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Model synopsis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,597,490,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our simulated world consists of a data-driven system of interconnected terrestrial communities composed of virtual, yet ecologically plausible,vertebrate species whose ecology and functional traits obey rules that we derived from combining several large, realworld datasets.The virtual vertebrates in each locality are organized into food webs according to their trophic ecology, diet breadth,and functional traits,with links assigned on the basis of trophic rules derived from empirical data.This generates a dynamic,globalscale system where the patterns and process of food webs are an emerging property of ecological mechanisms inferred from empirical data. Our implementation of the networks' responses to changes in species composition permits modeling and tracking communities at high spatial and temporal resolution,without the prohibitive challenge of modeling multispecies population dynamics and ecological interactions in thousands of sites hosting hundreds of species. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,830,489,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We tracked the future development of the virtual life planet from 2020 to 2100 at a spatial resolution of $1 ^ { \\circ } \\times 1 ^ { \\circ }$ latitude following three climate-projection scenarios [Coupled Model Intercomparison Project Phase 6 (CMIP6):Shared Socioeconomic Pathway (SSP) 2-4.5,SSP4-6.0,and SSP5-8.5] (25),running 100 replicates for each future climate-projection scenario.The model runs at a temporal increment of 1 month for climate and 1 year for spatially explicit land-use changes and food-web dynamics.We allowed species to disperse among localities,with the probability of colonization success depending on the geographic distance between the source and the target locality, compatibility between species'tolerance limits and the environmental conditions (species-specific suitability) of the target locality,and the ability of a species to enter the local food web at the target site.Last, the model includes a function allowing for some species-specific adaptation to changing climate conditions (see Materials and Methods for all modeling details). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,451,940,582]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,583,940,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"During the simulations,species went extinct owing to direct effects of environmental change (i.e., when no longer capable of tolerating local climatic conditions or following loss of primary land) or indirect (either bottom-up or top-down) effects propagating through network links.When a species went extinct,we explicitly accounted for the cascading effect of that extinction on its corresponding local food web. That is,interaction networks in the model continuously adapt and respond to changes in community composition.As species go extinct,and new species enter a local food web from different localities,nodes and links are added and removed,and interaction weights are recalculated on the basis of the new conditions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,757,940,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Recalculating weights permits simulating ecological mechanisms fundamental for food web functioning, such as changes in a consumer's diet and realized specialization driven by resource availability. The initial weights of a network are rescaled depending on resource availability and on the diversity of consumers having access to the different resources.Whenever something changes in the network (e.g.,species are added or removed),weights are adjusted to reflect the new ecological setting. Thus,a consumer that was initially consuming a particular resource might switch a substantial proportion of interaction weight to a novel (more compatible) resource (note that such change is reversible—the consumer can reallocate interaction weights to the initial resource should the situation return to a previous state). Similarly, the diet breadth (in terms of the distribution of interaction weights from a consumer to the set of available resources） might change substantially when species are either lost or added to the network. This might involve one species initially preying mostly on vertebrates to switch its interactions to invertebrates only.In this way,our model can simulate species' plasticity in response to altered conditions,with the coextinction risk of species changing as communities reorganize themselves in response to environmental and ecological change.The same set of rules permits simulating both positive and negative effects of colonizers,either rescuing local populations or increasing local diversity (see the Supplementary Materials),or driving local species to extinction due to overexploitation by the invader. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[59,75,490,277]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,280,490,395]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As a control in each simulation to assess the net effect of coextinctions on global diversity loss,we also ran a parallel experiment where we did not model coextinctions and the other networkrelated events,while maintaining all other ecological processes (primary extinctions,dispersal,and adaptation; also see the discussion in the Supplementary Materials). Further,model outputs were robust to assumptions of adaptive capacity (Supplementary Materials, figs. S6 and S7). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,411,217,424]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Species climatic niche ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,425,490,628]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We collected all available vertebrate ranges from the International Union for the Conservation of Nature (32) and BirdLife International (33).We rasterized the ranges on a $1 ^ { \\circ } \\times 1 ^ { \\circ }$ global grid and then retained only the species occurring in $> 5$ cells (terrestrial mammals: 4452; reptiles: 3903;amphibians:3040; birds: 9748; total $= 2 1 , 1 4 3$ ).We referred to the CMIP6 global circulation model for temperature and precipitation predictions,using three different scenarios: SSP2-4.5,SSP4-6.0,and SSP5-8.5 (approximately equivalent to updated versions of CMIP5 scenarios RCP4.5, $\\mathrm { R C P 6 . 0 }$ ,and RCP8.5,respectively) (25).In particular,we used the multimodel ensembles provided by the Canadian Centre for Climate Modelling and Analysis (34),at a spatial resolution of $1 ^ { \\circ } \\times 1 ^ { \\circ }$ latitude/longitude degrees and at a monthly temporal resolution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,629,490,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We modeled species' niches independently in each climatic scenario by identifying all temperature and precipitation values in the target scenario intersecting a species' range at a monthly interval from 2015 to 2019.We defined suitability $\\left( \\boldsymbol { p } \\right)$ of a species to the target climatic condition $x$ (a temperature or precipitation value) as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[178,708,367,751]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0594/a1f65ef71965b494304b529e8e4e4e6bc3c590d683793b8523c746341481715e.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { p = \\left\\{ \\begin{array} { l l } { 1 - \\frac { 1 } { 1 + e ^ { - c ( x - d ) } } , \\mathrm { i f } ~ x \\leq \\overline { { x } } } \\\\ { \\frac { 1 } { 1 + e ^ { - a ( x - b ) } } , \\quad \\mathrm { o t h e r w i s e } } \\end{array} \\right. } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[59,756,490,814]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\overline { { x } }$ is the average of the monthly measures of the target climatic condition across all $1 ^ { \\circ } \\times 1 ^ { \\circ }$ localities within the species' range in the period January 2015 to December 2019.For each species,we estimated the $a , b , c ,$ and $d$ parameters so that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[138,824,411,839]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0279/ad63e74ab426a8cd260d0deb87cdc759a41d6ad0d517e6ba40089544deda45ce.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\nu = \\nu _ { \\mathrm { m i n } } \\vee \\nu = \\nu _ { \\mathrm { m a x } } \\longrightarrow p = p _ { \\mathrm { t h r e s h } } = 0 . 9 5\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[59,845,490,932]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\nu _ { \\mathrm { m i n } }$ and $\\nu _ { \\mathrm { m a x } }$ are the maximum and minimum recorded values,respectively,of the target climatic condition in the species' range within the reference time interval, and $\\scriptstyle { \\frac { p _ { \\mathrm { t h r e s h } } } { P \\mathrm { t h r e s h } } }$ is an arbitrarily selected probability of species survival at the edges of the species tolerance limits. Here, we conservatively chose $p _ { \\mathrm { t h r e s h } } = 0 . 9 5$ assuming that a given species would have this probability of surviving when the local temperature equals either $\\nu _ { \\mathrm { m i n } }$ or $\\nu _ { \\mathrm { m a x . } }$ To derive the a,b,c,and\" $d$ parameters,we first set $\\begin{array} { l l l } { a } & { = } & { 0 . 0 0 0 1 } \\end{array}$ and $b = \\frac { \\log { \\left( \\frac { \\bar { P } _ { \\mathrm { t h r e s h } } } { 1 - \\bar { P } _ { \\mathrm { t h r e s h } } } \\right) } + a \\nu _ { \\mathrm { m a x } } } { a } .$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,75,940,134]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,137,940,175]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We then incremented $^ a$ progressively by 0.01 per step until I+e-ax-b)≤0.001.Similarly，we setc= 0.0001and $\\begin{array} { r } { d = \\frac { \\log \\Big ( \\frac { 1 - { \\cal P } _ { \\mathrm { t h r e s h } } } { { \\cal P } _ { \\mathrm { t h r e s h } } } \\Big ) + c \\nu _ { \\mathrm { m i n } } } { c } , } \\end{array}$ and we then incremented $c$ progressively by 0.01 per step until $\\textstyle { \\frac { 1 } { 1 + e ^ { - c ( x - d ) } } } \\geq 0 . 9 9 9 8 .$ . This procedure generates an asymmetric,bell-shaped probability curve that has values close to O when conditions are optimal,a probability of extinction $= 1 -$ $p _ { \\mathrm { t h r e s h } } = 0 . 0 5$ when the species is at its tolerance limits,and then it declines rapidly as the local variable of interest departs from the species' tolerance.The two curves obtained for temperature and precipitation define a bidimensional niche where at any given set of climate values,the probability of survival is given by the minimum probability of survival for both variables (fig. S19). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,173,942,334]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,335,940,654]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This approach can be considered as an advanced take on the idea of bioclimatic envelopes (35) because it produces a progressive probability of local extinction as temperature and precipitation ap-proach the most extreme conditions experienced in the species' range. During model development, we compared the probability of extinction from our niche model with those from other methods using nonlinear approaches to identify suitability. Such tests showed that our approach produced a more plausibly progressive increment in extinction risk as local environmental conditions approach the hypothetical tolerance limits compared to the niches produced by other techniques.For instance,we compared the extinction risks produced by either our approach or a RandomForest regressor on a random sample of 1oo vertebrate species across a continuous range of temperature and precipitation values (for a total of 400 unique combinations of temperature and precipitation covering all the ideal space from the minimum to the maximum values recorded on Earth in the reference period 2015-2019).Although we found overall consistency between the risk estimates yielded by the two approaches (Spearman's $\\rho = 0 . 4 1$ ； $P < < 2 . 2 \\times 1 0 ^ { - 1 6 }$ ),Random-Forest produced an unrealistic representation of the bidimensional niche space with abrupt jumps from low to high extinction probability (such as classical bioclimatic envelopes) (fig. S20). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,656,940,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although related to concepts typical of ecological niche models that aim to predict species distributions from environmental/climatic variables,our approach does not suffer from their common limitations. Our derived niches model the risk of local disappearance based on temperature and precipitation,and not to predict species distribution. While subtle,the distinction makes our model robust to the most common weakness associated with ecological niche models (36).A major limitation is that climatic suitability is just one of the many factors determining species presence, yet correlative niche models often ignore biogeographic history, the presence of other species,and stochastic events.However,while a species might not occur in a perfectly suitable area,it almost certainly does not occur/persist in unsuitable locations.In contrast, our modeled species occurrences are the combined and explicit result of niche,dispersal, and interactions with other species—i.e., our model is not affected by the potential biases that might be derived from equating suitability with presence.Instead,our model applies the robust and logical assumption that species cannot persist in an unsuitable area to determine the risk of local extinction. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[59,75,489,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,105,490,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our definition of local extinction risk in this context has a community-level interpretation: Niche predictions do not identify the most extreme conditions tolerable before physiological failure; rather, they are the likelihood that a local population will decline and eventually disappear when exposed to unfavorable conditions. This logic precluded deriving thermal tolerances directly from databases such as GlobTherm (37),as we did previously(11),because empirically derived limits probably overestimate the true population-level responses implicit in our model. However, the distribution of thermal tolerances we generated is consistent with that from GlobTherm (fig.S21),even if slightly shifted toward lower temperatures (a desirable attribute). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,293,414,308]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Species trophic level and body-mass relationship ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,309,490,584]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We obtained body mass for 31,098 species combining information from different sources (38-41).For a subset of those species, we also obtained data on trophic interactions by extracting all available resource-consumer interaction data from the GloBI online database (42）(714,465 at the time of the analysis retrieved from globalbioticinteractions.org/data). For a given species,we used the interaction data to identify both the maximum trophic level (measured as the maximum distance from a basal resource) and its trophic breadth (variation in trophic level of the consumed resources).We combined this information to generate two datasets: The first included body mass and environmental niche (temperature/ precipitation tolerance) for 17,238 species; the second included trophic level, trophic breadth,and body mass for l449 species. The second dataset gives a distribution of trophic level per bodysize interval for each taxonomic group (fig. S22),which assigns trophic level to a given species according to its body size and major phylogenetic grouping by sampling randomly from the distribution of trophic level observed in similar-sized species within the same taxon (described in the following section). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,600,229,613]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Creating virtual species ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,615,490,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To incorporate as much plausible variation as possible in this stochastic model, we generated an independent set of virtual species at the beginning of each global-extinction simulation according to the following procedure.We extracted species from the dataset associating species' niches to the respective body mass, with the sampling structured to match known relative vertebrate diversity according to theIUCN (32) (i.e.,5513 mammals,7302 amphibians,10,425 birds, and i0,038 reptiles).We then compared the body size of the selected species with all body sizes from the body-size and trophic datasets (in random order) until we found a species belonging to the same taxonomic grouping and with \"matching\" body size (see below), and then we associated the trophic information to the target species.In this way,we accounted for potential relationships between ecological niche,body mass, trophic level,and taxonomic group. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[79,833,411,846]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We considered that two body sizes were a match if ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[153,854,396,888]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0030/f8a75a640eed7bbfd11e7e469b59f772db04e06cdb128a11ac05b8c48bfbcf2d.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\frac { \\operatorname* { m a x } [ m _ { 1 } , m _ { 2 } ] - \\operatorname* { m i n } [ m _ { 1 } , m _ { 2 } ] } { \\operatorname* { m a x } [ m _ { 1 } , m _ { 2 } ] } < r _ { \\mathrm { t h r e s h } }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[60,894,489,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $m _ { 1 }$ and $m _ { 2 }$ are the body size of the two species, and $r _ { \\mathrm { t h r e s h } }$ $= 0 . 0 1$ ,a threshold for each species.If no match was found with this threshold,we progressively increased the threshold at steps of 0.01 until a match emerged. The average of final thresholds within a simulation was $0 . 0 6 5 \\pm 0 . 1 1$ with a maximum of 0.96. The largest thresholds are associated with the smallest species,so that the average absolute difference in body mass between matched species is $\\textless 3 0 0 \\mathrm { ~ g ~ }$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,76,940,162]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,164,940,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We then sampled trophic level and breadth corresponding to body-size class and taxonomic group.From this point, the taxonomic identity of a species is no longer maintained in the simulations.We added functional traits to the species following Strona and Bradshaw(11) in the form of a random string of letters (sampled from the standard, 26-letter English alphabet) of size varying stochastically between 1 and 10,ideally corresponding to the virtual species phenotype. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,280,940,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At the beginning of each simulation, we created a $2 6 \\times 2 6$ adjacency matrix filled with real numbers varying randomly between the limits of $- 1$ and 1, indicating the compatibility between any two functional traits (alphabet letters) when considered in isolation. We quantified the compatibility between any two phenotypes by summing all the compatibility values obtained by all pairwise combinations of letters in each phenotype.We then normalized these values between O and 1 (by estimating the minimum and maximum potential compatibility of two random phenotypes for a given trait-adjacency matrix; this is done by comparing $1 0 ^ { 6 }$ pairs of phenotypes generated at random according to the same criteria used in the virtual species-generation process). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,455,940,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The concept behind this approach is well-grounded in theoretical ecology because it corresponds to generating an ideal global square matrix of species-by-species compatibility [e.g. similar to stability-complexity matrices (43)].Adding explicit traits from another matrix of trait-by-trait compatibility adds realism by ensuring that phenotypic compatibility is spatially and temporally consistent.It also reduces the computational burden by providing an efficient way to assess compatibility of any two species in the world without needing to retain a large compatibility matrix; the approach also provides different degrees of specialization (as observed in real-world networks).Although this approach precludes comparing our functional traits to real-world traits,the mechanism produces realistic networks (fig.S4).The final step in the generation of a virtual species requires attributing a random real value between O and 1 to it to indicate its adaptive capacity to changing conditions (see the \"Adaptation\" section below and fig. S23). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,702,696,715]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Populating a virtual Earth ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,716,940,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We obtained land-use projections at annual temporal resolution from 2006 to 2100 from Chini et al. (44).We used projections calibrated using Integrated Assessment Model scenarios with radiative forcing by 2io0,consistent with the SSP scenarios used for climate projections- $\\cdot 4 . 5 \\mathrm { W } \\mathrm { \\ m } ^ { - 2 }$ 6W $\\mathrm { m } ^ { - 2 }$ ,and $8 . 5 ~ \\mathrm { W ~ m } ^ { - 2 }$ .The original data were at a resolution of $0 . 5 ^ { \\circ } \\times 0 . 5 ^ { \\circ }$ ，which we rescaled to our $1 ^ { \\circ } \\times 1 ^ { \\circ }$ grid.We did not consider all land-use categories; instead, we computed for each cell in our grid the fraction of primary and secondary land in a given year. We report the loss of primary and secondary land by 2050 and 2100 under the different climatic scenarios (fig. S24).Here,\"primary\"land is defined as natural vegetation that has never been affected by humans (e.g.,agriculture or wood harvesting),while secondary land is natural vegetation recovering from previous anthropogenic disturbance (44). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[59,76,490,206]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We assigned $4 5 0 0 \\times u$ species to each locality at random,where $u$ is the proportion of primary $^ +$ secondary land in the locality according to the target SSP scenario in 2019.We then reduced the local community to the set of species capable of persisting in the local climate as all those species for which the combined probability of extinction under local temperature and precipitation conditions is $< 0 . 0 5$ for the entire period 20l5-2019 (with probability computed monthly).Last, we arranged these species into food webs (see the next section),keeping only the species participating in the network. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,222,192,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Building networks ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,236,490,541]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For a given pool of species,all potential pairwise interactions are considered,and a directional link is drawn from a candidate resource to a candidate consumer if (i) the trophic level of the consumer is greater than the trophic level of the resource,and the trophic level of the resource is within the trophic breadth of the con-sumer (i.e., not less than the minimum trophic level ofa species possibly consumed by the consumer); (ii) the ratio between the body size of the resource and that of the consumer is greater than ${ l _ { l } } < { l _ { { \\mathrm { u } } } } ,$ with those limits assigned specifically to each combination of resource-consumer taxa (i.e.,birds consumed by mammals are assigned different values than birds consumed by reptiles);and (ii) functional compatibility ( $\\dot { c } _ { \\mathrm { f } } \\dot { s }$ see above) is $> 0 . 5 5$ .Toobtain $l _ { l }$ and $l _ { \\mathrm { u } } ,$ we computed the ratio between prey and predator body mass for each prey-predator interaction recorded in GloBI (42); this provided a distribution of prey-predator body-mass ratios.We then derived $l _ { l }$ and $l _ { \\mathrm { u } }$ as the lower and upper $9 0 \\%$ confidence limits of the distribution, respectively. We applied this procedure separately for each combination of vertebrate classes,such that we obtained a distribution of prey-predator body mass ratios for mammals eating birds,another one for birds eating mammals,another one for mammals eating reptiles, etc. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,542,490,644]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Functional compatibility is then readjusted to $\\begin{array} { r } { c _ { \\mathrm { f } } = 1 - \\frac { 1 - c _ { \\mathrm { f } } } { 1 - 0 . 5 5 } } \\end{array}$ and assigned as a weight to the target link.We chose the functional compatibility threshold( $c _ { \\mathrm { f } } = 0 . 5 5 )$ ）and the number of random species assigned to each locality (45oo) after calibration experiments as the best values permitting realism in terms of local diversity and network structure (figs.S1 to S4). See also low sensitivity of model outputs to variation in $c _ { \\mathrm { f } }$ (Supplementary Materials). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,658,150,670]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Colonization ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,673,490,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At each step of the simulation,a species attempts dispersal from each locality to neighboring localities.A distance (in degrees) of dispersal is first randomly extracted from a log-Normal distribution with mean $= 0$ and $\\mathrm { S D } = 1$ (fig. S25).We added 1 to that distance to ensure that in the shortest-distance case,a species can still move to an adjacent cell in the grid. One cell in the grid at the randomly selected dispersal distance is chosen at random.Then, the potential colonizer species moves to the target locality with a probability computed by testing a species' niche against the climatic condition of the target locality (in the same way as extinction probability is evaluated). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,833,490,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Such a basic treatment of movement of species from one locality to another could conceivably increase diversity indefinitely. However,in the coextinction scenario where we modeled food webs explicitly,the process is realistically constrained because species need to find their place in the food web that is conducive to survival. This is modeled so that when a new species enters a community based solely on climate compatibility, the local food web is rebuilt (according to the same rules described above), taking the new species into account. This might lead to different outcomes in each case. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,76,939,119]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,120,940,264]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For example,if the candidate colonizer is not a primary consumer and cannot find suitable resources,it cannot enter the food web, and colonization fails (i.e., it goes locally extinct).If a candidate colonizer does find a position in the food web,it can become associated with some resources and possibly become a resource for local consumers itself without driving those resources to extinction.Alternatively,if a candidate colonizer finds a position in the food web but ends up overexploiting one or more resources, it can lead to extinction of the resources and potentially itself and other species via extinction cascades. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,264,940,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"However,if acandidate colonizer is a \"primary\" consumer (i.e.,a vertebrate capable of consuming plants and/or invertebrates),it wil always be able to find a position in the food web and become a resource for local consumers,producing an ecologically unrealistic accumulation of diversity and resources.This is because of the specific architecture of the model,where we assumed herbivores and insectivores are the \"basal\" components of the networks (i.e.,we assumed continued and unlimited availability of their resources). For this reason,we treated the incidences of insectivores and herbivores moving to a new locality as a particular case.Here,candidate herbivore and insectivore colonizers are added to the local communityup toa maximum number of species,defined as the initial herbivore/insectivore diversity for that locality.If the diversity of insectivores and herbivores exceeds that number, the (herbivore and/or insectivore） species with least compatibility to local conditions are removed (i.e.，considered as outcompeted by the other species). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,513,940,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the scenario not accounting for coextinctions (i.e., not modeling food webs explicitly),we applied the same criterion but extended to all species in the locality,regardless of their trophic ecology (with the only other criterion for colonization success being climatic compatibility) (see the Supplementary Materials for caveats). In this way, we treat the null expectation of primary extinctions only as a conservative case. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,629,591,642]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adaptation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,644,940,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We assumed that species have a certain capacity to adapt to local (and changing) climates unrelated to the traits defining phenotype. For this,each species has the opportunity with probability $ { p _ { \\mathrm { a d p } } }$ $= 0 . 0 0 1$ of shifting the center of its niche closer to the average local conditions at yearly intervals (i.e., a species during year $y$ can move its niche to fit conditions recorded in year $y ^ { - 1 }$ ).Here, both the average and upper/lower tolerance limits for both temperature and precipitation are shifted along the segment connecting the center of the species' niche and the mean local temperature and precipitation of the preceding year at a length given by the formula $C _ { \\mathrm { a d p } } \\times A \\times d _ { \\mathrm { N } } ,$ where $C _ { \\mathrm { a d p } }$ is an overall simulation adaptation factor that we set to 0.Ol(fixed forall simulations), $A$ is species-specific adaptability (a random value between O and 1 assigned when creating the virtual species),and $d _ { \\mathrm { N } }$ is the total distance between the center of the species'niche and mean local conditions (see fig. S26). After that, the niche is recomputed on the basis of the updated parameters as described in the \"Species climatic niche\" section. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,891,940,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We also explored the sensitivity of results to the choice of the adaptation parameters $ { p _ { \\mathrm { a d p } } }$ and $C _ { \\mathrm { a d p } }$ (see the \"Sensitivity analyses\" section and figs. S6 and S7). Our goal in implementing adaptation was not to model this process explicitly,which would be unfeasible due to the countless unknowns associated with the process.Rather, we wanted to increase the conservativeness of our model by providing species and communities with an additional mechanism to cope with climate change.Such a mechanism mimics local acclimation (with species shifting their niches to match local climate,as described in fig. S26) and does not necessarily entail any evolutionary process. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,949,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[60,75,490,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,207,151,220]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Coextinction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,222,490,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We developed an original, intuitive model for simulating coextinctions that accounts for both bottom-up and top-down effects of diversity loss.The model is applied to weighted, directed networks (with weights corresponding to species' functional compatibility; see the previous section). Such networks can be represented in the form of a square adjacency matrix A of size $n \\times n$ (where $n$ is the total number of species in the network),with each entry $\\mathbf { A } _ { i , j }$ (with $i , j$ in $\\left[ 1 , \\mathbf { \\Omega } . . . , \\mathbf { \\Omega } n \\right] .$ ）representing the interaction strength between the $i ^ { \\mathrm { t h } }$ resource and the $j ^ { \\mathrm { t h } }$ consumer. Thus, $\\Sigma ( \\mathbf { A } _ { i , 1 : n } )$ represents the total consumer pressure on resource i. Each value in row i is divided by the total consumer pressure and then multiplied by its original value to obtain a standardized weight accounting for competition for that resource.For example,if one resource is used by three consumers with respective weights 0.5,0.2,and 0.1, the rescaled values are as follows: $0 . 5 ~ \\times ~ ( 0 . 5 / 0 . 8 ) ~ = ~ 0 . 3 1 2 5$ ， $0 . 2 \\times ( 0 . 2 / 0 . 8 ) = 0 . 0 5 0 _ { ! }$ and $0 . 1 \\times ( 0 . 1 / 0 . 8 ) = 0 . 0 1 2 5$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,455,490,584]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The overall idea behind this step is to account for both the overall competition on a certain resource and resource-consumer compatibility. Let us call the rescaled matrix $\\mathbf { A ^ { \\prime } }$ .The column sum of the rescaled values, $\\Sigma ( \\boldsymbol { \\boldsymbol { \\mathbf { A } } } _ { \\boldsymbol { \\mathbf { \\mathit { 1 } } } : \\boldsymbol { \\boldsymbol { n } } , j } ^ { \\prime } )$ , gives the amount of resource available to consumer $j .$ If that amount falls belowa certain threshold, the consumer goes extinct.Similarly,the row sum of the rescaled values, $\\Sigma ( \\mathbf { A ^ { \\prime } } _ { i , l : n } )$ ,indicates the pressure of consumers on resource i. Should this pressure go beyond a given threshold (see below), then resource $i$ goes extinct due to overconsumption. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,585,490,875]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Species can also go extinct whenever they become disconnected from basal resources (in our case, corresponding to being detached from herbivores or insectivores).For each network, thresholds for consumer extinctions correspond to the minimum observed $\\Sigma ( \\mathbf { A } ^ { \\prime } _ { I } \\mathbf { : }$ $_ { n , j } )$ for any species $i , j$ in the network at the time the network is generated.Similarly,thresholds for extinctions of resources following overconsumption are set to the maximum observed $\\Sigma ( \\boldsymbol { \\mathbf { A } } _ { i , l : n } ^ { \\prime } )$ for any species $i , j$ in the network at the time the network is generated. The thresholds are then updated after the burn-in phase (see the \"Simulations\" section) to ensure that networks are at equilibrium once the global-change simulation starts,and coextinction events can only be generated by removing some species from the network.Our initial, conservative assumption here is that no species goes extinct if conditions do not change (i.e.,if environmental conditions remain stable and no species immigrate from different locations). However, this does not prevent new species from entering the system and increasing local diversity. This assumption also necessarily gives a conservative estimate of total extinction rates given that our model does not explicitly incorporate existing extinction lags before each simulation beginning (45). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,876,489,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The threshold for consumer coextinctions is assgned specifically to each network by referring to the most exploited resource in the system.This conservative assumption provides substantial opportunity increase in consumer diversity (following species immigration from other localities） before top-down coextinctions are triggered. The top-down regulation mechanism serves two main purposes: (i) It accounts for the potential detrimental effects of alien colonizers on both native resources and potential competitors (with outcompetition processes treated with specific model rules; see the \"Colonization\" section),and (ii) it accounts for decreasing resource diversity in a food web eliciting two different,concomitant effects: less-efficient consumers might be outcompeted by more efficient ones,and resources targeted by many different consumers might be overexploited. There are clearly ecological settings where these processes can be buffered or even reversed,but the rapid environmental and ecological change we modeled here is more likely to destabilize than to stabilize systems,consistent with increasing empirical evidence of ongoing global ecosystem collapse (2-5,46). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,76,940,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,280,942,584]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our dynamic implementation of network weights also compensates for the choice (dictated by the insurmountable computational challenge of modeling multispecies population dynamics for almost 20,000 networks at a temporal span of nearly a century) of not track-ing explicitly species abundances. Our implementation of weights is conceptually linked to species abundances in that the total interaction weight of a consumer (which eventually determines its risk of going extinct following ecological change in the community/food web) increases with the availability of suitable resources and declines with diversity of competitors.At the same time,the total pressure on a resource determining its extinction risk increases with diversity of (compatible) consumers.It is reasonable to assume that when the consumer's population has access to a large variety of suitable resources and it has few competitors,it will be larger than a population able to access fewer resources shared among many consumers.Similarly, the population of a resource (and hence,its availability to consumers) will decrease with increasing consumer pressure.It is therefore also reasonable to consider weights in our networks as a proxy for abundances,accounting for multispecies population dynamics in the global model without explicitly implementing them. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,600,595,613]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Simulations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,615,940,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We ran l0o simulations per climate-projection scenario.In each simulation,we generated a pool of species,and we populated a virtual Earth as described in previous sections.We did a burn-in phase where we permitted species to disperse to new areas over 100 time steps.At each step of the burn-in and for each locality, we sampled one species and moved it to a randomly selected locality following a dispersal kernel of the form $1 + \\log \\mathcal { N }$ [0,1]. We then evaluated a species' survival probability under the climate conditions from 2015 to 2020,keeping it in the simulation only if the probability of extinction $ { p _ { \\mathrm { e x t } } } < 0 . 0 5$ . We rebuilt food webs every 10 steps.If the number of basal species increased because of colonizers exceeding the initial number of basal species (i.e.,at the beginning of the simulation),we evaluated climatic suitability of all basal species, removing species in increasing order of local adaptation until we restored the initial number of basal species.The burnin phase provided our simulated systems with biogeographical realism,giving species a chance to colonize contiguous areas if climatically suitable (and within a food web permitting the colonization).In addition,it increased the robustness of networks to local, current (2015-2020) climatic conditions through the potential replacement of basal species with better-adapted colonizers.Last, it ensures that the initial changes recorded in the model run are not biased by the short-range movements of species from the initial random pools assigned to each locality. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[900,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[59,75,489,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,107,490,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We then simulated climate and land-use changes from 2020 to 2100.At monthly steps and for each locality,we evaluated which species went extinct according to their suitability to withstand local temperature and precipitation conditions.We considered that species with $ { p _ { \\mathrm { e x t } } } \\leq 0 . 0 5$ never went extinct (we used this probability to assign species to localities). In this way,we avoided \"random\" extinctions,such that extinctions only occurred because of climate and/or land-use change.We also assumed that in each year and in a given locality,a fraction of the species identical to the fraction of primary and secondary land lost from the previous year went extinct (see the next paragraph for additional details). Last, we simulated coextinctions in food webs due to primary extinctions and then updated the networks.We replicated the same simulations in a control scenario not accounting for networks and secondary extinctions.The two scenarios (coextinction and control） started from the same initial virtual Earth (after the burn-in,predispersal/colonization phase） but then ran each independently. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,367,490,484]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The choice of using a monthly time step for climate change and yearly time steps for the land-use change was driven by the different temporal resolutions of the selected dataset.However, the different temporal resolutions are also well-suited to model the two different processes,considering the potential high variability of temperature and precipitation patterns on a relatively short time scale compared to the slower and usually nonreversible (at least in the short term) losses of primary land. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,498,391,513]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Effect of land-use change on species diversity ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,514,490,701]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Land use change might have complex and case-specific effects on vertebrate communities.The response of local vertebrate diversity to the intensity of land-use change-measured as the fraction of primary and secondary land lost at each yearly step in the simulation compared to the previous year-might assume different shapes. Those ideally range from cases where small land-use changes result in disproportionately high diversity loss to the opposite where diversity persists in the face of severe losses of primary and/or secondary habitat.We opted foran intermediate scenario where the loss of species diversity is linearly proportional to land conversion.However,we also explored the potential effects on model outcomes of simulating different forms and magnitudes of response of local diversity to land use change. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,702,490,746]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Specifically, we explored the potential impact on results of using different response curves of biodiversity loss versus relative land-use change of the following form ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[69,752,480,772]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0996/5682c762486a3c6b20e8011e276c52e645b13a042154db0d6da073519a248250.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { l o s s = 1 - ( 1 - P _ { L U C } ) ^ { R _ { 1 } } \\mathrm { ~ i f ~ } R _ { 2 } = - 1 , \\mathrm { ~ o r ~ } l o s s = P _ { L U C } ^ { R _ { 1 } } \\mathrm { ~ i f ~ } R _ { 2 } = 1 } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[59,777,490,850]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where loss is the fraction of biodiversity lost following habitat loss via land-use change; $P _ { \\mathrm { L U C } }$ is the fraction of primary and secondary land lost at a given time step compared to the previous one; $R _ { 1 }$ is a random number in the range $^ { \\{ 0 , 1 \\} }$ and $R _ { 2 }$ is sampled from $\\{ - 1 , 1 \\}$ with equal probability. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,851,490,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The two parameters $R _ { 1 }$ and $R _ { 2 }$ can be combined into a single parameter $S _ { \\mathrm { L U C } } ~ = ~ R _ { 2 } ( 1 ~ - ~ R _ { 1 } )$ ，which describes the response curves of diversity loss in a continuous way from 1 (full diversity loss occurs even with no habitat loss） to $- 1$ (diversity loss is invariant to full habitat loss)，with $S _ { \\mathrm { { L U C } } } = 0$ representing the linear response we used in the main simulations (fig. S27). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,76,940,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,103,940,585]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The effect ofland-use change could also affect species differently depending on body size and trophic level (themselves partially dependent properties).However,the mechanisms by which the impact of land-use change might reach different species in a community could be complex. Our model already accounts for such complexity. The expectation that large-bodied animals are more susceptible to the effects of climate and land use change results from observation of patterns,but the underlying mechanisms are unclear. This is where our model offers another unique advantage compared to existing studies-climate and land-use change are predicted to cause a global reduction in vertebrate body size (fig. S11) even without any initial assumption of an intrinsic relationship between body size and species vulnerability. That is,our model offers a mechanistic explanation of the process-body size reduction is mainly a consequence of how diversity loss propagates through food webs. That this well-known pattern arises naturally as an emergent property of \"simple\" rules provides strong additional support of our model's ecological realism.Nevertheless,we also explored the potential impact on our results of assuming an a priori relationship between vertebrate body sizes and vulnerability to landuse change in the sensitivity analyses (see below),devising a procedure controlled by a single parameter ( $( V _ { \\mathrm { L U C } } )$ as follows: Consider a local community with S species-at a given step, $l o s s \\times S$ species will go extinct due to land-use change (with loss being the fraction of biodiversity lost following habitat loss via land-use change,computed as described above). To identify such species within the local species pool, we first sorted species by decreasing size.We then iterated the procedure of randomly switching the position of two species in the ordered list $V _ { \\mathrm { L U C } } \\times S$ times. Last, we identified the first $l o s s \\times s$ species in the sorted list as extinct. When $V _ { \\mathrm { L U C } } = 0$ the largest species always go extinct due to land-use change at each step,while increasing $V _ { \\mathrm { L U C } }$ leads progressively toward random extinctions (fig. S28). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,600,650,613]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sensitivity analyses ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,615,940,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We explored the potential sensitivity of our model outputs to different combinations of parameter values by devising a global sensitivity analysis where we modified (i) the number of steps in the burnin phase $( s _ { \\mathrm { b - i } } )$ ,(ii) the threshold for functional compatibility $\\left( c _ { \\mathrm { f } } \\right)$ ， (ii) species adaptation probability $( p _ { \\mathrm { a d p } } )$ ,(iv) species adaptation factor $( C _ { \\mathrm { a d p } } )$ ,(v) the shape of the response curves of local diversity versus land-use change $( S _ { \\mathrm { L U C } } )$ ,and $( \\nu i )$ the potential relationship between vertebrate body mass and vulnerability to land-use change $( V _ { \\mathrm { L U C } } )$ .Here,we ran an additional set of 1oo simulations per future climatic scenario where we randomly sampled (uniformly) $s _ { \\mathrm { b - i } } \\operatorname { f r o m } 0$ to 1000, $c _ { \\mathrm { f } } \\mathrm { f r o m } 0 . 4 5$ to 0.65, $ { p _ { \\mathrm { a d p } } }$ from 0 to 0.005, $C _ { \\mathrm { a d p } }$ from O to 0.05, $S _ { \\mathrm { { L U C } } }$ from $- 1$ to 1,and $V _ { \\mathrm { L U C } }$ from 0 to 1. For each simulation, we recorded the percentage loss of diversity as the response for each climate change scenario.We then applied a machine-learning emulator—boosted-regression trees (47)-implemented using the dismo R library (48) and its function gbm.step to examine the relative importance of each of the four variables considered on the response.We set the error distribution family as Gaussian, the bag fraction to 0.75,the learning rate to 0.001,the tolerance to 0.0ool,and the tree complexity to 2 (i.e., first-order interactions only).To assess the relative effect of each variable on initial diversity,we calculated the boosted regression tree metrics of relative influence (relative influence $I$ is defined as the relative influences of the individual inputs $x _ { j }$ on the variation of the function that maps the explanatory variables $x$ to the response variable y) (49). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[895,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[59,75,490,133]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[59,164,241,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplementary Materials ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,178,166,236]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This PDF file includes: \nSupplementary Text \nFigs. S1 to S29 \nTable S1 \nReferences ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,267,241,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES AND NOTES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[59,276,494,932]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1．A.D.Barnosky, N. Matzke, S.Tomiya, G.O.U.Wogan, B.Swartz,T.B. Quental, C.Marshall, J. L. McGuire, E.L. Lindsey, K.C.Maguire,B.Mersey, E.A.Ferrer, Has the Earth's sixth mass extinction already arrived? Nature 471,51-57 (2011). \n2.G.Ceballos, P. R.Ehrlich, R.Dirzo, Biological annihilation via the ongoing sixth mass extinction signaled by vertebrate population losses and declines. Proc. Natl.Acad.Sci. U.S.A. 114，E6089-E6096 (2017). \n3.S. Diaz,J.Settele,E.S.Brondizio, H.T.Ngo,J.Agard,A.Arneth,P.Balvanera,K.A.Brauman, S. H.M. Butchart, K. M.A. Chan,L.A.Garibaldi, K. Ichi,J. Liu,S.M.Subramanian, G.F. Midgley,P.Miloslavich,Z.Molnar, D.Obura,A.Pfaf,S.Polasky,A.Purvis,J. Razzaque, B. Reyers,R. Roy Chowdhury,Y.-J.Shin,I.Visseren-Hamakers,K.J.Wilis, C.N.Zayas,Pervasive human-driven decline of life on Earth points to the need for transformative change. Science 366,eaax3100 (2019). \n4.G.Cebalos,P.R. Ehrlich,P.H. Raven, Vertebrates on the brink as indicators of biological annihilation and the sixth mass extinction.Proc. Natl. Acad.Sci. 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R package version 0.9-3.http://CRAN.R-project.org/package=dismo(2013). \n49.T.A.Prowse,C.J.A.Bradshaw,S.Delean,P.Cassey,R.C.Lacy, K.Wels,M.E.Aiell-Lammens, H.R.Akcakaya, B.W. Brook,An efficient protocol for the global sensitivity analysis of stochastic ecological models. Ecosphere 7,e01238 (2016). \n50.I. Morales-Castilla, M.G. Matias, D.Gravel, M.B.Araujo,Inferring biotic interactions from proxies.Trends Ecol.Evol.30,347-356 (2015). \n51.M.Dornelas,N.J. Gotelli, B. McGill,H. Shimadzu,F. Moyes, C.Sievers,A.E.Magurran,Assemblage time series reveal biodiversity change but not systematic loss.Science 344, 296-299 (2014). \n52.M.Dornelas, N.J.Gotell, H.Shimadzu,F. Moyes,A.E.Magurran,B.J.McGill,A balance of winners and losers in the Anthropocene. Ecol. Lett. 22,847-854 (2019). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,48,944,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,38,470,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCE ADVANCES丨RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[895,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,75,490,285]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,75,942,230]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"not in any circumstances be regarded as stating an official position of the European Commission.G.S.was partly funded bya Flinders University Honorary Visiting Scholar (May 2019). C.J.A.B.was partly funded by the Australian Research Council, Centre of Excelence for Australian Biodiversity and Heritage (CE170100015; July 2017 to June 2024).Author contributions: G.S.and C.J.A.B.conceived the idea, designed the research,did the analyses, and wrote the manuscript. G.S.collected data,developed the model,wrote the code,and ran the simulations.Competing interests: The authors declare that they have no competing interests.Data and materials availability:All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.All the data and code to replicate the simulationsare freely available at https://doi.org/10.5281/zenodo.7307443. Additional data and code for the sensitivity analyses are available from https://doi.org/10.5281/ zenodo.7255957.Development versions of the code for the simulations and the analyses are available from https://github.com/giovannistrona/global_coextinctions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,242,647,288]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Submitted 25 November 2021 \nAccepted 9 November 2022 \nPublished 16 December 2022 \n10.1126/sciadv.abn4345 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,948,440,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[895,948,942,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 of 12 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,37,470,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCIENCEADVANCES|RESEARCH ARTICLE ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[57,300,490,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments:We thank G. Ceballos and J.Llewelyn for useful comments and suggestions on the manuscript.The views expressed are purely those of the writers and may ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[129,60,546,108]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ScienceAdvances ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[133,160,865,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Coextinctions dominate future vertebrate losses from climate and land use change ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[131,181,389,194]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Giovanni Strona and Corey J.A. Bradshaw ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[131,231,315,257]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sci. Adv., 8 (50),eabn4345. DOI:10.1126/sciadv.abn4345 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[106,884,934,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Science Advances(ISSN）is publishedby the American Asociationfor teAdvancementof Science.1200 NewYork Avenue NW, Washington,DC 20o05.The title Science Advances is a registered trademark of AAAS. Copyright $\\circledcirc$ 2022The Authors,some rights reserved;exclusive licensee American Association forthe Advancement of Science.No claim to original U.S. Government Works. Distributed under a Creative Commons Atribution License 4.0 (CC BY). ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[131,346,458,400]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View the article online https://www.science.org/doi/10.1126/sciadv.abn4345 Permissions https://www.science.org/help/reprints-and-permissions ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[107,855,414,867]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Use of this article is subject to the Terms of service ","text_format":null,"text_level":null,"type":"discarded"}],"string":"[\n {\n \"bbox\": \"[59,75,139,89]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ECOLOGY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,99,768,150]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Coextinctions dominate future vertebrate losses from climate and land use change \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,161,409,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Giovanni Strona1,2\\\\* and Corey J. A. Bradshaw3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[816,78,942,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright @ 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Distributed under a Creative Commons Attribution License 4.0 (CC BY). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,190,789,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although theoryidentifies coextinctionsas amaindriverof biodiversityloss,their role atthe planetary scale has yet to be estimated.We subjected a global model of interconnected terrestrial vertebrate food webs to future (2020-21oo) climate and land-use changes.We predict a $1 7 . 6 \\\\%$ $( \\\\pm 0 . 1 6 \\\\%$ SE) average reduction of local vertebrate diversity globally by 21o0,with coextinctions increasing the efect of primary extinctions by $1 8 4 . 2 \\\\%$ $[ \\\\pm$ $10 . 9 \\\\%$ SE)on average under an intermediate emissions scenario.Communities willose up to a half of ecological interactions,thus reducing trophic complexity, network connectance,and community resilience.The model reveals that the extreme tollof globalchange for vertebrate diversity might be of secondary importance com-pared to the damages to ecological network structure. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,342,166,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,355,490,632]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The planet has entered the sixth mass extinction (1-5). There are multiple causes underlying the rapid increase in observed and modeled extinction rates in recent times,of which land-use change,overharvesting,pollution,climate change,and biological invasions figure as dominant processes (6). However,assessing the relative importance and the realistic impact of such drivers at the global scale remains a challenge.Another aspect rendering assessment difficult are the synergies between drivers-a species might go extinct for multiple, simultaneous reasons,and in such contexts,ecological interactions play a fundamental role in predicting its fate (7). Growing recognition of the importance of species interactions in promoting the emergence of biodiversity in complex natural communities implies that an additional, fundamental component of biodiversity loss is represented by the amplification of primary extinctions acrossecological networks. Coextinction—the loss of species caused by direct or indirect effects stemming from other extinctions—is now recognized as a major contributor to global biodiversity loss, strongly amplifying the effect of primary (e.g.,climate-driven) extinctions (8-11). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,633,490,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Networks of ecological interactions are central to global patterns of diversity loss not only because coextinctions can be triggered by other extinction drivers,but also because network structure and dynamics might modulate several processes that can either reduce or increase extinction rate.For example,it is intuitive that a species' success in colonizing a new area depends strongly on its ability to exploit local resources while simultaneously escaping enemies (predators and parasites). The addition of the new species might also initiate substantial changes to and have important cascading effects in the local network. Ignoring the structure of ecological networks and how they reconfigure as their constituent diversity changes therefore gives a possibly misleading view of the future of global diversity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,342,940,675]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Previous attempts to predict the future of global diversity in the face of climate change and habitat modification have only considered the direct effects of these drivers on species (typically on single taxonomic groups), without explicitly accounting for ecological interactions.For instance,Thomas et al.(12) used projections of species'distributions and species-area relationships to predict extinction rates for $2 0 \\\\%$ of Earth's surface,and Malcolm et al.(13) applied both species-area and endemic-area relationships to predictions of biome shift under climate change in Biodiversity Hotspots. van Vuuren et al. (14) also applied species-area relationships to vascular plants to project extinctions under different land-use and climate-change scenarios within the Millennium Ecosystem Assessment,and Jetz et al.(15) used a similar approach for birds.Others have applied analogous techniques to many other taxa, including lizards (16),crop wild relatives (17),chelonians (18),bird,amphibians,and corals (19).Later,Warren et al. (20) applied point-process and global circulation models to predict climate change-induced shifts in species' distributions,and Urban (21) did a meta-analysis (including many of the studies cited above) to predict extinction rates of various taxa under several climate-change scenarios. Despite this extensive research foundation, future inferences of biodiversity's fate over the coming century are likely to underestimate extinctions arising from global change (11). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,677,940,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Apart from the obvious modeling and computational challenges to incorporate interactions among species,the main reason why there are few studies accounting for interactions is that obtaining sufficient data in most communities is intractable.Therefore, global-scale modeling of entire ecosystems appears to be the only viable solution, even if a challenging one (11,22). Recent developments in network approaches have shown that potential ecological interactions can be derived by applying different techniques (e.g., machine learning) to available datasets on species distribution and ecology (23,24). In previous work $( I I )$ ,we built on that idea to generate global-scale models of biodiversity by including species interactions using virtual species constructed to follow real-world archetypes.In such synthetic approaches,a virtual species is a plausible ecological entity that has a combination of ecological traits consistent with real-world species despite not corresponding exactly to them. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,865,490,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1European Commission,Joint Research Centre (JRC),Ispra,Italy.2Facultyof Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, Biocentre 3, 00790 Helsinki, Finland.'Global Ecology, College of Science and Engineering and ARC Centre of Excellence for Australian Biodiversity and Heritage, Flinders University,GPO Box 2100,Adelaide, South Australia 50oi,Australia. \\\\*Corresponding author. Email: giovanni.strona@ec.europa.eu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[902,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[59,76,490,306]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There are several advantages in using virtual species in this manner. The first is that once the rules have been set to generate virtual species, current gaps and biases in biodiversity sampling cease to be a limitation; we can use virtual species to populate the entire Earth and generate plausible ecological communities,even in areas where data on local diversity are scarce or missing. Second, virtual species avoid preconceptions (and biases) about current biodiversity patterns,permitting instead a focus on the processes involved in change.Here,we can populate an entire virtual planet with species,let them develop communities based on a modest set of realistic ecological rules and assumptions,and then explore the emerging patterns.With such an approach,real-world data serve as a template for generating the virtual species and for identifying the basic ecological rules controlling community dynamics and as a benchmark with which to validate the realism of modeled predictions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,309,490,555]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We previously demonstrated how coextinctions increase the pace of annihilation of life on Earth by up to 10 times relative to primary extinctions,but only in the face of catastrophic,noreturn environmental change modeled as either extreme planetary heating or cooling (11).Although an instructive proof of concept, that model contained many simplifications and was applied to (hopefully） unrealistic scenarios of global change.Building on that original approach,here we developed a more complex,and ecologically realistic dynamic model to represent all terrestrial vertebrate communities with which we project future biodiversity trends.By accounting for both primary extinctions and their resulting coextinctions,the model predicts the cumulative toll on global biodiversity of different climate and land-use change projections up to 2100 at a spatial scale of $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ and at a monthly temporal resolution.In addition to providing estimates of potential global diversity loss,the model quantifies the relative contribution of the different extinction drivers at the global scale for the first time. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,585,119,597]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,600,490,846]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A limited set of assumptions regarding species' ecology (niche $^ +$ interactions) in the model generates a realistic map of initial (i.e., 2015) terrestrial vertebrate diversity that matches contemporary diversity patterns at the global scale(Fig.1 and figs. S1 to S3;in all climate-projection scenarios,Pearson's $r > 0 . 6$ and a slope $\\\\approx 1$ when regressing species richness in the model in each $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ cell in the global grid against a proxy for \\\"true\\\" diversity obtained by overlaying distributional ranges of 21,l43 real-world vertebrate species; see Materials and Methods for details). The consistency in observed versus simulated global diversity patterns provides support for the ecological realism of our network model, showing that it can reproduce plausible, broad-scale patterns of diversity. Notably,our modeled diversity map shows a finer-grained variation in diversity patterns derived from the interplay of climate,land use, and ecological interactions compared to maps of range overlap. The model also produced realistically structured networks and a plausible regional distribution of species body masses (figs.S4 and S5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,847,490,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our model predicted global biodiversity to experience local losses by 2050 ranging [across different CMIP6 carbon-emissions scenarios (25)] from $6 . 0 \\\\%$ $ { \\\\left( \\\\pm \\\\ \\\\mathrm { S E } = 0 . 1 \\\\% \\\\right. }$ ,SSP2-4.5) to $1 0 . 8 \\\\%$ （ $\\\\dot { \\\\underline { + } }$ $0 . 1 \\\\%$ ， SSP5-8.5） on average compared to initial diversity (and from $1 3 . 0 \\\\pm 0 . 1 \\\\%$ to $2 7 . 0 \\\\pm 0 . 2 \\\\%$ by 2100; Fig. 2,left column). In all climate scenarios,climate change was directly responsible (see also Discussion) for the most substantial fraction of local extinction events ( $6 2 . 1 \\\\pm 7 . 2 \\\\%$ SD in the intermediate SSP4-6.0 scenario), followed by secondary extinctions $( 2 0 . 3 \\\\pm 5 . 4 \\\\%$ ),local extirpations due to overcompetition by colonizers $( 1 3 . 9 \\\\pm 4 . 1 \\\\%$ ),and land-use change $( 3 . 7 \\\\pm 3 . 1 \\\\%$ see fig. S8 and table S1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,75,940,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,149,940,380]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tracking network structure as it varied through time,we could also quantify how the loss of species resulted in the loss of network interactions (edges). This loss of edges was substantial, averaging $2 3 . 6 \\\\pm 0 . 2 \\\\%$ by 2050 in the worst-case scenario ( $( 4 7 . 0 \\\\pm 0 . 3 \\\\%$ by 2100; Fig.2,middle column).The high rate of loss of network edges resulted in an overall strong reduction in network connectance (computed as number of edges $\\\\div$ squared number of nodes, because we are not preventing any interaction from occurring a priori, including cannibalistic interactions). Specifically,connectance declined $1 8 . 2 \\\\pm 0 . 2 \\\\%$ by 2050 on average in the worst-case climate-change scenario $( 2 6 . 7 ~ \\\\pm ~ 0 . 2 \\\\%$ by 2100；Fig.2,right column).This result is consistent with the expectation that the vulnerability of species to climate change will be insensitive to their position and role in local networks,making the observed trajectories of network disassembly worse than those expected under stable conditions (see fig. S9). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,382,940,701]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Networks also became \\\"shorter\\\" in diameter (the longest of all the shortest paths connecting any two nodes in a network),with a reduction of $1 1 . 7 \\\\pm 0 . 1 \\\\%$ by 2050 and $2 6 . 0 \\\\pm 0 . 2 \\\\%$ by 2100 in the worst-case scenario (fig. S1oA),and increasingly fragmented, with a loss of $1 2 . 8 \\\\pm 0 . 1 \\\\%$ by2050 ( $2 3 . 5 \\\\pm 0 . 1 \\\\%$ by 2100) of the fraction of nodes in the largest, weakly connected component of the network (i.e., the largest cluster of nodes having at least one path to one of the nodes in the same cluster) in the worst-case climatechange scenario (fig. S1oB). In terms of community structure and composition,we observed a moderate reduction in the average and maximum trophic level in local communities ( $( 1 2 . 0 \\\\pm 0 . 1 \\\\%$ and $1 3 . 2 \\\\ \\\\pm \\\\ 0 . 1 \\\\%$ ，respectively,by 21oo in the worst-case climatechange scenario),and a large reduction in the average and maximum body mass of local (vertebrate） species $( 2 6 . 0 \\\\pm 0 . 2 \\\\%$ and $3 8 . 3 \\\\pm 0 . 2 \\\\%$ ,respectively; fig. S8).As expected, larger species in high trophic levels will be the most threatened by future climate and land use changes.The reduction in body size and trophic level will be mainly driven by coextinction processes,with weaker patterns in the control simulations where we modeled primary extinctions only (i.e., those occurring due to climate and land-use change,and biological invasions), but not their cascading effects through trophic links (fig. S11). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,703,940,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When we compared the simulations including coextinction events to the controls that only accounted for primary extinctions, the average effects of coextinctions (measured as the percentage decrease in biodiversity between the coextinction and control simulations）were $2 7 . 5 \\\\pm 1 . 5 \\\\%$ ， $3 9 . 2 \\\\pm 2 . 5 \\\\%$ ，and $2 1 . 8 \\\\pm 0 . 6 \\\\%$ by 2050 $( 2 7 . 1 \\\\pm 2 . 0 \\\\%$ ， $3 4 . 0 \\\\pm 4 . 0 \\\\%$ ,and $1 8 . 1 \\\\pm 0 . 7 \\\\%$ by 2100) in the three climate-change scenarios SSP2-4.5,SSP4-6.0,and SSP5-8.5,respectively (Fig.3,left column).However,a potentially overoptimistic assumption of the model is that herbivores and invertebrate feeders never run out of plant and insect biomass.Our model treats insects and plants as nondepletable resources,despite growing evidence for invertebrate declines globally (26). This implies that both consumers capable of only using vertebrates and those also using invertebrates (insectivores and omnivores） are \\\"invulnerable\\\" to bottom-up coextinctions—extinctions of consumers triggered by resource depletion,which is the most common expectation for the mechanism underlying secondary extinctions (8-11)—and could therefore go extinct \\\"only\\\" due to climate and land-use change,as well as top-down network effects and outcompetition by new colonizers. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[64,78,485,519]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig.1.Observed versus modeled vertebrate diversity in 2020 in the CMIP6 SSP4-6.0 scenario.Observed diversity (A) is calculated by overlaying distributional ranges of all vertebrates used as an ecological mold for the virtual species (see Materials and Methods).Modeled diversity (B) corresponds to the ${ \\\\\\\\mathsf { l o g } } _ { e }$ -transformed number of virtual species per locality (averaged across 10o model replicates).The distribution of the virtual species does not result directly from the distribution of real-world vertebrates.Instead, the modeled diversity is an emergent property of the simulated system,stemming from the interaction between virtual species and the local virtual community/food web and environment. Map resolution is $1 ^ { \\\\\\\\circ } \\\\\\\\times 1 ^ { \\\\\\\\circ }$ .Maps for initial diversity in the other climate scenarios (CMIP6 SSP2-4.5 and SSP5-8.5),consistent with this one,are provided in figs.S2 and S3. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0963/897a0f1a77e6cd1d37e56826db659fe2eafdb48f355075bb7700f758dad8c33c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,707,490,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,765,490,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Focusing instead on \\\"vulnerable\\\" species only—those at a trophic level higher than strict herbivores and insectivores—to avoid potentially underestimating the effectof coextinctions,diversity loss and the differences between the coextinction and control scenarios rise substantially (Fig.3,right column).Here, the effect of coextinctions amplified biodiversity loss relative to the primary-extinction scenario by $1 1 5 . 3 \\\\pm 3 . 9 \\\\%$ ， $1 4 8 . 0 \\\\pm 6 . 3 \\\\%$ ，and $1 0 7 . 8 ~ \\\\pm ~ 4 . 3 \\\\%$ by 2050 ( $1 7 3 . 7 ~ \\\\pm ~ 9 . 4 \\\\%$ ， $1 8 4 . 2 ~ \\\\pm ~ 1 0 . 9 \\\\%$ ，and $1 4 4 . 4 \\\\pm 6 . 1 \\\\%$ by 210o) in the three climate-change scenarios,with $9 0 ^ { \\\\mathrm { t h } }$ percentiles of 191.2, 223.7,and $1 7 2 . 4 \\\\%$ by 2050 (250.0,237.3, and $2 2 3 . 2 \\\\%$ by 2100),respectively.In all climate change scenarios (and in both the simulations accounting for coextinctions and those not),the average rate of diversity loss was higher from 2020 to 2050 than from 2051 to 2100 (Fig.2,bottom left panel,and fig. S12).Consequently, the greatest changes in diversity and network structure are already appreciable before 2050 (fig.S13), highlighting how the bleakest time for natural communities might be imminent and that the next few decades will be decisive for the future of global biodiversity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,76,935,357]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig.2.Simulated,relative local loss of terrestrial vertebrate diversity, interactions,and connectance by 21oo compared to 2o20 under different climatic projections.Maps show local lossin 21oo relative to initial conditions,while plots show the average loss across all Earth localities per year from 2020 to 210o.In both maps and plots,results are the average of 1oo replicates (for the plots,first, we averaged local loss in the 1oo replicates and then averaged local loss values across all localities. Shaded areas are $9 5 \\\\\\\\%$ confidence intervals, showing the variation across localities in the average map obtained with 10o simulations). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0829/10846bd463b29020a44082adf8a5ca2432af2a52f151f303756f48501775fa34.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[509,492,942,608]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,609,940,724]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Intriguingly,the strongest coextinction effect is predicted in the intermediate-severity SSP4-6.0 scenario.These relatively lower predicted losses in the worst-case SSP5-8.5 climate change projection are explained by the greater number of species in that scenario that are wiped out by primary extinctions arising directly from intolerance to climate change compared to milder climate-change projections,a characteristic that slightly reduces the relative importance of coextinctions therein (Fig.3,right column). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,726,940,871]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When we examine network diversity and structure among biomes,most of the expected losses are predicted to occur in areas with the highest species richness.This shows that Biodiversity Hotspots not only have more species under threat and hence will lose more species (27,28) but that they will also experience the highest rates of loss due to coextinctions over the coming decades (Fig. 4).In general,and regardless of biogeographical region, diversity loss tended to increase with initial diversity (fig. S14). Consistent patterns were also predicted in the decline of network interactions (fig. S15) and connectance (fig. S16). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[60,76,482,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig.3.Coextinction effect by 2o5o.This is quantified as the percentage increase in diversity loss in the coextinction scenario compared to the reference (primary extinctions only) scenario.To ease visualization and comparisons,we set the maximum value of the color bar to 2 (i.e., $2 0 0 \\\\\\\\%$ increase), but black pixels indicate all values $\\\\\\\\geq 2 0 0 \\\\\\\\%$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0755/166a61193fb2812d88989ae87602aa1d5ccf50acb75a8841b33a41ab04bb82be.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[59,447,145,458]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,460,490,560]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our virtual-Earth model reveals the magnitude of and mechanisms driving biodiversity loss expected from climate change and land conversion this coming century. These results not only suggest a much greater loss than previously anticipated (21), they also demonstrate that biodiversity loss will be accompanied by an additional weakening of community resilience via erosion of the connectance of ecological networks. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,562,490,706]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An important caveat is that while our virtual species are functionally realistic,they do not have taxonomic or phylogenetic meaning. Hence,our results reveallocal changes in species diversity but do not provide information on global species extinctions per se. Neither does the model claim to produce an Earth replica, but instead aims to build an ecologically plausible Earth.Hence, the model cannot forecast Earth's future but instead projects relative potential scenarios based on different assumptions (mainly carbon emissions) and reveals the underlying processes leading to those outcomes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,708,490,924]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Examining the different drivers of extinction,our model reveals that the effect of climate change at the global scale is dominant, while land-use change played a comparatively minor role （fig. S8).However,in no way does that result refute the conclusion that land-use change is a major element of biodiversity loss; rather, it emphasizes that climate change is becoming more important. This emerges from two aspects of the model.First,we only considered relative land-use change from 2020 onward, meaning that the results reflect the relative future impact of land-use change,and not its dominant historical impact on biodiversity loss (3). Second,a strength of our model is that it can map extinctions everywhere on Earth.Even considering the extent of current human impacts,human presence and land-use change still directly affect only a small fraction of the total land inhabited by species. The area of primary and secondary cumulative land projected to be lost from 2020 to the end of the century for the worst-case climate change scenario (SSP5-8.5） is $8 , 0 0 \\\\dot { 0 } , 0 0 0 ~ \\\\mathrm { k m } ^ { 2 }$ in total; however, this value represents only $6 . 5 \\\\%$ of the global area in the simulation inhabited by at least one species in 2020 $\\\\mathrm { ~ ( \\\\sim ~ 1 3 0 , 0 0 0 , 0 0 0 ~ k m ^ { 2 } ) }$ (fig. S17). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,75,940,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,149,940,337]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It is also important to consider that the climatic projections take into account land-use change as one of the inputs to derive climatic variables.Therefore,the contribution of climate change to diversity loss also includes,in principle,the indirect effect ofland-use change on climate. Our model does take this into account,as well as other potential indirect, detrimental effects of land-use change,such as increasing fragmentation and then possible alterations to species dispersal and colonization patterns.However,our analysis of the relative importance of extinction drivers focuses exclusively on the direct effects of climate change,land-use change,coextinctions, and biological invasions.Under these caveats,the direct contribution of habitat loss to global extinction is still high,albeit relatively lower than what climate change will occasion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,338,940,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"These results are also robust to different assumptions regarding the local impact of land-use change on diversity; these different choices do not change our overall conclusions (figs. S6, S7,and S18).The main results presented here refer to a model where we assumed a linear relationship between the fraction of primary and secondary land lost at each step in a given locality and the resulting loss of local diversity. More pessimistic scenarios assuming high diversity loss following moderate changes in land use led to more extinctions globally (with a threshold effect observed for $S _ { \\\\mathrm { L U C } } > 0 . 2 $ see Materials and Methods and fig. S27),but did not change our conclusions on the relative disproportionate importance of climate change. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,513,940,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"By modeling food webs explicitly, our approach reveals synergies among extinction drivers (7),thereby confirming that overexploitation of resources by novel colonizers combined with climate change (i.e.,biological invasions) will become a major cause of diversity loss worldwide (29,30). Our model therefore provides the first global quantitative assessment of the impacts of biological invasions on planetary diversity over the coming century. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,615,940,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An interesting outcome from the sensitivity analyses is that increasing the frequency and intensity of acclimation events in local populations can counterintuitively lead to a higher global extinction rate.The \\\"adaptation\\\" mechanism implemented in our model (see Materials and Methods) assumes that species can shift their niches to match the climate of the preceding year. Such a mechanism一although reducing the risk of extinction for species capable of adapting under a stable climatic regime-does not necessarily ensure protection against future changes.When we assume a high probability of adaptation (e.g., $0 . 5 \\\\%$ of species shift their niche in all localities every year),the net effect is a reduction in average persistence of global diversity.This suggests that a strong and widespread adaptation to local conditions might both increase robustness toward steady conditions while simultaneously increasing vulnerability to change.This outcome is consistent with predictions based on a completely different approach (artificial life evolution simulations) showing that as ecological networks become more resilient to stable environmental conditions,they also become increasingly susceptible to change (31). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,891,940,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our results confirm that coextinctions are fundamental drivers of mass extinctions (5-11) and suggest that previous large extinction events revealed from the fossil record would likely have been exacerbated beyond their primary environmental drivers via the negative feedbacks arising from ecological dependencies.Unless conservation practitioners rapidly start to incorporate the complexity of ecological interactions and their role in extinction processes in their planning,averting the ongoing biodiversity crisis will become an unachievable target. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[99,74,888,369]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig.4.DiversitylosspredictedtobehigherinhighlydiversebiomesandlowerinthePalearcticandNearctic.Diversitylos is the $\\\\\\\\%$ loss in species number per oli average values,while shaded areas indicate $9 5 \\\\\\\\%$ confidence intervals,showing the variationacross localities within a region in the average map obtained with 100 simulations.Equivalent maps forloss of interactions and connectanceare provided in the Supplementary Materials. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0895/0ae3901dc846654dddf3cbd03998a3aacc02c5eb590ad655786729f7572882c2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[59,452,490,538]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,567,247,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MATERIALSAND METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,583,172,596]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Model synopsis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,597,490,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our simulated world consists of a data-driven system of interconnected terrestrial communities composed of virtual, yet ecologically plausible,vertebrate species whose ecology and functional traits obey rules that we derived from combining several large, realworld datasets.The virtual vertebrates in each locality are organized into food webs according to their trophic ecology, diet breadth,and functional traits,with links assigned on the basis of trophic rules derived from empirical data.This generates a dynamic,globalscale system where the patterns and process of food webs are an emerging property of ecological mechanisms inferred from empirical data. Our implementation of the networks' responses to changes in species composition permits modeling and tracking communities at high spatial and temporal resolution,without the prohibitive challenge of modeling multispecies population dynamics and ecological interactions in thousands of sites hosting hundreds of species. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,830,489,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We tracked the future development of the virtual life planet from 2020 to 2100 at a spatial resolution of $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ latitude following three climate-projection scenarios [Coupled Model Intercomparison Project Phase 6 (CMIP6):Shared Socioeconomic Pathway (SSP) 2-4.5,SSP4-6.0,and SSP5-8.5] (25),running 100 replicates for each future climate-projection scenario.The model runs at a temporal increment of 1 month for climate and 1 year for spatially explicit land-use changes and food-web dynamics.We allowed species to disperse among localities,with the probability of colonization success depending on the geographic distance between the source and the target locality, compatibility between species'tolerance limits and the environmental conditions (species-specific suitability) of the target locality,and the ability of a species to enter the local food web at the target site.Last, the model includes a function allowing for some species-specific adaptation to changing climate conditions (see Materials and Methods for all modeling details). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,451,940,582]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,583,940,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"During the simulations,species went extinct owing to direct effects of environmental change (i.e., when no longer capable of tolerating local climatic conditions or following loss of primary land) or indirect (either bottom-up or top-down) effects propagating through network links.When a species went extinct,we explicitly accounted for the cascading effect of that extinction on its corresponding local food web. That is,interaction networks in the model continuously adapt and respond to changes in community composition.As species go extinct,and new species enter a local food web from different localities,nodes and links are added and removed,and interaction weights are recalculated on the basis of the new conditions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,757,940,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Recalculating weights permits simulating ecological mechanisms fundamental for food web functioning, such as changes in a consumer's diet and realized specialization driven by resource availability. The initial weights of a network are rescaled depending on resource availability and on the diversity of consumers having access to the different resources.Whenever something changes in the network (e.g.,species are added or removed),weights are adjusted to reflect the new ecological setting. Thus,a consumer that was initially consuming a particular resource might switch a substantial proportion of interaction weight to a novel (more compatible) resource (note that such change is reversible—the consumer can reallocate interaction weights to the initial resource should the situation return to a previous state). Similarly, the diet breadth (in terms of the distribution of interaction weights from a consumer to the set of available resources） might change substantially when species are either lost or added to the network. This might involve one species initially preying mostly on vertebrates to switch its interactions to invertebrates only.In this way,our model can simulate species' plasticity in response to altered conditions,with the coextinction risk of species changing as communities reorganize themselves in response to environmental and ecological change.The same set of rules permits simulating both positive and negative effects of colonizers,either rescuing local populations or increasing local diversity (see the Supplementary Materials),or driving local species to extinction due to overexploitation by the invader. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[59,75,490,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,280,490,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As a control in each simulation to assess the net effect of coextinctions on global diversity loss,we also ran a parallel experiment where we did not model coextinctions and the other networkrelated events,while maintaining all other ecological processes (primary extinctions,dispersal,and adaptation; also see the discussion in the Supplementary Materials). Further,model outputs were robust to assumptions of adaptive capacity (Supplementary Materials, figs. S6 and S7). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,411,217,424]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Species climatic niche \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,425,490,628]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We collected all available vertebrate ranges from the International Union for the Conservation of Nature (32) and BirdLife International (33).We rasterized the ranges on a $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ global grid and then retained only the species occurring in $> 5$ cells (terrestrial mammals: 4452; reptiles: 3903;amphibians:3040; birds: 9748; total $= 2 1 , 1 4 3$ ).We referred to the CMIP6 global circulation model for temperature and precipitation predictions,using three different scenarios: SSP2-4.5,SSP4-6.0,and SSP5-8.5 (approximately equivalent to updated versions of CMIP5 scenarios RCP4.5, $\\\\mathrm { R C P 6 . 0 }$ ,and RCP8.5,respectively) (25).In particular,we used the multimodel ensembles provided by the Canadian Centre for Climate Modelling and Analysis (34),at a spatial resolution of $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ latitude/longitude degrees and at a monthly temporal resolution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,629,490,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We modeled species' niches independently in each climatic scenario by identifying all temperature and precipitation values in the target scenario intersecting a species' range at a monthly interval from 2015 to 2019.We defined suitability $\\\\left( \\\\boldsymbol { p } \\\\right)$ of a species to the target climatic condition $x$ (a temperature or precipitation value) as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[178,708,367,751]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0594/a1f65ef71965b494304b529e8e4e4e6bc3c590d683793b8523c746341481715e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { p = \\\\left\\\\{ \\\\begin{array} { l l } { 1 - \\\\frac { 1 } { 1 + e ^ { - c ( x - d ) } } , \\\\mathrm { i f } ~ x \\\\leq \\\\overline { { x } } } \\\\\\\\ { \\\\frac { 1 } { 1 + e ^ { - a ( x - b ) } } , \\\\quad \\\\mathrm { o t h e r w i s e } } \\\\end{array} \\\\right. } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[59,756,490,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\overline { { x } }$ is the average of the monthly measures of the target climatic condition across all $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ localities within the species' range in the period January 2015 to December 2019.For each species,we estimated the $a , b , c ,$ and $d$ parameters so that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[138,824,411,839]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0279/ad63e74ab426a8cd260d0deb87cdc759a41d6ad0d517e6ba40089544deda45ce.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\nu = \\\\nu _ { \\\\mathrm { m i n } } \\\\vee \\\\nu = \\\\nu _ { \\\\mathrm { m a x } } \\\\longrightarrow p = p _ { \\\\mathrm { t h r e s h } } = 0 . 9 5\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[59,845,490,932]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\nu _ { \\\\mathrm { m i n } }$ and $\\\\nu _ { \\\\mathrm { m a x } }$ are the maximum and minimum recorded values,respectively,of the target climatic condition in the species' range within the reference time interval, and $\\\\scriptstyle { \\\\frac { p _ { \\\\mathrm { t h r e s h } } } { P \\\\mathrm { t h r e s h } } }$ is an arbitrarily selected probability of species survival at the edges of the species tolerance limits. Here, we conservatively chose $p _ { \\\\mathrm { t h r e s h } } = 0 . 9 5$ assuming that a given species would have this probability of surviving when the local temperature equals either $\\\\nu _ { \\\\mathrm { m i n } }$ or $\\\\nu _ { \\\\mathrm { m a x . } }$ To derive the a,b,c,and\\\" $d$ parameters,we first set $\\\\begin{array} { l l l } { a } & { = } & { 0 . 0 0 0 1 } \\\\end{array}$ and $b = \\\\frac { \\\\log { \\\\left( \\\\frac { \\\\bar { P } _ { \\\\mathrm { t h r e s h } } } { 1 - \\\\bar { P } _ { \\\\mathrm { t h r e s h } } } \\\\right) } + a \\\\nu _ { \\\\mathrm { m a x } } } { a } .$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,75,940,134]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,137,940,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We then incremented $^ a$ progressively by 0.01 per step until I+e-ax-b)≤0.001.Similarly，we setc= 0.0001and $\\\\begin{array} { r } { d = \\\\frac { \\\\log \\\\Big ( \\\\frac { 1 - { \\\\cal P } _ { \\\\mathrm { t h r e s h } } } { { \\\\cal P } _ { \\\\mathrm { t h r e s h } } } \\\\Big ) + c \\\\nu _ { \\\\mathrm { m i n } } } { c } , } \\\\end{array}$ and we then incremented $c$ progressively by 0.01 per step until $\\\\textstyle { \\\\frac { 1 } { 1 + e ^ { - c ( x - d ) } } } \\\\geq 0 . 9 9 9 8 .$ . This procedure generates an asymmetric,bell-shaped probability curve that has values close to O when conditions are optimal,a probability of extinction $= 1 -$ $p _ { \\\\mathrm { t h r e s h } } = 0 . 0 5$ when the species is at its tolerance limits,and then it declines rapidly as the local variable of interest departs from the species' tolerance.The two curves obtained for temperature and precipitation define a bidimensional niche where at any given set of climate values,the probability of survival is given by the minimum probability of survival for both variables (fig. S19). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,173,942,334]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,335,940,654]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This approach can be considered as an advanced take on the idea of bioclimatic envelopes (35) because it produces a progressive probability of local extinction as temperature and precipitation ap-proach the most extreme conditions experienced in the species' range. During model development, we compared the probability of extinction from our niche model with those from other methods using nonlinear approaches to identify suitability. Such tests showed that our approach produced a more plausibly progressive increment in extinction risk as local environmental conditions approach the hypothetical tolerance limits compared to the niches produced by other techniques.For instance,we compared the extinction risks produced by either our approach or a RandomForest regressor on a random sample of 1oo vertebrate species across a continuous range of temperature and precipitation values (for a total of 400 unique combinations of temperature and precipitation covering all the ideal space from the minimum to the maximum values recorded on Earth in the reference period 2015-2019).Although we found overall consistency between the risk estimates yielded by the two approaches (Spearman's $\\\\rho = 0 . 4 1$ ； $P < < 2 . 2 \\\\times 1 0 ^ { - 1 6 }$ ),Random-Forest produced an unrealistic representation of the bidimensional niche space with abrupt jumps from low to high extinction probability (such as classical bioclimatic envelopes) (fig. S20). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,656,940,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although related to concepts typical of ecological niche models that aim to predict species distributions from environmental/climatic variables,our approach does not suffer from their common limitations. Our derived niches model the risk of local disappearance based on temperature and precipitation,and not to predict species distribution. While subtle,the distinction makes our model robust to the most common weakness associated with ecological niche models (36).A major limitation is that climatic suitability is just one of the many factors determining species presence, yet correlative niche models often ignore biogeographic history, the presence of other species,and stochastic events.However,while a species might not occur in a perfectly suitable area,it almost certainly does not occur/persist in unsuitable locations.In contrast, our modeled species occurrences are the combined and explicit result of niche,dispersal, and interactions with other species—i.e., our model is not affected by the potential biases that might be derived from equating suitability with presence.Instead,our model applies the robust and logical assumption that species cannot persist in an unsuitable area to determine the risk of local extinction. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[59,75,489,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,105,490,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our definition of local extinction risk in this context has a community-level interpretation: Niche predictions do not identify the most extreme conditions tolerable before physiological failure; rather, they are the likelihood that a local population will decline and eventually disappear when exposed to unfavorable conditions. This logic precluded deriving thermal tolerances directly from databases such as GlobTherm (37),as we did previously(11),because empirically derived limits probably overestimate the true population-level responses implicit in our model. However, the distribution of thermal tolerances we generated is consistent with that from GlobTherm (fig.S21),even if slightly shifted toward lower temperatures (a desirable attribute). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,293,414,308]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Species trophic level and body-mass relationship \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,309,490,584]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We obtained body mass for 31,098 species combining information from different sources (38-41).For a subset of those species, we also obtained data on trophic interactions by extracting all available resource-consumer interaction data from the GloBI online database (42）(714,465 at the time of the analysis retrieved from globalbioticinteractions.org/data). For a given species,we used the interaction data to identify both the maximum trophic level (measured as the maximum distance from a basal resource) and its trophic breadth (variation in trophic level of the consumed resources).We combined this information to generate two datasets: The first included body mass and environmental niche (temperature/ precipitation tolerance) for 17,238 species; the second included trophic level, trophic breadth,and body mass for l449 species. The second dataset gives a distribution of trophic level per bodysize interval for each taxonomic group (fig. S22),which assigns trophic level to a given species according to its body size and major phylogenetic grouping by sampling randomly from the distribution of trophic level observed in similar-sized species within the same taxon (described in the following section). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,600,229,613]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Creating virtual species \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,615,490,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To incorporate as much plausible variation as possible in this stochastic model, we generated an independent set of virtual species at the beginning of each global-extinction simulation according to the following procedure.We extracted species from the dataset associating species' niches to the respective body mass, with the sampling structured to match known relative vertebrate diversity according to theIUCN (32) (i.e.,5513 mammals,7302 amphibians,10,425 birds, and i0,038 reptiles).We then compared the body size of the selected species with all body sizes from the body-size and trophic datasets (in random order) until we found a species belonging to the same taxonomic grouping and with \\\"matching\\\" body size (see below), and then we associated the trophic information to the target species.In this way,we accounted for potential relationships between ecological niche,body mass, trophic level,and taxonomic group. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[79,833,411,846]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We considered that two body sizes were a match if \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[153,854,396,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0030/f8a75a640eed7bbfd11e7e469b59f772db04e06cdb128a11ac05b8c48bfbcf2d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\frac { \\\\operatorname* { m a x } [ m _ { 1 } , m _ { 2 } ] - \\\\operatorname* { m i n } [ m _ { 1 } , m _ { 2 } ] } { \\\\operatorname* { m a x } [ m _ { 1 } , m _ { 2 } ] } < r _ { \\\\mathrm { t h r e s h } }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[60,894,489,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $m _ { 1 }$ and $m _ { 2 }$ are the body size of the two species, and $r _ { \\\\mathrm { t h r e s h } }$ $= 0 . 0 1$ ,a threshold for each species.If no match was found with this threshold,we progressively increased the threshold at steps of 0.01 until a match emerged. The average of final thresholds within a simulation was $0 . 0 6 5 \\\\pm 0 . 1 1$ with a maximum of 0.96. The largest thresholds are associated with the smallest species,so that the average absolute difference in body mass between matched species is $\\\\textless 3 0 0 \\\\mathrm { ~ g ~ }$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,76,940,162]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,164,940,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We then sampled trophic level and breadth corresponding to body-size class and taxonomic group.From this point, the taxonomic identity of a species is no longer maintained in the simulations.We added functional traits to the species following Strona and Bradshaw(11) in the form of a random string of letters (sampled from the standard, 26-letter English alphabet) of size varying stochastically between 1 and 10,ideally corresponding to the virtual species phenotype. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,280,940,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At the beginning of each simulation, we created a $2 6 \\\\times 2 6$ adjacency matrix filled with real numbers varying randomly between the limits of $- 1$ and 1, indicating the compatibility between any two functional traits (alphabet letters) when considered in isolation. We quantified the compatibility between any two phenotypes by summing all the compatibility values obtained by all pairwise combinations of letters in each phenotype.We then normalized these values between O and 1 (by estimating the minimum and maximum potential compatibility of two random phenotypes for a given trait-adjacency matrix; this is done by comparing $1 0 ^ { 6 }$ pairs of phenotypes generated at random according to the same criteria used in the virtual species-generation process). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,455,940,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The concept behind this approach is well-grounded in theoretical ecology because it corresponds to generating an ideal global square matrix of species-by-species compatibility [e.g. similar to stability-complexity matrices (43)].Adding explicit traits from another matrix of trait-by-trait compatibility adds realism by ensuring that phenotypic compatibility is spatially and temporally consistent.It also reduces the computational burden by providing an efficient way to assess compatibility of any two species in the world without needing to retain a large compatibility matrix; the approach also provides different degrees of specialization (as observed in real-world networks).Although this approach precludes comparing our functional traits to real-world traits,the mechanism produces realistic networks (fig.S4).The final step in the generation of a virtual species requires attributing a random real value between O and 1 to it to indicate its adaptive capacity to changing conditions (see the \\\"Adaptation\\\" section below and fig. S23). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,702,696,715]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Populating a virtual Earth \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,716,940,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We obtained land-use projections at annual temporal resolution from 2006 to 2100 from Chini et al. (44).We used projections calibrated using Integrated Assessment Model scenarios with radiative forcing by 2io0,consistent with the SSP scenarios used for climate projections- $\\\\cdot 4 . 5 \\\\mathrm { W } \\\\mathrm { \\\\ m } ^ { - 2 }$ 6W $\\\\mathrm { m } ^ { - 2 }$ ,and $8 . 5 ~ \\\\mathrm { W ~ m } ^ { - 2 }$ .The original data were at a resolution of $0 . 5 ^ { \\\\circ } \\\\times 0 . 5 ^ { \\\\circ }$ ，which we rescaled to our $1 ^ { \\\\circ } \\\\times 1 ^ { \\\\circ }$ grid.We did not consider all land-use categories; instead, we computed for each cell in our grid the fraction of primary and secondary land in a given year. We report the loss of primary and secondary land by 2050 and 2100 under the different climatic scenarios (fig. S24).Here,\\\"primary\\\"land is defined as natural vegetation that has never been affected by humans (e.g.,agriculture or wood harvesting),while secondary land is natural vegetation recovering from previous anthropogenic disturbance (44). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[59,76,490,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We assigned $4 5 0 0 \\\\times u$ species to each locality at random,where $u$ is the proportion of primary $^ +$ secondary land in the locality according to the target SSP scenario in 2019.We then reduced the local community to the set of species capable of persisting in the local climate as all those species for which the combined probability of extinction under local temperature and precipitation conditions is $< 0 . 0 5$ for the entire period 20l5-2019 (with probability computed monthly).Last, we arranged these species into food webs (see the next section),keeping only the species participating in the network. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,222,192,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Building networks \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,236,490,541]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For a given pool of species,all potential pairwise interactions are considered,and a directional link is drawn from a candidate resource to a candidate consumer if (i) the trophic level of the consumer is greater than the trophic level of the resource,and the trophic level of the resource is within the trophic breadth of the con-sumer (i.e., not less than the minimum trophic level ofa species possibly consumed by the consumer); (ii) the ratio between the body size of the resource and that of the consumer is greater than ${ l _ { l } } < { l _ { { \\\\mathrm { u } } } } ,$ with those limits assigned specifically to each combination of resource-consumer taxa (i.e.,birds consumed by mammals are assigned different values than birds consumed by reptiles);and (ii) functional compatibility ( $\\\\dot { c } _ { \\\\mathrm { f } } \\\\dot { s }$ see above) is $> 0 . 5 5$ .Toobtain $l _ { l }$ and $l _ { \\\\mathrm { u } } ,$ we computed the ratio between prey and predator body mass for each prey-predator interaction recorded in GloBI (42); this provided a distribution of prey-predator body-mass ratios.We then derived $l _ { l }$ and $l _ { \\\\mathrm { u } }$ as the lower and upper $9 0 \\\\%$ confidence limits of the distribution, respectively. We applied this procedure separately for each combination of vertebrate classes,such that we obtained a distribution of prey-predator body mass ratios for mammals eating birds,another one for birds eating mammals,another one for mammals eating reptiles, etc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,542,490,644]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Functional compatibility is then readjusted to $\\\\begin{array} { r } { c _ { \\\\mathrm { f } } = 1 - \\\\frac { 1 - c _ { \\\\mathrm { f } } } { 1 - 0 . 5 5 } } \\\\end{array}$ and assigned as a weight to the target link.We chose the functional compatibility threshold( $c _ { \\\\mathrm { f } } = 0 . 5 5 )$ ）and the number of random species assigned to each locality (45oo) after calibration experiments as the best values permitting realism in terms of local diversity and network structure (figs.S1 to S4). See also low sensitivity of model outputs to variation in $c _ { \\\\mathrm { f } }$ (Supplementary Materials). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,658,150,670]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Colonization \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,673,490,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At each step of the simulation,a species attempts dispersal from each locality to neighboring localities.A distance (in degrees) of dispersal is first randomly extracted from a log-Normal distribution with mean $= 0$ and $\\\\mathrm { S D } = 1$ (fig. S25).We added 1 to that distance to ensure that in the shortest-distance case,a species can still move to an adjacent cell in the grid. One cell in the grid at the randomly selected dispersal distance is chosen at random.Then, the potential colonizer species moves to the target locality with a probability computed by testing a species' niche against the climatic condition of the target locality (in the same way as extinction probability is evaluated). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,833,490,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Such a basic treatment of movement of species from one locality to another could conceivably increase diversity indefinitely. However,in the coextinction scenario where we modeled food webs explicitly,the process is realistically constrained because species need to find their place in the food web that is conducive to survival. This is modeled so that when a new species enters a community based solely on climate compatibility, the local food web is rebuilt (according to the same rules described above), taking the new species into account. This might lead to different outcomes in each case. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,76,939,119]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,120,940,264]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For example,if the candidate colonizer is not a primary consumer and cannot find suitable resources,it cannot enter the food web, and colonization fails (i.e., it goes locally extinct).If a candidate colonizer does find a position in the food web,it can become associated with some resources and possibly become a resource for local consumers itself without driving those resources to extinction.Alternatively,if a candidate colonizer finds a position in the food web but ends up overexploiting one or more resources, it can lead to extinction of the resources and potentially itself and other species via extinction cascades. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,264,940,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"However,if acandidate colonizer is a \\\"primary\\\" consumer (i.e.,a vertebrate capable of consuming plants and/or invertebrates),it wil always be able to find a position in the food web and become a resource for local consumers,producing an ecologically unrealistic accumulation of diversity and resources.This is because of the specific architecture of the model,where we assumed herbivores and insectivores are the \\\"basal\\\" components of the networks (i.e.,we assumed continued and unlimited availability of their resources). For this reason,we treated the incidences of insectivores and herbivores moving to a new locality as a particular case.Here,candidate herbivore and insectivore colonizers are added to the local communityup toa maximum number of species,defined as the initial herbivore/insectivore diversity for that locality.If the diversity of insectivores and herbivores exceeds that number, the (herbivore and/or insectivore） species with least compatibility to local conditions are removed (i.e.，considered as outcompeted by the other species). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,513,940,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the scenario not accounting for coextinctions (i.e., not modeling food webs explicitly),we applied the same criterion but extended to all species in the locality,regardless of their trophic ecology (with the only other criterion for colonization success being climatic compatibility) (see the Supplementary Materials for caveats). In this way, we treat the null expectation of primary extinctions only as a conservative case. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,629,591,642]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adaptation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,644,940,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We assumed that species have a certain capacity to adapt to local (and changing) climates unrelated to the traits defining phenotype. For this,each species has the opportunity with probability $ { p _ { \\\\mathrm { a d p } } }$ $= 0 . 0 0 1$ of shifting the center of its niche closer to the average local conditions at yearly intervals (i.e., a species during year $y$ can move its niche to fit conditions recorded in year $y ^ { - 1 }$ ).Here, both the average and upper/lower tolerance limits for both temperature and precipitation are shifted along the segment connecting the center of the species' niche and the mean local temperature and precipitation of the preceding year at a length given by the formula $C _ { \\\\mathrm { a d p } } \\\\times A \\\\times d _ { \\\\mathrm { N } } ,$ where $C _ { \\\\mathrm { a d p } }$ is an overall simulation adaptation factor that we set to 0.Ol(fixed forall simulations), $A$ is species-specific adaptability (a random value between O and 1 assigned when creating the virtual species),and $d _ { \\\\mathrm { N } }$ is the total distance between the center of the species'niche and mean local conditions (see fig. S26). After that, the niche is recomputed on the basis of the updated parameters as described in the \\\"Species climatic niche\\\" section. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,891,940,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We also explored the sensitivity of results to the choice of the adaptation parameters $ { p _ { \\\\mathrm { a d p } } }$ and $C _ { \\\\mathrm { a d p } }$ (see the \\\"Sensitivity analyses\\\" section and figs. S6 and S7). Our goal in implementing adaptation was not to model this process explicitly,which would be unfeasible due to the countless unknowns associated with the process.Rather, we wanted to increase the conservativeness of our model by providing species and communities with an additional mechanism to cope with climate change.Such a mechanism mimics local acclimation (with species shifting their niches to match local climate,as described in fig. S26) and does not necessarily entail any evolutionary process. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,949,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[60,75,490,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,207,151,220]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Coextinction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,222,490,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We developed an original, intuitive model for simulating coextinctions that accounts for both bottom-up and top-down effects of diversity loss.The model is applied to weighted, directed networks (with weights corresponding to species' functional compatibility; see the previous section). Such networks can be represented in the form of a square adjacency matrix A of size $n \\\\times n$ (where $n$ is the total number of species in the network),with each entry $\\\\mathbf { A } _ { i , j }$ (with $i , j$ in $\\\\left[ 1 , \\\\mathbf { \\\\Omega } . . . , \\\\mathbf { \\\\Omega } n \\\\right] .$ ）representing the interaction strength between the $i ^ { \\\\mathrm { t h } }$ resource and the $j ^ { \\\\mathrm { t h } }$ consumer. Thus, $\\\\Sigma ( \\\\mathbf { A } _ { i , 1 : n } )$ represents the total consumer pressure on resource i. Each value in row i is divided by the total consumer pressure and then multiplied by its original value to obtain a standardized weight accounting for competition for that resource.For example,if one resource is used by three consumers with respective weights 0.5,0.2,and 0.1, the rescaled values are as follows: $0 . 5 ~ \\\\times ~ ( 0 . 5 / 0 . 8 ) ~ = ~ 0 . 3 1 2 5$ ， $0 . 2 \\\\times ( 0 . 2 / 0 . 8 ) = 0 . 0 5 0 _ { ! }$ and $0 . 1 \\\\times ( 0 . 1 / 0 . 8 ) = 0 . 0 1 2 5$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,455,490,584]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The overall idea behind this step is to account for both the overall competition on a certain resource and resource-consumer compatibility. Let us call the rescaled matrix $\\\\mathbf { A ^ { \\\\prime } }$ .The column sum of the rescaled values, $\\\\Sigma ( \\\\boldsymbol { \\\\boldsymbol { \\\\mathbf { A } } } _ { \\\\boldsymbol { \\\\mathbf { \\\\mathit { 1 } } } : \\\\boldsymbol { \\\\boldsymbol { n } } , j } ^ { \\\\prime } )$ , gives the amount of resource available to consumer $j .$ If that amount falls belowa certain threshold, the consumer goes extinct.Similarly,the row sum of the rescaled values, $\\\\Sigma ( \\\\mathbf { A ^ { \\\\prime } } _ { i , l : n } )$ ,indicates the pressure of consumers on resource i. Should this pressure go beyond a given threshold (see below), then resource $i$ goes extinct due to overconsumption. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,585,490,875]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Species can also go extinct whenever they become disconnected from basal resources (in our case, corresponding to being detached from herbivores or insectivores).For each network, thresholds for consumer extinctions correspond to the minimum observed $\\\\Sigma ( \\\\mathbf { A } ^ { \\\\prime } _ { I } \\\\mathbf { : }$ $_ { n , j } )$ for any species $i , j$ in the network at the time the network is generated.Similarly,thresholds for extinctions of resources following overconsumption are set to the maximum observed $\\\\Sigma ( \\\\boldsymbol { \\\\mathbf { A } } _ { i , l : n } ^ { \\\\prime } )$ for any species $i , j$ in the network at the time the network is generated. The thresholds are then updated after the burn-in phase (see the \\\"Simulations\\\" section) to ensure that networks are at equilibrium once the global-change simulation starts,and coextinction events can only be generated by removing some species from the network.Our initial, conservative assumption here is that no species goes extinct if conditions do not change (i.e.,if environmental conditions remain stable and no species immigrate from different locations). However, this does not prevent new species from entering the system and increasing local diversity. This assumption also necessarily gives a conservative estimate of total extinction rates given that our model does not explicitly incorporate existing extinction lags before each simulation beginning (45). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,876,489,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The threshold for consumer coextinctions is assgned specifically to each network by referring to the most exploited resource in the system.This conservative assumption provides substantial opportunity increase in consumer diversity (following species immigration from other localities） before top-down coextinctions are triggered. The top-down regulation mechanism serves two main purposes: (i) It accounts for the potential detrimental effects of alien colonizers on both native resources and potential competitors (with outcompetition processes treated with specific model rules; see the \\\"Colonization\\\" section),and (ii) it accounts for decreasing resource diversity in a food web eliciting two different,concomitant effects: less-efficient consumers might be outcompeted by more efficient ones,and resources targeted by many different consumers might be overexploited. There are clearly ecological settings where these processes can be buffered or even reversed,but the rapid environmental and ecological change we modeled here is more likely to destabilize than to stabilize systems,consistent with increasing empirical evidence of ongoing global ecosystem collapse (2-5,46). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,76,940,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,280,942,584]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our dynamic implementation of network weights also compensates for the choice (dictated by the insurmountable computational challenge of modeling multispecies population dynamics for almost 20,000 networks at a temporal span of nearly a century) of not track-ing explicitly species abundances. Our implementation of weights is conceptually linked to species abundances in that the total interaction weight of a consumer (which eventually determines its risk of going extinct following ecological change in the community/food web) increases with the availability of suitable resources and declines with diversity of competitors.At the same time,the total pressure on a resource determining its extinction risk increases with diversity of (compatible) consumers.It is reasonable to assume that when the consumer's population has access to a large variety of suitable resources and it has few competitors,it will be larger than a population able to access fewer resources shared among many consumers.Similarly, the population of a resource (and hence,its availability to consumers) will decrease with increasing consumer pressure.It is therefore also reasonable to consider weights in our networks as a proxy for abundances,accounting for multispecies population dynamics in the global model without explicitly implementing them. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,600,595,613]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Simulations \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,615,940,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We ran l0o simulations per climate-projection scenario.In each simulation,we generated a pool of species,and we populated a virtual Earth as described in previous sections.We did a burn-in phase where we permitted species to disperse to new areas over 100 time steps.At each step of the burn-in and for each locality, we sampled one species and moved it to a randomly selected locality following a dispersal kernel of the form $1 + \\\\log \\\\mathcal { N }$ [0,1]. We then evaluated a species' survival probability under the climate conditions from 2015 to 2020,keeping it in the simulation only if the probability of extinction $ { p _ { \\\\mathrm { e x t } } } < 0 . 0 5$ . We rebuilt food webs every 10 steps.If the number of basal species increased because of colonizers exceeding the initial number of basal species (i.e.,at the beginning of the simulation),we evaluated climatic suitability of all basal species, removing species in increasing order of local adaptation until we restored the initial number of basal species.The burnin phase provided our simulated systems with biogeographical realism,giving species a chance to colonize contiguous areas if climatically suitable (and within a food web permitting the colonization).In addition,it increased the robustness of networks to local, current (2015-2020) climatic conditions through the potential replacement of basal species with better-adapted colonizers.Last, it ensures that the initial changes recorded in the model run are not biased by the short-range movements of species from the initial random pools assigned to each locality. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[900,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[59,75,489,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,107,490,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We then simulated climate and land-use changes from 2020 to 2100.At monthly steps and for each locality,we evaluated which species went extinct according to their suitability to withstand local temperature and precipitation conditions.We considered that species with $ { p _ { \\\\mathrm { e x t } } } \\\\leq 0 . 0 5$ never went extinct (we used this probability to assign species to localities). In this way,we avoided \\\"random\\\" extinctions,such that extinctions only occurred because of climate and/or land-use change.We also assumed that in each year and in a given locality,a fraction of the species identical to the fraction of primary and secondary land lost from the previous year went extinct (see the next paragraph for additional details). Last, we simulated coextinctions in food webs due to primary extinctions and then updated the networks.We replicated the same simulations in a control scenario not accounting for networks and secondary extinctions.The two scenarios (coextinction and control） started from the same initial virtual Earth (after the burn-in,predispersal/colonization phase） but then ran each independently. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,367,490,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The choice of using a monthly time step for climate change and yearly time steps for the land-use change was driven by the different temporal resolutions of the selected dataset.However, the different temporal resolutions are also well-suited to model the two different processes,considering the potential high variability of temperature and precipitation patterns on a relatively short time scale compared to the slower and usually nonreversible (at least in the short term) losses of primary land. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,498,391,513]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Effect of land-use change on species diversity \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,514,490,701]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Land use change might have complex and case-specific effects on vertebrate communities.The response of local vertebrate diversity to the intensity of land-use change-measured as the fraction of primary and secondary land lost at each yearly step in the simulation compared to the previous year-might assume different shapes. Those ideally range from cases where small land-use changes result in disproportionately high diversity loss to the opposite where diversity persists in the face of severe losses of primary and/or secondary habitat.We opted foran intermediate scenario where the loss of species diversity is linearly proportional to land conversion.However,we also explored the potential effects on model outcomes of simulating different forms and magnitudes of response of local diversity to land use change. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,702,490,746]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Specifically, we explored the potential impact on results of using different response curves of biodiversity loss versus relative land-use change of the following form \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[69,752,480,772]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0996/5682c762486a3c6b20e8011e276c52e645b13a042154db0d6da073519a248250.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { l o s s = 1 - ( 1 - P _ { L U C } ) ^ { R _ { 1 } } \\\\mathrm { ~ i f ~ } R _ { 2 } = - 1 , \\\\mathrm { ~ o r ~ } l o s s = P _ { L U C } ^ { R _ { 1 } } \\\\mathrm { ~ i f ~ } R _ { 2 } = 1 } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[59,777,490,850]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where loss is the fraction of biodiversity lost following habitat loss via land-use change; $P _ { \\\\mathrm { L U C } }$ is the fraction of primary and secondary land lost at a given time step compared to the previous one; $R _ { 1 }$ is a random number in the range $^ { \\\\{ 0 , 1 \\\\} }$ and $R _ { 2 }$ is sampled from $\\\\{ - 1 , 1 \\\\}$ with equal probability. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,851,490,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The two parameters $R _ { 1 }$ and $R _ { 2 }$ can be combined into a single parameter $S _ { \\\\mathrm { L U C } } ~ = ~ R _ { 2 } ( 1 ~ - ~ R _ { 1 } )$ ，which describes the response curves of diversity loss in a continuous way from 1 (full diversity loss occurs even with no habitat loss） to $- 1$ (diversity loss is invariant to full habitat loss)，with $S _ { \\\\mathrm { { L U C } } } = 0$ representing the linear response we used in the main simulations (fig. S27). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,76,940,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,103,940,585]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The effect ofland-use change could also affect species differently depending on body size and trophic level (themselves partially dependent properties).However,the mechanisms by which the impact of land-use change might reach different species in a community could be complex. Our model already accounts for such complexity. The expectation that large-bodied animals are more susceptible to the effects of climate and land use change results from observation of patterns,but the underlying mechanisms are unclear. This is where our model offers another unique advantage compared to existing studies-climate and land-use change are predicted to cause a global reduction in vertebrate body size (fig. S11) even without any initial assumption of an intrinsic relationship between body size and species vulnerability. That is,our model offers a mechanistic explanation of the process-body size reduction is mainly a consequence of how diversity loss propagates through food webs. That this well-known pattern arises naturally as an emergent property of \\\"simple\\\" rules provides strong additional support of our model's ecological realism.Nevertheless,we also explored the potential impact on our results of assuming an a priori relationship between vertebrate body sizes and vulnerability to landuse change in the sensitivity analyses (see below),devising a procedure controlled by a single parameter ( $( V _ { \\\\mathrm { L U C } } )$ as follows: Consider a local community with S species-at a given step, $l o s s \\\\times S$ species will go extinct due to land-use change (with loss being the fraction of biodiversity lost following habitat loss via land-use change,computed as described above). To identify such species within the local species pool, we first sorted species by decreasing size.We then iterated the procedure of randomly switching the position of two species in the ordered list $V _ { \\\\mathrm { L U C } } \\\\times S$ times. Last, we identified the first $l o s s \\\\times s$ species in the sorted list as extinct. When $V _ { \\\\mathrm { L U C } } = 0$ the largest species always go extinct due to land-use change at each step,while increasing $V _ { \\\\mathrm { L U C } }$ leads progressively toward random extinctions (fig. S28). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,600,650,613]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sensitivity analyses \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,615,940,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We explored the potential sensitivity of our model outputs to different combinations of parameter values by devising a global sensitivity analysis where we modified (i) the number of steps in the burnin phase $( s _ { \\\\mathrm { b - i } } )$ ,(ii) the threshold for functional compatibility $\\\\left( c _ { \\\\mathrm { f } } \\\\right)$ ， (ii) species adaptation probability $( p _ { \\\\mathrm { a d p } } )$ ,(iv) species adaptation factor $( C _ { \\\\mathrm { a d p } } )$ ,(v) the shape of the response curves of local diversity versus land-use change $( S _ { \\\\mathrm { L U C } } )$ ,and $( \\\\nu i )$ the potential relationship between vertebrate body mass and vulnerability to land-use change $( V _ { \\\\mathrm { L U C } } )$ .Here,we ran an additional set of 1oo simulations per future climatic scenario where we randomly sampled (uniformly) $s _ { \\\\mathrm { b - i } } \\\\operatorname { f r o m } 0$ to 1000, $c _ { \\\\mathrm { f } } \\\\mathrm { f r o m } 0 . 4 5$ to 0.65, $ { p _ { \\\\mathrm { a d p } } }$ from 0 to 0.005, $C _ { \\\\mathrm { a d p } }$ from O to 0.05, $S _ { \\\\mathrm { { L U C } } }$ from $- 1$ to 1,and $V _ { \\\\mathrm { L U C } }$ from 0 to 1. For each simulation, we recorded the percentage loss of diversity as the response for each climate change scenario.We then applied a machine-learning emulator—boosted-regression trees (47)-implemented using the dismo R library (48) and its function gbm.step to examine the relative importance of each of the four variables considered on the response.We set the error distribution family as Gaussian, the bag fraction to 0.75,the learning rate to 0.001,the tolerance to 0.0ool,and the tree complexity to 2 (i.e., first-order interactions only).To assess the relative effect of each variable on initial diversity,we calculated the boosted regression tree metrics of relative influence (relative influence $I$ is defined as the relative influences of the individual inputs $x _ { j }$ on the variation of the function that maps the explanatory variables $x$ to the response variable y) (49). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[895,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[59,75,490,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,164,241,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplementary Materials \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,178,166,236]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This PDF file includes: \\nSupplementary Text \\nFigs. S1 to S29 \\nTable S1 \\nReferences \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,267,241,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES AND NOTES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[59,276,494,932]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1．A.D.Barnosky, N. Matzke, S.Tomiya, G.O.U.Wogan, B.Swartz,T.B. Quental, C.Marshall, J. L. McGuire, E.L. 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Lett. 22,847-854 (2019). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,48,944,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,38,470,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCE ADVANCES丨RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[895,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,75,490,285]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,75,942,230]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"not in any circumstances be regarded as stating an official position of the European Commission.G.S.was partly funded bya Flinders University Honorary Visiting Scholar (May 2019). C.J.A.B.was partly funded by the Australian Research Council, Centre of Excelence for Australian Biodiversity and Heritage (CE170100015; July 2017 to June 2024).Author contributions: G.S.and C.J.A.B.conceived the idea, designed the research,did the analyses, and wrote the manuscript. G.S.collected data,developed the model,wrote the code,and ran the simulations.Competing interests: The authors declare that they have no competing interests.Data and materials availability:All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.All the data and code to replicate the simulationsare freely available at https://doi.org/10.5281/zenodo.7307443. Additional data and code for the sensitivity analyses are available from https://doi.org/10.5281/ zenodo.7255957.Development versions of the code for the simulations and the analyses are available from https://github.com/giovannistrona/global_coextinctions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,242,647,288]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Submitted 25 November 2021 \\nAccepted 9 November 2022 \\nPublished 16 December 2022 \\n10.1126/sciadv.abn4345 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,948,440,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strona and Bradshaw,Sci.Adv.8,eabn4345 (2022)16 December 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[895,948,942,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 of 12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,37,470,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCIENCEADVANCES|RESEARCH ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[57,300,490,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments:We thank G. Ceballos and J.Llewelyn for useful comments and suggestions on the manuscript.The views expressed are purely those of the writers and may \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[129,60,546,108]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ScienceAdvances \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[133,160,865,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Coextinctions dominate future vertebrate losses from climate and land use change \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[131,181,389,194]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Giovanni Strona and Corey J.A. Bradshaw \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[131,231,315,257]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sci. Adv., 8 (50),eabn4345. DOI:10.1126/sciadv.abn4345 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[106,884,934,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Science Advances(ISSN）is publishedby the American Asociationfor teAdvancementof Science.1200 NewYork Avenue NW, Washington,DC 20o05.The title Science Advances is a registered trademark of AAAS. Copyright $\\\\circledcirc$ 2022The Authors,some rights reserved;exclusive licensee American Association forthe Advancement of Science.No claim to original U.S. Government Works. Distributed under a Creative Commons Atribution License 4.0 (CC BY). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[131,346,458,400]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View the article online https://www.science.org/doi/10.1126/sciadv.abn4345 Permissions https://www.science.org/help/reprints-and-permissions \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[107,855,414,867]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Use of this article is subject to the Terms of service \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1126/sciadv.abn4345"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Life Sciences/Earth and Atmospheric Sciences"},"sha256":{"kind":"string","value":"ca86fda7bbe2ec860f71971f50b36b715cf236d926bb12be5c0d9298b5b739e0"},"title":{"kind":"string","value":"Coextinctions dominate future vertebrate losses from climate and land use change"}}},{"rowIdx":175,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Indira Rodríguez|Josep Poblet|Mayte Bulnes|Joan Flinch|Massimiliano Masini"},"content_list":{"kind":"list like","value":[{"bbox":"[57,206,776,271]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Horizontal/vertical motion and wedge geometry of the Sinú Fold Belt, South-Caribbean accretionary prism, NW Colombia: Implications for a morphostructural zoning ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[838,185,890,223]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0881/6b3e5aceba9ef8ae9ff455372c8723e2b5b80e64382db015ed59e5296bb8781c.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,283,781,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Indira Rodríguez a, Josep Poblet a,\\*, Mayte Bulnes a, Joan Flinch b,\\*, Massimiliano Masini b ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,308,563,332]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"$^{a}$ Departamento de Geología, Universidad de Oviedo, C/Jesús Arias de Velasco s/n, 33005, Oviedo, EU, Spain \",\"b Repsol, C/ Mendez Álvaro 44, 28045, Madrid, EU, Spain \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[58,360,194,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ARTICLEINFO ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,385,109,395]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,395,127,406]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Sinu fold belt ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,407,157,417]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accretionary wedge ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,418,115,428]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Shortening ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,428,157,438]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tectonic subsidence ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,440,126,448]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Critical taper ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,450,142,460]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Morphostructure ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[334,360,435,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ABSTRACT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[332,384,939,566]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Sinú Fold Belt, located in the southwestern part of the South Caribbean Deformed Belt, northwest Colombia, has been interpreted as the outer portion of an accretionary wedge resulting from the subduction of the Caribbean Plate under the South American Plate. Several geological sections, across and along the offshore portion of the Sinú Fold Belt, have been constructed through geological interpretation of 2D seismic sections constrained by a few exploration wells. Their analysis has allowed us to quantify the amount of horizontal motion (shortening responsible for the structures and basal detachment displacement) and vertical motion (tectonic subsidence/uplift and wedge vertical thickening) undergone by the belt over time; unravel its recent evolution consisting of almost no active structures in the south edge and a large amount of active structures northwards; quantify its pore pressure, coefficient of friction and strength using its wedge geometry consisting of high taper angles in the lower continental slope near the deformation front and lower taper angles in the upper continental slope away from it; and understand the aseismic and trench-lacking character of the belt. These observations have been crucial to identify the main features of the morphostructural zones across the belt (Colombian Basin, lower continental slope, upper continental slope and continental shelf) and establish a new along-strike zoning (north region influenced by the Magdalena Fan/Canoas Oblique Ramp, Sinú Fold Belt s.s., and south salient influenced by the Uramita Fault). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,602,164,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,629,487,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Sinú Fold Belt (SFB), located mostly offshore northwest Colombia, together with the San Jacinto Fold Belt, located onshore northwest Colombia, are the leading and trailing parts respectively of a NE-SW trending accretionary wedge developed to the south of the Colombian Basin (Fig. 1a and b). This NW-directed accretionary wedge resulted from eastwards, low-angle subduction of oceanic rocks and sediments belonging to the Caribbean Plate under arc terranes along the northwest edge of the South American continent that belong to the South American Plate (e.g., Ladd and Truchan, 1983; Ladd et al., 1984) (Fig. 1c). In this paper we will focus on the offshore part of the SFB between the Uramita Fault to the south and the Magdalena Fan to the north. This part of the belt is exceptionally well imaged in high quality ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,604,591,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"seismic data. ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,616,939,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Most of the knowledge on the large-scale structure of the SFB come from geological interpretation of seismic reflection profiles, which has allowed the construction of geological sections (e.g., Toto and Kellogg, 1992; Bernal-Olaya et al., 2015) as well as structural maps (e.g., Vitali et al., 1985; Cediel and Caceres, 2000; Flinch et al., 2003b; Cediel, 2011; Martínez et al., 2015; Rodríguez et al., 2021) of the belt, and their integration into lithosphere-scale transects from the Colombian Basin, across the Sinú-San Jacinto belt, to the San Jorge Basin (included in the Lower Magdalena Basin), to the mountain range (Central and Eastern Cordillera) (e.g., Flinch et al., 2003a; Mantilla-Pimiento, 2007; Bernal-Olaya et al., 2015; Flinch and Castillo, 2015; Mora-Bohórquez et al., 2017) (Fig. 1c), or even to the foreland basin developed eastwards of the mountain range (e.g., Vargas and Mann, 2013). Thus, the SFB has been ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[357,42,640,55]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[58,74,164,163]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ELSEVIER ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[379,75,621,88]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Contents lists available at ScienceDirect ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[334,105,667,127]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[319,145,680,160]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"journal homepage: www.elsevier.com/locate/marpetgeo ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[838,66,937,160]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,818,203,831]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"* Corresponding author. ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[63,832,564,843]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"** Corresponding author. Independent Geoscience & Energy Consultant, Madrid, EU, Spain. ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[58,844,937,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E-mail addresses: indira@geol.uniovi.es (I. Rodríguez), jpoblet@geol.uniovi.es (J. Poblet), maite@geol.uniovi.es (M. Bulnes), flinchjoan@gmail.com (J. Flinch), massimiliano.masini@repsol.com (M. Masini). ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[58,877,337,889]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1016/j.marpetgeo.2022.105780 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,890,552,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received 10 January 2022; Received in revised form 16 May 2022; Accepted 6 June 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,902,226,912]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Available online 11 June 2022 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[58,912,934,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"0264-8172/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[55,65,485,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the subject of many studies, not only because of its scientific interest, but because of its hydrocarbon potential explored from the sixties to present day by many oil companies. However, in our opinion some interesting large-scale issues still need to be fully understood. Some refer to the belt kinematics, i.e., belt shortening, basal detachment displacement and vertical subsidence/uplift, whereas others refer to its geometry, i.e., taper angle, morphology, relief and thickness. Likewise, the interrelationships between its geometry and kinematics, and how these elements influence each other spatially and through time, must be established. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,197,485,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Regarding horizontal movements of the SFB, some studies have quantified the shortening responsible for the SFB (e.g., Ruiz et al., 2000; Kellogg et al., 2005; Bernal-Olaya et al., 2015) and the magnitude of tectonic plate motion (e.g., Freymueller et al., 1993; Kellogg and Vega, 1995; Trenkamp et al., 2002), however, neither the amount of displacement along the accretionary-prism basal detachment nor its relationship with the belt shortening and plate motion have been analyzed. As regards vertical movements of the SFB, we are aware of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,276]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"only one study on the subsidence/uplift in a Colombian Basin section adjacent to the SFB (Sánchez et al., 2019), but there have been no studies of the SFB up to date. With respect to the taper angle, two analyses have been carried out (Toto and Kellogg, 1992; Bernal-Olaya et al., 2015), but the new data available allow for more detailed measurements of the taper angle, as well as for quantification of its across- and along-strike variations and the parameters that control it. Regarding the SFB relief, recent sedimentation/erosion processes have been documented in detail (Vinnels et al., 2010), however, this information has not been correlated yet with the activity and kinematics of the underlying structures. Transversal and longitudinal variations in elements such as the SFB morphology, taper angle and crustal thickness have been documented (e.g., Toto and Kellogg, 1992; Vinnels et al., 2010; Bernal-Olaya et al., 2015), however, the relationship between these variations and the belt kinematics has not been examined, and no zoning of the belt has been established yet. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,277,937,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To address these issues, we have carried out a geological interpretation of six regional, depth-converted 2D seismic profiles, with the help ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,327,937,843]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. a) Satellite image of the Caribbean region showing the main tectonic elements, the ODP well (yellow circle) and the region enlarged in b) (red rectangle). b) Satellite image of the Caribbean margin of northwest Colombia showing the major structural units and faults, as well as the study area in the offshore portion of the SFB (red dashed polygon), the seismic lines illustrated here (white lines) and wells (yellow circles), and the location of the section depicted in c) (pink line). Figures a) and b) modified from Case and Holcombe (1980) and Cediel et al. (2003), and base maps from GEBCO Digital Atlas by GIS map services. We are not allowed to show the location of all the interpreted seismic profiles due to confidentiality agreements with the owning companies. c) Vertically exaggerated crustal section illustrating the Sinu and San Jacinto fold belts (modified from Mantilla-Pimento, 2007). SJFB: San Jacinto Fold Belt, SJB: San Jorge Basin. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0424/d3bdd37fc549e15e10b17e0858b23658f5feac85c40e8614058e49ef978a60b0.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,145]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of a few well-logs and a high-density grid of 2D time seismic profiles. The data obtained have been employed to characterize and quantify large-scale aspects of the SFB, such as horizontal/vertical motion, taper and morphology, and their variations, together with variations in the structural style, have allowed us to define different morphostructural regions both across and along strike. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,158,200,171]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Geological setting ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,184,487,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The South Caribbean Deformed Belt, developed along the Colombian and Venezuelan coasts, is an accretionary wedge that runs along the convergent margin between the Caribbean and South American tectonic plates (Fig. 1a). The Caribbean-Plate relative motion towards ESE since Late Miocene (e.g., Minster and Jordan, 1978; Trenkamp et al., 2002; Pindell and Kennan, 2007) caused different tectonic regimes depending on the shape of the South American Plate boundary. Motion almost parallel to the coastline gave rise to a strike-slip regime in north Colombia and Venezuela, however, motion mainly perpendicular to the coastline produced a compressional setting in the northwestern Colombian coast. The South Caribbean Deformed Belt in northwest Colombia consists of a NE-SW trending double belt called Sinú-San Jacinto Fold Belt (Fig. 1b), which resulted from a two-stage development (e.g., Galindo and Lonegan, 2013). Thus, the San Jacinto Fold Belt is the innermost portion of the accretionary belt formed by dextral-transpressional collision/accretion between the Caribbean and South American tectonic plates from Paleocene to Oligocene (e.g., Flinch, 2003a, 2003b), whereas the SFB is the outermost part of the accretionary belt and reflects a Late Miocene to Recent compressive stage related to the Andean orogeny (e.g., Duque-Caro, 1979; Ruiz et al., 2000). This complex scenario was caused by the clockwise rotation of the Caribbean Plate from Cretaceous to the present (e.g., Escalona and Mann, 2011; Ardila and Diaz, 2015). The Sinú-San Jacinto Fold Belt is bounded to the west by the Uramita Fault which separates it from the North Panama Fold Belt (Fig. 1b); to the south it is bounded by the Western and Central cordilleras; to the east, the Romeral Fault Zone ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,939,343]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"separates it from the San Jorge and Plato basins; it is bounded to the north by the Magdalena Fan; to the northeast, it is separated from the Santa Marta Massif by the Santa Marta-Bucaramanga Fault; and to the northwest, the deformation front is responsible for its thrusting over the Colombian Basin. The Sinú Fault Zone is the eastern boundary of the SFB and the western boundary of the San Jacinto Fold Belt. The SFB developed over a subducting Mesozoic basement (e.g., Toto and Kellogg, 1992; Ruiz et al., 2000; Alfaro and Holz, 2014b) and comprises a Cenozoic sedimentary cover mainly made up of shales with sporadic cherts, sandstones, conglomerates and limestones (Duque-Caro, 1979) (Fig. 2). The most important structure is an imbricate system of W-directed thrusts and related folds (Fig. 3), as well as piggy-back basins filled with thick sequences of syn-tectonic strata (Kolla et al., 1984; Toto and Kellogg, 1992; Flinch et al., 2003a; Vinnels et al., 2010). The thrusts emanate from a deep main detachment located within deep over-pressed shales, which are the source for mud diapirs and related ductile deformation in the host sediments (Shepard et al., 1968; Ramirez, 1969; Shepard, 1973; Duque-Caro, 1979, 1984; Vernette, 1986; Vernette et al., 1992; Briceno and Vernette, 1992; Ruiz et al., 2000). These diapirs, together with normal faults, are mainly developed in the trailing part of the belt (Flinch et al., 2003a,b; Mantilla-Pimiento, 2007). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,356,633,369]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Data employed ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,380,939,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Six pre-stack depth migrated seismic lines have been interpreted from the geological point of view although only four are shown here (Fig. 1b). The chosen four lines are approximately perpendicular to the belt, i.e., NW-SE, have an average length of $100\\mathrm{km}$ and reach a depth of around $22\\mathrm{km}$ . The spacing between them ranges from 35 to $60\\mathrm{km}$ . Two additional seismic lines are approximately parallel to the belt, i.e., NE-SW, are more than $800\\mathrm{km}$ long but we have interpreted around $250\\mathrm{km}$ , and reach a depth of $22\\mathrm{km}$ . The spacing between these two lines ranges from 30 to $70\\mathrm{km}$ . Nowadays, pre-stack depth migration is considered the most accurate method to perform depth conversions of time seismic lines, and that guarantees the precision of the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,554,934,890]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 2. Stratigraphic section of the study area including additional information on the seismic stratigraphy and tectonics-sedimentation relationships, constructed using our own data, wells, an idealized stratigraphic column built by Alfaro and Holz (2014a, b) based on various studies (Duque-Caro, 1979, 1984, 1990; Aleman, 1983; Duque-Caro et al., 1996; Guzmán, 2007), and Vinnels et al. (2010) data. \"]","image_footnote":"[]","img_path":"images/0901/fcf9b221e7a2cbe70a9075aeb2c23cfc645c77293aecdbc50843c854417485ff.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,65,872,742]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3. Structural map of the SFB constructed by drawing the traces of the emergent structures and plotting vertically the fault tips and the fold hinges of the buried structures. Colombian-Basin normal faults developed during Cretaceous-Paleocene, reactivated as normal faults during Pliocene-Quaternary, are also shown in the west part of the study area. The location of the seismic profiles displayed in Fig. 4 is shown. \"]","image_footnote":"[]","img_path":"images/0000/9ae484d3743930052445a3e157bc56395330548317f45c27f36b4a56c4ce2aab.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,803,485,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"measurements of angles and distances taken in the depth-converted seismic lines. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,829,485,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition, we have interpreted sixty-one 2D time seismic lines acquired in eight different surveys. These seismic lines exhibit two predominant directions: NW-SE, i.e., approximately perpendicular to the SFB, and NE-SW, i.e., approximately parallel to the SFB. This dataset covers an area of approximately $17,000\\mathrm{km}^2$ , the length of the time seismic sections ranges from $23\\mathrm{km}$ to more than $400\\mathrm{km}$ , although most of them exhibit a length in between 50 and $150\\mathrm{km}$ , and reach two-way travel times from 6 to 8 s. The spacing between the time seismic lines ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,803,937,854]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ranges from 1.5 to $5\\mathrm{km}$ . Both the depth-converted and the time seismic lines were acquired by the oil companies BP-Amoco, BP Exploration, Intercol, Ecopetrol and Gulf Oil Corporation from 1967 to 2004 and were supplied to us by the company Repsol. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,854,937,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data from six wells has been employed: a) the Ocean Drilling Project (ODP) Site 999 (Sigurdsson et al., 1997), located in the Caribbean Sea approximately $400\\mathrm{km}$ to the northwest of the SFB deformation front, that penetrates more than $1\\mathrm{km}$ of Upper Cretaceous-Upper Pleistocene strata (Fig. 1a); and b) five exploration wells, located in the continental shelf about $20\\mathrm{km}$ from the Colombian coast, that penetrate up to $4.5\\mathrm{km}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,118]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of Neogene-Quaternary strata (Fig. 1b). The exploration wells in the continental shelf were drilled by the companies Colombian Gulf Oil, Provincia Petroleum, Citco Colombia Petroleum Corporation and Phillips Petroleum from 1969 to 1979 and were supplied to us by Repsol. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,118,485,224]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Up to nine stratigraphic units have been defined based on the amplitude, frequency, continuity and geometry of the seismic reflectors (Figs. 2 and 4). The software Petrel E&P (Schlumberger), Kingdom Suite (IHS Markit) and Move (Midland Valley-Petroleum Exploration Experts) have been used to carry out the geological interpretation of the seismic data and subsequent data analysis. The specific methodology used to decipher each of the different issues discussed below is explained at the beginning of each section. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,237,258,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Main stratigraphic features ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,263,487,368]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study area is made up by a Jurassic to present-day succession (Fig. 2). The Cretaceous to present-day succession is mainly siliciclastic and approximately coarsening upwards (from shales in the lower part to shales, sandstones and some conglomerates in the upper part), as well as shallowing upwards (from deep water sediments evolving upwards to shallow water/transitional environments). Perpendicularly to the Colombian coast, the thickness of the Cretaceous-Miocene succession increases from the abyssal plain (less than $1\\mathrm{km}/$ more than $3\\mathrm{km}$ ) to the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,262]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"continental shelf (5 km/almost 6 km) (Fig. 4). Approximately parallel to the Colombian coast in the continental slope, the Mesozoic-Neogene succession increases from the center-south part of the SFB (Fig. 4c) towards the northeast and southwest, whereas in the continental shelf, it reaches its maximum thickness in the south part (Fig. 4d) and decreases northwards. Although the thickness of the Pliocene-Quaternary sequence is quite variable, approximately perpendicular to the Colombian coast it thickens from the continental slope (approximately $1 - 2\\mathrm{km}$ ) to the continental shelf (almost $3 - 4\\mathrm{km}$ ), i.e., similarly to the pre-Miocene sequence. Approximately parallel to the Colombian coast, the Pliocene-Quaternary succession is thin in the south-central part of the belt and thickens both to the northeast and to the southwest. The different stratigraphic units mapped in the seismic lines are bounded by unconformities. In some localities they become angular unconformities that truncate underlying beds and may be onlapped by overlaying beds. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,263,937,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the Colombian Basin, the Cretaceous and Paleocene successions are syn-rift strata (Fig. 2), although a few normal faults cut and offset Eocene, Oligocene and Miocene strata. Occasionally, the uppermost Pliocene and Quaternary strata are coeval to the normal reactivation of these older faults. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,329,937,368]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Paleocene, Eocene, Oligocene and Miocene strata that constitute the SFB, as well as older underlying rocks, are pre-tectonic with respect to the SFB structures, i.e., they are pre-growth strata (Fig. 2). The ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[124,392,863,501]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0543/5b63d436d99303df36f6fd811def32be202814ac08113a78b3a2c69fc41ae102.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,506,801,622]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0160/6afa1f13a07c779bb2cd5c5ed7e48b7006008f6d0b210be827957a0d9c02fc20.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,631,860,733]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0730/71242ddba1544f26b1f64f204fd74b6f285aa5dff0cb35d535ecb77604ac7ae9.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,744,868,851]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 4. Geological interpretation of four depth-converted seismic profiles across the SFB from north (a) to south (b) showing thrusts and related folds, normal faults and mud diapirs. The pin (left part of the seismic profiles) and loose (right part of the seismic profiles) lines employed to measure the shortening in the four profiles are shown. See Figs. 1b and 3 for location. The stratigraphic sections used to infer the tectonic subsidence curves depicted in Fig. 9 are located at the left border of the seismic profiles (Fig. 9a, 9b, 9c and 9d - Colombian Basin), to the right of the pin line (Fig. 9e, 9f, 9g and 9h - SFB Deformation Front) and at the right border of the seismic profiles (Fig. 9i, 9j, 9k and 9l - SFB Continental Shelf). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0301/b4decedd6904c80cab6faef2ab1d694f77369819a0b94a5afe3ee9100f8518da.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,952,502,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,182]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pliocene and Quaternary strata exhibit a number of features diagnostic of syn-tractonic deposition associated with faults, folds and diapirs, and therefore, they are interpreted as growth strata. Nevertheless, the lower part of the Pliocene-Quaternary sequence can be also considered pregrowth or growth, while the upper part can be growth or post-growth strata, so that the stratigraphic position of the boundary between these sequences vary from one structure to another because faults, folds and diapirs developed in the SFB are diachronic (Rodríguez et al., 2021, 2022a; 2022b). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,197,315,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5. Main structural elements of the SFB ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,223,485,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The SFB is a NE-SW trending fold and thrust belt, more than $200\\mathrm{km}$ long and around $130\\mathrm{km}$ wide in its widest part, developed mainly in the continental slope and in the continental shelf offshore northwest Colombia (Fig. 1b). In map view it is a curved belt convex to the northwest (seawards) and it is slightly asymmetric, so that it is wider in the central-north part, and a minor recess and salient occur towards the south (Fig. 3). A NNE-SSW trending and approximately rectilinear fault, named Sinú Fault Zone, separates the SFB trailing part from the San Jacinto Fold Belt (Figs. 1c and 3). The SFB leading part is separated from the Colombian Basin by the deformation front defined by a frontal thrust or a triangle zone. It exhibits a stepped morphology along strike caused by faults that disrupt its continuity, and is the belt tectonic element that best reflects the belt curved shape (Fig. 3). The SFB is covered by the Magdalena Fan towards the northeast, whereas it ends against the NNW-SSE trending Uramita fault towards the southwest (Fig. 1b). In profile view, the SFB is a wedge bounded by a submarine topography gently inclined to the NW and by a basal detachment gently dipping to the SE (Fig. 4). The wedge apex is located seawards, while the thickest part of the wedge, which may reach more than $10\\mathrm{km}$ of vertical thickness in the study area, is located landwards. Ductile structures, such as folds and mud diapirs, as well as fragile structures apparently developed under contractional (thrusts), extensional (normal faults) and strike-slip (strike-slip faults) tectonic regimes, occur within the SFB. Some of these structures, such as thrusts, folds, mud diapirs and some normal faults, are longitudinal with respect to the belt, and some of them are transverse, such as tear faults and strike-slip faults (Rodriguez, 2020; Rodríguez et al., 2021) (Fig. 3). A brief description of these structures is presented below. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,607,228,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.1. Contractional structures ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,633,485,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thrusts, together with related folds, are the most abundant longitudinal structures, particularly in the continental slope. Their strike bends from approximately N-S in the south portion of the SFB to NE-SW in the north (Fig. 3). Most thrusts exhibit a listric geometry and form an imbricate thrust system that emanates from a SE gently dipping basal detachment located within Paleocene strata (Fig. 4). Although NW-directed thrusts are the most common structures, a few SE-directed thrusts, i.e., backthrusts, occur. Pop-ups and triangular zones developed in those regions where thrusts and backthrusts coexist. Growth ramp folds, in the form of single-hinge anticlines, box-fold type anticlines and anticlinal monoclines, make up the hangingwall of these thrusts (Fig. 4a, 4b and 4c). Two large anticlines and a syncline, interpreted as growth detachment folds, developed in the SFB south salient (Fig. 4d). The imbricate thrust system and related folds developed according to a roughly forward propagation sequence (piggy-back) from southeast to northwest, both at the scale of a few structures and at the scale of the whole SFB (Rodríguez et al., 2021, 2022a). Sporadic out-of-sequence thrusts are recognized, such as those in the transition from the upper continental slope to the lower continental slope. The basins filled in with Pliocene to present-day growth strata, located above the folds in between thrusts, are piggy-back basins (Fig. 4). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,910,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An E-W trending fault oblique to the trend of the longitudinal structures, named Canoas fault (Vernette et al., 1992; Ruiz et al., 2000), ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"has been mapped in the north part of the SFB (Fig. 3). The thrusts and related folds developed in the south fault block exhibit different morphologies and are much more abundant than those developed in the north fault block, where there are almost no structures. This fault, developed during recent times, is interpreted as an oblique thrust ramp. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,145,660,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.2. Strike-slip structures ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,171,937,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Several faults, sub-perpendicular to the longitudinal structures, i.e., transverse structures, have been identified in the continental slope (Fig. 3). Their strike ranges from WNW-ese in the south part of the belt to NW-SE in the north part and they are usually sub-vertical. While the strike of the thrusts and related folds cut by these faults is approximately the same in both fault blocks, the number, spacing and geometry of the thrusts and related folds are different in both fault blocks, and therefore, they have been interpreted as tear faults. The activity of some of these faults ended before the deposition of the youngermost sediments, whereas others are active in recent times. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,303,937,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Rosario Fault (Vernette et al., 1992; Ruiz et al., 2000) is a large fault oblique to the trend of the longitudinal structures, i.e., a transverse structure, developed in the north part of the SFB and in part of the Colombian Basin (Fig. 3). It is a right-lateral, steep fault whose average strike is E-W, and it cuts and offsets thrusts and related folds as well as a tear fault. Its activity is relatively young. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,395,670,408]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.3. Extensional structures ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,422,937,617]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Small-scale normal faults, involving shallow sediments, developed above the steepest limbs of some anticlines that show bathymetric expression in the continental slope. These faults are longitudinal structures, whose average strike is NNE-SSW in the central part of the SFB and NE-SW in the northern area. Most of them are listric, with dips from moderately to gently to the W and NW (Figs. 3, 4a, 4b and 4c). Some of these NW-directed normal faults branch at depth with a gently NW-dipping detachment, which may be the Bottom Simulating Reflector (BSR), i.e., the base of the gas hydrate stability zone (Shipley et al., 1979), forming imbricate normal fault systems. NW-directed, listric thrusts, whose dip varies from gently to moderately to the ESE and SE, emanate from the leading edge of the detachment forming toe thrusts. These normal faults and their associated toe thrusts developed in recent times, and are from simultaneous to younger than the thrusts and related folds. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,620,937,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Large listric normal faults, dipping both to the NW and to the SE, have been mapped in the continental shelf (Fig. 3). The average strike of these longitudinal structures ranges from NNE-SSW to NE-SW. Gentle rollover anticlines and sets of second-order normal faults occur in the hangingwall of these normal faults. Some faults root into the basal detachment, whereas others are shallower faults that become horizontal at intermediate depths and become toe thrusts. Some of these normal faults were reactivated as reverse and normal faults, remaining inactive in between fault reactivation periods. These normal faults cut and offset the thrusts and related folds, and some toe thrusts related to these normal faults resulted from reactivation of a portion of previous thrusts. These normal faults developed approximately during middle Pliocene time, and their reactivation took place up to present-day. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,805,630,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5.4. Mud structures ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,831,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Diapirs are longitudinal structures developed mainly in the continental shelf. They exhibit an elongated shape in map view and their main elongation axis ranges from N-S to NE-SE (Fig. 3). In general, the sidewalls of the diapirs are steeply inclined to vertical (Fig. 4a, 4b and 4d). Some overburden sediments located above the crests of the diapirs and the sediments pierced by the diapirs exhibit anticline geometries caused by the intrusion of the diapirs. Crestal-collapse normal faults developed above some mud diapirs. Mud diapirs occur in the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"hangingwall and foot wall of thrusts, and in the core of some hangingwall anticlines related to thrusts, so that they probably initiated slightly before or synchronously to the thrusts and related folds from Pliocene to present-day. Some mud diapirs are located close to listric normal faults with related rollover anticlines. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,143,394,157]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6. Main structural features of the Colombian basin ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,170,485,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Colombian Basin is a large elongated basin located offshore northwest of Colombia (Fig. 1a). Only the south part of the basin adjacent to the SFB has been studied here. It is filled in by sub-horizontal Cenozoic strata on top of Cretaceous and Jurassic sedimentary and igneous rocks (Fig. 4). All these rocks are involved in a basement high developed in the south part of the study area (Fig. 5). In addition, horsts and grabens bounded by NE-SW faults, that dip from moderately to steeply both to the SE and to the NW, occur (Figs. 3 and 5). These normal faults were active mainly during Cretaceous and Paleocene times, however, some normal faults also cut and offset Eocene, Oligocene and part of the Miocene strata. Some of these normal faults propagated up section in recent times and were active as normal faults. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,341,327,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7. Amount of horizontal tectonic motion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,369,164,380]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7.1. Plate motion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,395,485,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The shortening responsible for the SFB formation in the study area started in the Pliocene and is still active today according to the age of the syn-contractional strata (Rodriguez, 2020; Rodriguez et al., 2021, 2022a); this means that this region has been shortened approximately during the last 5.3 Myr. The present-day rates of convergence between the Caribbean and South American tectonic plates for this region, estimated by taking GPS measurements during 25 years, are $10\\mathrm{mm / yr}$ (Freymueller et al., 1993), $10 - 15\\mathrm{mm / yr}$ (Kellogg and Vega, 1995) and $20\\pm 2\\mathrm{mm / yr}$ (Trenkamp et al., 2002). Assuming that these plate motion rates (from 10 to $20\\mathrm{mm / yr}$ ) remained constant during the whole 5.3 Myr of SFB development, and that the South American tectonic plate remained stationary with respect to the Caribbean tectonic plate, then the Caribbean tectonic plate would have moved approximately from 53 km to $106\\mathrm{km}$ from Early Pliocene to present-day. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,580,485,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Some NE-SW normal faults developed during Mesozoic and/or Paleogene-early Neogene in the south portion of the Colombian Basin adjacent to the SFB deformation front (Fig. 3), reactivated as normal faults during Pliocene-Quaternary time, may furnish information on the rates of SFB development. Thus, we propose that the Caribbean tectonic plate bended as it subducted under the South American tectonic plate and supported the weight of the overlying SFB while it was being emplaced. This lithospheric flexure probably induced extension in the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,939,540]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"outer portion of the lithosphere flexure hinge resulting in normal faulting, i.e., flexural extension. This extension was not accommodated by new normal faults in the Colombian Basin but by reactivation of old normal faults with favorable orientation, such as the NE-SW faults mapped in the west part of the study area (Figs. 3 and 6b) whose strike may be sub-parallel to the flexure hinge. As the Caribbean tectonic plate subducted, the flexure hinge probably migrated away from the continent at a similar rate to that of the SFB advance seawards (Fig. 6a). This would explain why one of the normal faults located closer to the continent (Cretaceous-Paleocene fault reactivated during Pliocene, intersected by section lines C-C' and D-D' in Fig. 3) ceased to be active by the end of the Pliocene, while the normal fault located farther away from the continent (Cretaceous-Paleocene fault reactivated during Quaternary, intersected by section line C-C' in Fig. 3) ended its activity in recent times. Assuming that the lithospheric flexure hinge migrated from southeast to northwest, the distance between these two normal faults measured perpendicularly to their traces depicted on the map in Fig. 3 could reflect the spatial migration of the lithospheric flexure hinge. This distance divided by the time elapsed between the termination of activity of both normal faults might give us an approximate rate of the lithospheric-flexure hinge migration from the end of the Pliocene to the present-day. Since the distance measured between these two faults is $29\\mathrm{km}$ and the approximate time difference between the termination of activity of both faults is $2.58\\mathrm{Myr}$ , the rate obtained is $11\\mathrm{mm / yr}$ . If we assume that the rate of lithospheric-flexure hinge migration is approximately equivalent to the rate of advance of the SFB deformation front, then the rate of advance of the SFB deformation front from Pliocene to Present, obtained using flexure-related normal faults, is in full agreement with the $10 - 20\\mathrm{mm / yr}$ rate of convergence between the Caribbean and South American tectonic plates for the study area, estimated during 25 years using GPS measurements (Freymueller et al., 1993; Kellogg and Vega, 1995; Trenkamp et al., 2002). Obviously, the rate of lithospheric-flexure hinge migration estimated should be taken with caution since precise ages of the strata are not available and some assumptions may not be totally correct, such as the direction of migration of the lithospheric flexure hinge. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,562,699,576]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7.2. Overriding plate shortening ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,588,937,694]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Pliocene to present-day shortening responsible for the SFB has been measured in the continental slope and in part of the continental shelf using the four depth-converted seismic profiles sub-perpendicular to the SFB trend (Fig. 4). The boundary between the pre- and syncontractional sequences has been used to estimate the shortening. This is an easy identifiable, well imaged and continuous reflector, and its age is approximately Lower Pliocene, although it may vary across the belt. The shortening has been estimated as the difference between the length ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[161,709,836,901]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5. Geological interpretation of a time seismic profile within the Colombian Basin showing a basement high as well as normal faults. See Fig. 1b for location. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0008/1109ffd8822f2d65ecba3d8e5d0cc7732921838be6b1069a634e6a7d88389fa9.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[233,66,700,181]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0327/76db41e337dbb3b3244db652d2103787dc84f1c2b1df6e8d2323ed4054474a74.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[290,191,700,284]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0020/b7697a38333b308ae6d112deee251c8850049f63c2d3ce9aefd257beebed0d7f.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[290,292,700,383]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0025/ed789147a3e8a9eaf4fd773e3de29866a90adab928efb98089c83e004540d006.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[161,395,836,568]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 6. a) Cartoon illustrating the advance of the SFB from older (upper part of the figure) to younger (lower part of the figure) times and the development of normal faults in the hinge of the lithospheric flexure suffered by the subducting Caribbean Plate. We have assumed that the dip of the subducting plate remains constant over time for simplicity. Black normal faults: active normal faults, grey normal faults: inactive normal faults. b) Geological interpretation of a depth-converted seismic profile across the Colombian Basin showing normal faults. See Fig. 1b for location. The stratigraphic sections used to infer the tectonic subsidence curves depicted in Fig. 8a and b are located at the overthrow hangingwall and at the uplifted foot wall of the northwesternmost normal fault. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0626/e45d779ba5cff73400aaa856dd715e2956c62c540eba6c8a088b4ee17a12eac1.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[60,663,489,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of the folded/faulted reflector and the cross-section width in between the sub-vertical pin lines located in the Colombian Basin and the subvertical loose lines in the continental shelf (Fig. 4). The shortening has been underestimated because: a) strain is likely to have occurred in the shale succession but it has not been accounted for because the measurement method employed assumes constant bed length, b) the shortening has been only estimated in the continental slope and in a portion of the continental shelf adjacent to the continental slope since we do not have depth-converted seismic profiles across the portion of the continental shelf closest to the coast and on land, and c) the significant amount of sediment volume loss due to water expel during accretion (Moore et al., 2011) has not been considered in our estimations. The shortening obtained using the four seismic sections ranges from $11.3\\mathrm{km}$ to $22.8\\mathrm{km}$ . These shortening values are apparent values because the seismic profiles are oblique to the tectonic transport vector. They have been converted to true shortening values using Cooper (1983) equations and taking into account the angle between the direction of the seismic lines and the tectonic transport vector (approximately from N110E to N120E, i.e., WNW-ESE according to Rodriguez, 2020; Rodriguez et al., 2021). The true shortening values range from $13.82 \\pm 0.71\\mathrm{km}$ to 23.9 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,669,939,854]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\pm 0.53 \\mathrm{~km}$ , i.e., from almost $19\\% - 30\\%$ shortening. These values must be taken with caution due to possible errors made in their measurement, in the geological interpretation of the seismic data and in the depth conversion. Our shortening values are lower than those obtained by Ruiz et al. (2000) and Kellogg et al. (2005) based on the analysis of folds and faults depicted in cross sections, which are $60 - 65 \\mathrm{~km}$ ( $40\\%$ ) and more than $50 \\mathrm{~km}$ ( $40\\%$ ) respectively; the reason is that our depth-converted sections do not cover the whole SFB from the deformation front to the boundary with the San Jacinto Belt. However, our shortening values are relatively similar to those obtained by Bernal-Olaya et al. (2015) which range from 27.6 to $31.4 \\mathrm{~km}$ ( $27 - 32\\%$ ). Taking into account that the estimated shortening has been produced during 5.3 Myr and assuming a constant shortening rate, the average shortening rates range from 2.5 to $4.5 \\mathrm{~mm} / \\mathrm{yr}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,870,623,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7.3. Interplate slip ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,897,939,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The consistency between the average rates of tectonic plate motion (measured during 25 years) and those of lithospheric-flexure hinge migration (derived from data covering the last 2.58 Myr), both ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,146,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,568]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"estimated using different methods, makes it reasonable to assume that: a) the plate motion rates measured using GPS during the last 25 years remained approximately constant during the last 2.58 Myr, and perhaps during the whole 5.3 Myr of SFB development, and b) much of the motion of the Caribbean and South American plates has been accommodated at the edge of the plates with not much intraplate deformation. At subduction plate boundaries, strains accumulate within the overriding plate in response to motion of the down-going plate. To a first approximation, the sum of the margin interplate slip and the shortening in the overriding plate is equivalent to the total plate convergence (Nicol and Beavan, 2003) (Fig. 7). Therefore, margin interplate slip can be estimated by subtracting the shortening in the overriding plate from the total plate convergence. Assuming that the motion rate of the Caribbean tectonic plate has been approximately constant from 10 to $20\\mathrm{mm / yr}$ over the last 5.3 Myr, then the overriding plate shortening values obtained from the seismic lines represent from $13\\%$ to $45\\%$ of the total Pliocene-Quaternary movement of the Caribbean tectonic plate estimated above. These percentages are minimum values that would increase if considering the strain, plus the sum of all the SFB shortening from the deformation front to the trailing part of the SFB (Sinu Fault Zone), plus possible mistakes derived from measurements, interpretation and processing. Thus, the remaining $55 - 87\\%$ of plate convergence would be the maximum values accommodated by margin interplate slip, i.e., slip on the subduction thrust. This means that the maximum displacement along the basal detachment would range from 29.15 to $92.22\\mathrm{km}$ . Taking into account that the shortening has been produced during 5.3 Myr and assuming a constant rate of basal detachment displacement, the average rates of basal detachment displacement range from 5.5 to $17.5\\mathrm{mm / yr}$ . If the Caribbean-Plate motion rate in the past had been less than the current one and/or part of the plate movement would have been accommodated by intraplate deformation, then the displacement along the basal detachment would be less. Apparently, the percentage of basal detachment displacement seems very high with respect to the plate convergence, however, similar values have been obtained in other regions, such as the Hikurangi margin located in the boundary between the Pacific and Australian tectonic plates, where $\\geq 80\\%$ of the convergent component of relative plate motion was accommodated by interplate slip (Nicol and Beavan, 2003). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,582,310,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8. Amount of vertical tectonic motion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,607,240,622]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8.1. Tectonic subsidence/uplift ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,634,487,713]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A backstripping analysis has been carried out to estimate the tectonic component of subsidence in both the SFB and the Colombian Basin. The thickness of the stratigraphic units has been measured in the depth-converted seismic profiles. The ages in million years of the stratigraphic tops have been taken from the International Stratigraphic Chart v 2019/05 (International Commission on Stratigraphy, 2019). Although ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,939,408]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the different stratigraphic units are separated by unconformities, we have assumed that no hiatuses occur between them, because no accurate information about their ages is available. We have used the same exponential function of porosity variation with depth for all the stratigraphic units, being the c coefficient equal to 0.5 and the porosity at zero depth equal to $50\\%$ , because no porosity well logs are available and all the stratigraphic units are mainly made up of shales. We have assumed that the water depth at the time of sedimentation of the different stratigraphic units was the current water depth in the Colombian Basin, because they are interpreted to be deposited in similar deep-water environments. However, since the deposition of the Pliocene and Quaternary sediments was approximately coeval to the SFB formation, we have assumed that the water depth during their deposition in the SFB was the same as it is at their current location. Standard values of density equal to $3.3~\\mathrm{g/cm^3}$ for the asthenosphere and $1.0~\\mathrm{g/cm^3}$ for water have been used. Thus, the numerical values obtained for the tectonic subsidence may not be reliable, however, the trend of the functions obtained probably is. The purposes of this analysis are: a) decipher whether tectonic subsidence or uplift occurred in the different regions and at different times, b) identify variations in the tectonic subsidence/uplift patterns across strike (Colombian Basin-deformation front-continental shelf) and along strike (south part-central part-north part), c) estimate rates and values of tectonic subsidence/uplift due to the Pliocene-Quaternary SFB development, and d) link the tectonic subsidence/uplift patterns to geodynamic phenomena derived from the SFB development. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,409,939,672]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Firstly, we have compared two tectonic subsidence curves (Fig. 8a and b), derived from two stratigraphic columns located in two different structural positions within the Colombian Basin (Fig. 8c). These columns are located in the southwestern part of one depth-converted seismic profile approximately parallel to the SFB trend; one in the downthrown hangingwall and the other in the uplifted foot wall of a normal fault that bounds the graben mapped in the northwest part of the seismic section depicted in Fig. 6b. These two columns have helped us to figure out small-scale variations in the tectonic subsidence pattern in the Colombian Basin. All the stratigraphic units from Cretaceous to present-day occur in the downthrown fault-block column, whereas the Eocene and Oligocene are absent in the uplifted fault-block column due to a hiatus or eroded section. The tectonic subsidence was moderate in both columns from Cretaceous to Paleocene when normal faulting with relatively high displacement took place in the Colombian Basin; null in the uplifted fault block and slow in the downthrown fault block during the Eocene, Oligocene and Miocene, when sporadic normal faults with relatively small displacement still developed in the Colombian Basin; and very fast during Pliocene and Quaternary in both columns when the development of the SFB caused lithospheric flexuring in the Colombian Basin. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,672,939,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Secondly, we have compared twelve tectonic subsidence curves (Fig. 9), derived from stratigraphic columns located in three different structural positions along the four depth-converted seismic profiles ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[211,730,788,904]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 7. Sketch showing that plate motion at convergent margins is accommodated by belt shortening plus slip along the basal detachment (modified from Nicol and Beavan, 2003). \"]","image_footnote":"[]","img_path":"images/0304/3615c0c2509a92b0ccde75a96d984040d5747fd4f031cfa4ab201a5c413b15ec.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[494,950,504,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[60,68,339,428]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0315/d29a40a857aeb7bdb5cf84c2185e19db1678ace25d68b8aaf9499d7c6611d4e3.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[357,66,636,426]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 8. Depth versus time graphs illustrating two tectonic subsidence curves constructed in the Colombian Basin in: a) the downthrow fault block and b) in the uplifted fault block of a normal fault that bounds a graben. c) Structural sketch of the SFB and Colombian Basin showing the location of the tectonic subsidence curves shown in a) (black stars) and in Fig. 9 (black circles). The thin black lines indicate the position of the seismic profiles where the tectonic subsidence curves are located. See also caption of Fig. 6 for location. \"]","image_footnote":"[]","img_path":"images/0409/45dfed5a0ec1f10575bf728b3b2ea8e0334003ef829d2f21b6dc1eed137c02ae.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,455,485,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"approximately perpendicular to the SFB trend (Fig. 4). Three columns have been built in each profile: one in the Colombian Basin, one in the continental slope adjacent to the SFB deformation front, and one in the continental shelf adjacent to the SFB shelf break (Fig. 7c). Thus, we have obtained four tectonic subsidence curves in the Colombian Basin, four in the deformation front and four in the trailing part of the belt. Our purpose is to characterize large-scale variations, both along and across strike, in the tectonic subsidence pattern as a result of the SFB development. The path of the tectonic subsidence curves derived from the four columns located in the Colombian Basin is very similar (Fig. 9a, 9b, 9c and 9d). Similarly, the tectonic subsidence pattern obtained for the four columns located in the continental slope is similar (Fig. 9e, 9f, 9g and 9h), and the tectonic subsidence pattern obtained for the four columns located in the continental shelf is almost identical (Fig. 9i, 9j, 9k and 9l). Thus, there are no significant differences along strike. According to the twelve curves, the tectonic subsidence is fast during Paleocene, and slow during Eocene, Oligocene, and Miocene, although it increases from the Colombian Basin to the continental shelf. The main differences occur during Pliocene and Quaternary. In the Colombian Basin, the Pliocene-Quaternary tectonic subsidence increases with respect to the Eocene-Oligocene-Miocene tectonic subsidence (Fig. 9a, 9b, 9c and 9d). In the continental slope, the Pliocene-Quaternary tectonic subsidence is similar to the tectonic subsidence during the Eocene-Oligocene-Miocene except for the southernmost profile where uplift occurs (Fig. 9e, 9f, 9g and 9h). In the continental shelf, a pronounced uplift occurs during the Pliocene-Quaternary (Fig. 9i, 9j, 9k and 9l). We believe the Colombian Basin suffered a remarkable tectonic subsidence during Pliocene and Quaternary times because it is located on the Caribbean subducting plate that sank below the South-American overriding plate and supported the SFB tectonic and sedimentary load. The Pliocene-Quaternary subsidence near the SFB deformation front was partially compensated by the belt uplift, and therefore, there was little tectonic subsidence or even some small tectonic uplift. A noticeable tectonic uplift took place in the continental shelf during Pliocene and Quaternary due to the SFB development. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,916,485,929]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although the numerical values derived from the tectonic subsidence ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,455,939,759]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"curves are not reliable, the comparison between values obtained in different times and in different regions might be significant. Thus, we have estimated tectonic subsidence/uplift values during the SFB development by subtracting the tectonic subsidence values obtained at the end of the Miocene from the values obtained during the Pliocene-Quaternary. While there has been tectonic uplift of approximately 0.6 km in the southern part of the SFB deformation front (Fig. 9e), in the central and northern parts of the deformation front there has been about 0.2 km of tectonic subsidence (Fig. 9f, g and 9h). In the continental shelf the tectonic uplift ranges from 2.6 km in the southern part of the belt (Fig. 9i), to 2.7–3 km in the central part (Fig. 9j and k), to slightly more than 2.2 km in the northern part (Figure 9l). Thus, the most similar behavior between the deformation front and the continental shelf in terms of subsidence/uplift has occurred in the southern portion of the belt where uplift has taken place at both sites. On the contrary, in the central portion of the belt, the behavior has been dramatically different with slight subsidence in the deformation front and large uplift in the continental shelf. The behavior has been intermediate in the northern portion of the belt with slight subsidence in the deformation front and moderate uplift in the continental shelf. Since these figures were achieved during a time span of approximately 5.3 Myr, the average rates of tectonic uplift inferred in the most uplifted region, i.e., the continental shelf, range from 0.4 to 0.6 mm/yr. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,778,700,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8.2. Vertical tectonic thickening ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,804,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The wedge vertical thickness has been estimated at different localities in the four depth-converted seismic profiles approximately perpendicular to the SFB (Fig. 4) and a map of iso-contours of wedge vertical thickness in the continental slope has been constructed by interpolating the available data (Fig. 10). The wedge vertical thickness near the deformation front, measured from the seafloor to the basal detachment, is less than $4\\mathrm{km}$ in the central profiles across the belt and increases to almost $6\\mathrm{km}$ in the southern profile, and to more than $5\\mathrm{km}$ in the northern profile (Fig. 10). The wedge vertical thickness near the shelf break is $10\\mathrm{km}$ in the northern profile and decreases progressively ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,507,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[164,66,196,80]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0761/28cf81d3ab874a55671bfa7877f8a1a5aabe2594b3ec6b2d0585ccc13d93907c.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,100,321,315]","code_body":null,"code_caption":null,"image_caption":"[\"COLOMBIAN BASIN \"]","image_footnote":"[]","img_path":"images/0664/f691a80acc3d4f9f5ba866b0c699e5d4fbaf01a7c992e0d189a21a732ac43933.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[332,100,505,315]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0817/18a2c68e8bb85a1b855d4107bad166110f8e81a9359aed57f0b352b3770dbe85.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,100,687,315]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0827/6e0bfee1febb3a3bee553ec078e6ef872fb6d44c6c4e8126e8ca66a15059104d.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[699,100,870,315]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0940/aa0af62fe04beb80e3171325ceca8f0fc97f8aa9191df7e4149ddbbdd15b2884.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,341,321,557]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0610/37d119e9415bdae54fec9e33b4d76b1b2472b8512ae3216fcfc41ce3a1e5e38f.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[334,325,507,556]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0239/42c5fae7e931a56025f8be9386dc83c83f2a281b2904ee7e267fe0e3446e0361.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[517,341,687,556]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0880/85caa72fc1d3f614ae5efc02d9538d5eb96fd711c9b54ba5a3a26f6025b7f7fc.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[700,341,870,556]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0992/c7d13252e134e1e420cb95cedb633bad287546d28f6f3da9df17ac9a1d7a1cd5.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[124,582,321,814]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0122/3c09f5fa34b82b95a221030399c27545f59123ae13e17beed38c194896f010bb.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[334,567,505,814]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0114/ab223762140a31a63d1e155ead2b03432db18b5359418ea6eda895942025ebfa.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,582,687,814]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0151/0a70179a9c37f5bfd525817496bcac15dc8be8408129c8b9652b4fead041c1ac.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[699,582,870,814]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 9. Depth versus time graphs illustrating twelve tectonic subsidence curves for: a), b), c) and d) the Colombian Basin; e), f), g) and h) the SFB deformation front; and i), j), k) and l) the continental shelf. C: Cretaceous, P: Paleocene, E: Eocene, O: Oligocene, M: Miocene, PQ: Pliocene-Quaternary. See Fig. 8c and caption of Fig. 4 for location. \"]","image_footnote":"[]","img_path":"images/0366/44ea758e33cc091e15c7cedc51aa7afc4b9f15350365ec62cdbdc801da21506f.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,873,487,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"to approximately $9\\mathrm{km}$ towards the southern profile. Thus, the difference between the wedge vertical thickness measured in the deformation front and in the continental shelf break is maximum in the central profiles across the belt, minimum in the southern profile, and intermediate in the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,873,613,886]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"northern profile. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,887,937,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The orthogonal thickness of the whole stratigraphic sequence has been measured at different localities in the four depth-converted seismic profiles approximately perpendicular to the SFB (Fig. 4) and an isopach ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,146,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[171,65,823,738]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 10. Map of isopachs and iso-contours of wedge vertical thickness of the SFB continental slope from the deformation front to the shelf break. The data used to construct this figure come from values measured in the depth-converted seismic lines shown in Fig. 4. The location of the seismic profiles displayed in Fig. 4 is shown. \"]","image_footnote":"[]","img_path":"images/0284/71eb8847b04e6067900c835287a0a10008d89849749bad21818a5f4e9c87c2fa.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,786,485,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"map has been constructed by interpolating the available data (Fig. 10). The amount of vertical tectonic thickening has been estimated by subtracting the orthogonal thickness of the stratigraphic sequence from the wedge vertical thickness at each locality. As expected, the amount of vertical tectonic thickening increases from the deformation front, where it is 0, to values around $0.5 - 2.1\\mathrm{km}$ in the shelf break area. The stratigraphic thickness contours and the wedge vertical-thickness contours (Fig. 10) are not strictly parallel but intersect each other more than once. This indicates that the sedimentary basin infilling did not fully control the SFB structure, so that variations occurred along strike. The greatest difference between the magnitude of the isopachs and that of the wedge ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,786,937,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"vertical thickness occurs at the central part of the belt, indicating a greater vertical tectonic thickening in this region. The minimum tectonic thickening occurs in the south part of the belt and an intermediate tectonic thickening occurs in the north part. Taking into account that this thickening occurred during a time span of approximately 5.3 Myr, the average rate of vertical tectonic thickening in the most thickened regions has been $0.4\\mathrm{mm / yr}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,878,937,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The absolute values of horizontal tectonic motion estimated in the section above have been compared with the values of vertical tectonic movement estimated in this section. The total horizontal motion has been estimated as the sum of the SFB shortening and the displacement ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodriguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"along the SFB basal detachment. The vertical motion has been estimated as the maximum tectonic uplift. The horizontal component of motion is far greater than the vertical one; thus, the horizontal motion component reaches percentages higher than $90\\%$ , whereas less than $10\\%$ has been accommodated as vertical motion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,146,179,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9. Recent motion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[58,172,186,186]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9.1. Morphostructure ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,199,485,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The SFB reaches around $130\\mathrm{km}$ in width in its central portion, measured from the Sinú Fault Zone to the deformation front, decreasing towards both edges to approximately $95\\mathrm{km}$ to the north and $110\\mathrm{km}$ so the south (Figs. 3 and 11a). The width of the continental shelf and its adjacent land, measured from the shelf break to the Sinú Fault Zone, reaches its maximum value (around $75\\mathrm{km}$ ) in the south part of the belt decreasing progressively to approximately $45\\mathrm{km}$ in the north. The continental slope can be divided into upper continental slope, bounded by the shelf break and a slope break within the continental slope, and lower continental slope, that extends from this slope break within the continental slope to the deformation front (Fig. 11). The width of the whole continental slope, i.e., from the shelf break to the deformation ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,157]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"front including both the upper and lower continental slopes, is maximum in the central part of the belt (almost $40\\mathrm{km}$ wide the upper continental slope and almost $30\\mathrm{km}$ wide the lower continental slope) and decreases both to the north (almost $30\\mathrm{km}$ wide the upper continental slope and almost $15\\mathrm{km}$ wide the lower continental slope) and to the south (slightly more than $15\\mathrm{km}$ wide the upper continental slope and $0\\mathrm{km}$ wide the lower continental slope). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,157,937,316]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The dip of the seafloor in the continental shelf and in the abyssal plain changes from less than a degree to slightly more than a degree to the NW, whereas the dip of the continental slope seafloor ranges from slightly less than $2^{\\circ}$ to slightly more than $7^{\\circ}$ to the NW (Fig. 4). The seafloor dip in the upper continental slope, from less than $2^{\\circ}$ to almost $4^{\\circ}$ , is lesser than the seafloor dip in the lower continental slope, from slightly more than $3^{\\circ}$ to slightly more than $7^{\\circ}$ . The seafloor dip in the upper and lower continental slopes increases from the central part towards both the north and south parts of the belt. The seafloor dip difference in the upper versus the lower continental slope increases from less than $2^{\\circ}$ in the central part of the belt up to almost $5^{\\circ}$ in the north and up to almost $4^{\\circ}$ in the south. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,316,937,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The seafloor in the continental shelf and in the abyssal plain is approximately a planar surface, but the continental slope seafloor may be either planar or irregular (Fig. 11). The width of the irregular portion ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[62,373,581,878]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0435/e6748ca8aabaad21fd8d907f45048d5f5b066b8509eb0c9c47d406f41ba0fa08.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[586,373,934,880]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 11. a) Slope map constructed using the interpretation of the seafloor in the available seismic profile grid showing the location of eleven bathymetric profiles displayed in b). The profiles are vertically exaggerated and their section lines are approximately perpendicular to the slope. AP: abyssal plain, LCS: lower continental slope, UCS: upper continental slope, CS: continental shelf. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0310/ed2cccee65473c336195c6f3ac0065f0fe678872c1545ecfbb2c5e3916146ac3.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,170]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of continental slope seafloor increases progressively from south to north, so that almost no irregularities occur in the south part of the belt, whereas the whole continental slope seafloor is irregular in the north part of the SFB (Fig. 11b). The boundary between regular and irregular bathymetry is oblique to the boundary between the upper and lower continental slope, so that, the seafloor in the upper continental slope displays a more regular bathymetry than that of the lower continental slope. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,66,616,76]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9.2. Neotectonics ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,92,937,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The seafloor in the SFB shows evidence of recent superficial processes, such as sedimentation, channel and canyon erosion, slumping, etc. (Vinnels et al., 2010). However, these processes have not been intense enough to mask the bathymetric expression of recent thrusts and related folds, recognized as elongated hills in the case of anticlines and elongated depressions in the case of synclines. Since all the structures involve approximately the same lithologies and submarine erosion is similar throughout the entire SFB, we can assume that an irregular ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[121,214,870,890]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 12. Structural map of the SFB shown in Fig. 3 overlapped on the map shown in Fig. 11 to illustrate the emergent structures domain and the buried structures domain. The geometry of the boundary between both domains has been drawn taking into account not only seafloor irregularities but geological elements such as folds, thrusts and tear faults. \"]","image_footnote":"[]","img_path":"images/0761/fc5083c75e2fd6bf29e5cf635518f4ecfdc3751fccfb63ccd8c9392d6879afe4.jpg","list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,484,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"seafloor is due to active underlying structures, while a regular seafloor, either because of erosion or because of structures mantled by sediment fill, indicates that the underlying structures are inactive. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,105,485,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Many structures located in the east portion of the SFB are not topped by seafloor irregularities, whereas many structures located in the westernmost part of the belt have caused bathymetric irregularities in the seafloor (Figs. 11 and 12). This suggests that the tectonic activity responsible for the development of thrusts and related folds propagated from ESE (inactive structures at present) to WNW (active structures in recent times). This is in accordance with the forward or piggy-back sequence of propagation of thrusts and related folds deduced from growth stratal patterns (Rodriguez, 2020; Rodriguez et al., 2021, 2022b). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,238,487,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The continental slope seafloor in the south edge of the belt is approximately regular, except for the most frontal structure that constitutes the deformation front in this area; thus, only this structure may be presently active, whereas the rest of structures seem to be inactive. The irregular geometry of the whole continental slope seafloor in the north part of the belt suggests that most structures located in this region are presently active (Figs. 11 and 12). The width of the region in which the structures have bathymetric expression, the number of structures developed below the irregular area and the seafloor irregularity is much greater to the north than to the south. This suggests that the tectonic activity of the belt in recent times has been much higher in the north sector of the belt than in the south one. This along-strike variation in tectonic activity could be explained in two different ways. a) If we assume that the Caribbean tectonic plate is slightly rotating clockwise with respect to the South American tectonic plate along an axis located south of the study area, then a larger amount of Caribbean Plate would subduct below the South American Plate in the north part of the SFB than in the south part. b) In the southern profile, the Pliocene and Quaternary sediments are very thick and are distributed throughout the entire profile (Fig. 4d). This could be the result of a possible increased sediment influx during the Pliocene-Quaternary coming from the Atrato River, located south of the study area (Connors, pers. com.). Because of increased sediment, the taper in this region could be maintained (or even be supercritical) without internal tectonic thickening, i.e., without structure activity. If this hypothesis were true, one of the most remarkable consequences would be that uplift produced onshore to the south of the study area could influence the SFB development. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,592,485,750]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In outline, the boundary between regular and irregular bathymetry is not strictly parallel to the strike of the thrusts and related folds developed in the continental slope (Fig. 12). Thus, some structures with no bathymetric expression to the south exhibit bathymetric irregularities to the north, suggesting that the tectonic activity responsible for the development of these particular structures stopped before in the south (inactive part of the structure) than in the north (active part of the structure). This points out that these structures propagated according to a combined frontal and lateral propagation model (Poblet, 2020). Although the available seismic profile grid is not dense enough, it seems that the position of the boundary between active and inactive structures in some localities is controlled by tear faults. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,751,487,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A positive bathymetric relief, much higher than the adjacent reliefs, developed above a thrust-related anticline located at the boundary between the upper and lower continental slopes in the north (bathymetric profiles 1 and 2 in Fig. 11b) and south-central (bathymetric profiles 6 and 8 in Fig. 11b) parts of the SFB. It is likely that the relief height is somehow related to the amount of thrust displacement and to the age of activity cessation of the underlying structure. Assuming that the temporal factor is the most important controlling parameter, we can state that the structure located at the boundary between the upper and lower continental slopes is younger than the surrounding structures. Thus, this structure would be an out-of-sequence thrust with respect to the general piggy-back thrust sequence. This timing is in accordance with that deduced from growth strata and cross-cutting relationships between this structure and adjacent structures in the geological interpretation of the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,65,862,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"seismic profiles (Rodriguez, 2020; Rodriguez et al., 2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,92,628,105]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10. Critical taper ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,118,670,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.1. Taper measurements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,143,937,315]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The taper angle is the sum of the bathymetric surface slope $(\\alpha)$ , measured from the deformation front to remarkable slope changes within the continental slope or to the continental shelf, and the basal detachment dip $(\\beta)$ (Davis et al., 1983). A large number of points corresponding to the seafloor and the basal detachment have been digitized in each of the four depth-converted seismic profiles depicted in Fig. 4. These points have been adjusted by linear best-fit functions to calculate the average slope of the submarine topography and the average dip of the basal detachment. The coefficients of determination $\\mathbb{R}^2$ obtained for the best-fit linear functions vary between 0.8 and almost 1 in the case of the submarine topographic slope, and from 0.9 to almost 1 for the basal detachment dip. The values of these coefficients, very close to 1, guarantee that the linear functions obtained are reasonable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,316,937,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The azimuths of the four depth-converted seismic profiles are N154E for the southernmost one and from N132E to N136E for the other three (Fig. 1b). The azimuth of these seismic profiles is not strictly perpendicular to the bathymetric contours (Fig. 11a) and to the trace of the main longitudinal structures on the structural SFB map (Fig. 3). Thus, the average slope of the submarine topographic surface and the average dip of the basal detachment obtained from the four seismic profiles using best-fit functions are not true but apparent dips. The azimuth of the depth-converted seismic profiles forms an angle from $3^{\\circ}$ to $34^{\\circ}$ with the azimuth of the maximum dip line of the main thrust surfaces and that of the main fold limbs. In order to estimate the true average slope of the submarine topographic surface and the true average dip of the basal detachment from their apparent average dips in the four seismic profiles, the following equation has been used: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,509,937,523]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\varphi = \\arctan \\left(\\tan \\varphi^ {\\prime} / \\cos \\gamma\\right), \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[507,533,937,585]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\varphi$ is the true dip, $\\varphi^{\\prime}$ is the apparent dip measured on the seismic profile using a best-fit function and $\\gamma$ is the angle between the seismic profile azimuth and the azimuth of the maximum dip line of the longitudinal main structural elements. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,586,937,742]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition, the four sections obtained from the seismic profiles (Fig. 13) have been compared with the bathymetric profiles obtained from the bathymetric map to double check them (Fig. 11b). The average dips of the upper and lower continental slopes in the section obtained from the center-south seismic profile (Fig. 13c) are very similar, while these dips are different in the bathymetric profiles perpendicular to the bathymetric contours constructed by ourselves (bathymetric profiles 5, 6 and 8 in Fig. 11b). The center-south seismic profile is more oblique to the SFB trend than the rest of profiles. To sort this out, the geometry of the lower continental slope in this profile has been modified (Fig. 13c) according to a 3D surface generated from our bathymetry and a new true slope has been calculated. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,745,937,889]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The taper angle in the lower continental slope ranges from $6.9^{\\circ}$ to $8.4^{\\circ}$ , while it ranges from $5.5^{\\circ}$ to $7.2^{\\circ}$ in the upper continental slope (Fig. 14). The taper angle estimated in the lower continental slope decreases from the central-south portion of the SFB to the north edge. This decrease occurs because the detachment dip in the north edge increases but the dip of the lower continental slope decreases more. The taper angle in the upper continental slope remains approximately constant along strike, except for the SFB south edge where it increases. This increase is due to an increment in the dip of the upper continental slope in the south part of the belt, although the detachment dip remains approximately constant along strike. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,507,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,68,860,712]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 13. Four simplified profiles showing the seafloor and basal detachment extracted from the four depth-converted seismic profiles across the SFB depicted in Fig. 4. In the center-south profile (c), the continental slope and the basal detachment underneath have been reconstructed using information from the bathymetric profiles displayed in Fig. 11b and from the rest of depth-converted seismic profiles (see text for an explanation), so that the grey lines come from the original profile. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0356/e4a622803a78ec4963b770a21ce419e5f9d557c40206ad760cd11655337762ce.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,783,381,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.2. Estimations of pore pressure, friction and strength ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,808,485,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The critical angle is the equilibrium angle established at the leading edge of a wedge that can slide along a basal detachment without undergoing internal deformation (Davis et al., 1983). In the SFB, folds related to thrusts and out-of-sequence thrusts giving rise to marked seafloor irregularities in some localities of the transition zone between the lower and upper continental slope (Fig. 11b) contributed to increase the taper, while normal faults and related toe thrusting, as well as erosional unconformities, developed in some portions of the continental slope and the continental shelf (Figs. 3 and 4) contributed to reduce the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,781,937,861]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"taper angle. These observations suggest that the SFB taper angle might have been subcritical in some periods and regions, and supercritical in others. A numerical analysis of the parameters that control the taper angle has been carried out in order to gain insight into the understanding of the causes of the across- and along-strike variations of the SFB taper angle. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,862,937,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Since the critical angle theory is fulfilled for mechanically homogeneous wedges (e.g., Davis et al., 1983), we have assumed that the SFB is a homogeneous wedge, and this has allowed us to perform a simple analytical approach. The fact that variations in the bathymetric surface inclination are reflected in slight changes in the basal detachment dip ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,952,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"16 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,65,870,672]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 14. Map showing the taper angles measured in the SFB continental slope constructed by interpolating values measured in the four depth-converted seismic profiles approximately perpendicular to the SFB shown in Fig. 4. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0229/142f469556f88732642faf1df4bbab415de68f9bd5496756075e8a17631aa466.jpg","list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,732,485,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Fig. 13) suggest that the SFB may be a mechanically homogeneous wedge, because in non-mechanically homogeneous wedges variations in the slope of the bathymetric surface are not associated with variations in the basal detachment dip (Suppe, 2007). Of course, the basal detachment dip is not the only determining factor to infer whether a wedge is homogeneous or heterogeneous, since, for instance, variations in the strength of the basal detachment could take place due to lithology and/or fluid pressure changes. In fact, we must keep in mind that the across- and along-strike variations described by Bernal-Olaya et al. (2015), Rodríguez (2020) and Rodríguez et al. (2021) rather suggest that the SFB is not strictly a homogeneous wedge. Thus, the results obtained should be taken with caution. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,891,485,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Since the geometry of a wedge depends on the pore pressure and internal friction (Davis et al., 1983; Dahlen, 1990), first of all, we have searched the literature for the most appropriate range of values for these ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,732,937,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"physical parameters to be applied to the SFB taking into account its characteristics. We have assumed that the pore pressure in the wedge $(\\lambda)$ is approximately equal to the pore pressure at the detachment $(\\lambda b)$ although we admit that the wedge pore pressure may be up to $10\\%$ lower than the detachment pore pressure, and that the friction coefficient in the wedge $(\\mu)$ is equal or greater than the basal friction coefficient at the detachment $(\\mu b)$ with a maximum difference of $30\\%$ between both values. The minimum pore pressure considered is 0.4, since we assume that the sediments within the wedge are close to the fracturing point, and therefore, their pore pressure must be greater than the hydrostatic pore pressure $(\\lambda h \\sim 0.4)$ . According to Hubbert and Rubey (1959), a pore pressure equal to 1.0 would correspond to a subaerial wedge in which there is no fluid in the pores. Thus, the value of 1.0 has been discarded for the SFB, but values up to 0.9 have been admitted because these values can be reached in overpressured wedges, such as the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodriguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"17 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,525]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Makran (Harms in Davis et al., 1983), Barbados (Moore and Von Huene, 1980), Aleutians (Hottman et al., 1979) and Oregon (Moore and Von Huene, 1980) wedges amongst others. The coefficients of internal friction, estimated from fracturing laboratory experiments, range from 0.6 to 1.0 (Dahlen, 1990), being 0.85 the universal value of Byerlee (1978) for most rocks; their corresponding internal friction angles $(\\varphi)$ are $30 - 45^{\\circ}$ . Since the resistance of rocks decreases in saturated samples with high clay content (Morrow et al., 1981), coefficients of friction below 0.6 (equivalent to friction angles below $30^{\\circ}$ ) have been also admitted because the sediments involved in the SFB include a large amount of clays. Summarizing, the range of values chosen are: a) pore pressure in the wedge $(\\lambda)$ and at the base of the wedge $(\\lambda b)$ from 0.4 to 0.9, b) coefficient of friction in the wedge $(\\mu)$ and at the base of the wedge $(\\mu b)$ from 0 to 1, and c) angle of friction $(\\varphi)$ (related to the coefficient of friction $\\mu$ ) from $10^{\\circ}$ to $45^{\\circ}$ . All the range of values for the pore pressures, coefficients of friction and friction angles, as well as the dips of the detachment measured in the four depth-converted seismic profiles approximately perpendicular to the SFB trend, have been introduced in equation (86) of Dahlen (1990) to obtain theoretical taper angles $(\\alpha + \\beta)$ , wedge strengths (W) and basal detachment strengths (F). This equation is a useful approximation for wedges with narrow taper angles, where the maximum compressional stress axis is almost horizontal and the basal detachment is very weak. The SFB accomplishes these requirements because: a) the taper angles range from 5.5 to $8.4^{\\circ}$ , i.e., they are small, b) thrusts and backthrusts with similar dips coexist, i.e., the maximum compressional stress axis is almost horizontal, and c) shales constitute the detachment horizon, i.e., the basal detachment is very weak. Varying the pore pressure 0.1 units and the friction angles $2^{\\circ}$ each time, we have obtained thousands of theoretical taper angles. These results have been compared with the actual taper values measured in the four depth-converted profiles. At first sight, the best pore pressures, coefficients of friction and strength values would be those whose resulting theoretical taper angles were more similar to the actual taper values measured in the depth-converted profiles, however, more issues need to be considered. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,527,485,698]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to determine the most appropriate pore pressure, friction and strength values for the continental slope, solutions that do not meet the following three conditions have been discarded: a) the difference between the taper angles estimated using the equation and those measured in the four seismic profiles must be as low as possible (we have assumed that less than $0.867^{\\circ}$ is a good approximation for the upper continental slope and less than $0.838^{\\circ}$ is a good approximation for the lower continental slope); b) the pore pressure, friction and strength values must be the same for the four transects because we have assumed that the wedge is approximately homogeneous; and c) the wedge pore pressure must be equal to or up to $10\\%$ lower than the detachment pore pressure, and the wedge friction coefficient must be equal to or up to $30\\%$ higher than the detachment friction coefficient. Three solutions ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,274]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"meet these conditions for the upper continental slope and four coincidences have been obtained for the lower continental slope (Table 1). We have chosen the solutions whose pore pressure, friction and strength values for the upper continental slope are more similar to those obtained for the lower continental slope following the principle that the wedge is approximately homogeneous (solutions framed by red rectangles in Table 1). The taper angle of the upper continental slope measured in the seismic profiles that differs more from the theoretically estimated taper angle is that of the south profile (underestimated by $0.86^{\\circ}$ ), whereas the taper angle measured in the seismic profiles that resembles more the estimated taper angle is that of the north profile (overestimated by $0.50^{\\circ}$ ) (Fig. 15). The greatest difference between the theoretically estimated taper angle and the measured taper angle for the lower continental slope occurs in the center-south profile (underestimated by $0.83^{\\circ}$ ), whereas the minimum difference occurs in the center-north profile (overestimated by $0.30^{\\circ}$ ) (Fig. 15). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,276,937,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To double-check the wedge strength and the basal detachment strength obtained for the active part of the SFB, i.e., mainly the lower continental slope, a technique created by Suppe (2007) has been applied. According to this author, the strength of active, mechanically-homogeneous wedges and the strength of their basal detaches can be directly determined from the linear covariation of surface slope $(\\alpha)$ and detachment dip $(\\beta)$ , without strong assumptions about the specific strength-controlling mechanisms. This strategy has been successfully applied to experimental dry sand wedges, the Niger Delta thrust belt, the Taiwan mountain belt, and a particular thrust responsible for an earthquake. The wedge strength and the basal detachment strength obtained for the lower continental slope of the SFB using the linear best-fit function and equations (3) and (4) of Suppe (2007) is 1.74 and 0.27 respectively, although we must admit that the $R^2$ coefficient is 0.4, which indicates that the fit is not very good as only three data points are available (Fig. 16). The difference between the values calculated from combining all the parameters in Dahlen (1990) equation and from the linear covariance strategy of Suppe (2007) is 0.287 for the wedge strength and 0.034 for the basal detachment strength, being always greater the values estimated using the linear covariance method. These small differences point out that the results obtained from both methods are consistent, and suggest that they could be reasonable values since they are similar and have been calculated employing methods unrelated to each other. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,593,939,699]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The values chosen in our simulation of the taper angles for the upper continental slope and for the lower continental slope are identical in terms of basal pore pressure, internal friction, basal friction and fault strength, but they differ in the internal pore pressure (0.6 for the upper continental slope and 0.7 for the lower continental slope) and in the wedge strength (1.93 for the upper continental slope and 1.45 for the lower continental slope). The fact that the calculated internal pore pressure is smaller in the upper continental slope with respect to that of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,776,939,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0935/95ec95891cd58d91ce9447174e6f359962958a899fbef15839959c6225066026.jpg","list_items":null,"page_idx":"17","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>TAPER</td><td>ANGLE</td><td>(α + β)</td><td>(°)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td>Seismic</td><td>profiles</td><td></td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td></td><td></td><td>South</td><td>C-South</td><td>C-North</td><td>North</td><td>λ</td><td>λb</td><td>μ</td><td>φ</td><td>μb</td><td>F</td><td>W</td></tr><tr><td>Lower</td><td>1</td><td></td><td>7.61</td><td>7.17</td><td>7.92</td><td>0.5</td><td>0.6</td><td>0.6</td><td>32</td><td>0.5</td><td>0.200</td><td>1.127</td></tr><tr><td>continental slope</td><td>2</td><td></td><td>7.53</td><td>7.26</td><td>7.63</td><td>0.4</td><td>0.5</td><td>0.9</td><td>41</td><td>0.7</td><td>0.350</td><td>2.289</td></tr><tr><td>(dmax=0.838°)</td><td>3</td><td></td><td>7.58</td><td>7.16</td><td>7.76</td><td>0.6</td><td>0.7</td><td>0.8</td><td>37</td><td>0.7</td><td>0.210</td><td>1.209</td></tr><tr><td></td><td>4</td><td></td><td>7.54</td><td>7.16</td><td>7.69</td><td>0.7</td><td>0.7</td><td>1.0</td><td>45</td><td>0.8</td><td>0.240</td><td>1.449</td></tr><tr><td>Upper</td><td>1</td><td>6.33</td><td>6.22</td><td>6.34</td><td>5.96</td><td>0.9</td><td>0.9</td><td>0.4</td><td>22</td><td>0.4</td><td>0.040</td><td>0.120</td></tr><tr><td>continental slope</td><td>2</td><td>6.33</td><td>6.30</td><td>6.33</td><td>6.22</td><td>0.6</td><td>0.7</td><td>1.0</td><td>45</td><td>0.8</td><td>0.240</td><td>1.931</td></tr><tr><td>(dmax=0.867°)</td><td>3</td><td>6.32</td><td>6.25</td><td>6.33</td><td>6.08</td><td>0.9</td><td>0.9</td><td>1.0</td><td>45</td><td>0.8</td><td>0.080</td><td>0.483</td></tr></table>","table_caption":"[\"Table 1 Theoretical taper angles, as well as pore pressures, coefficients of friction, friction angles and strength values, calculated for the lower and upper continental slope. The most plausible combinations of parameters are inside red rectangles. The taper angles obtained in the two most plausible solutions are represented graphically in Fig. 15. $\\\\mathbf{d}_{\\\\mathrm{max}}$ : maximum difference allowed between the measured taper angle and the theoretical one. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,507,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"18 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[208,66,786,262]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 15. Graphical comparison between the taper angles measured in the four depth-converted profiles approximately perpendicular to the SFB shown in Fig. 4 and the theoretical taper angles obtained, both in the lower continental slope and in the upper continental slope. The values of the taper angles measured in the seismic profiles have been extracted from Fig. 14, while the values of the theoretical taper angles have been extracted from Table 1. \"]","image_footnote":"[]","img_path":"images/0856/28766075944dbd390b5f3d34c2f0f64deb49f08c331cdd7715761b74ca480153.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[208,330,789,607]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 16. Graph showing the bathymetric slope versus the basal detachment dip, in which the values measured for the lower continental slope in three depth-converted seismic profiles shown in Fig. 4 have been plotted. The wedge strength (W) and the basal detachment strength (F) have been estimated from the linear best-fit function according to Suppe (2007) method. \"]","image_footnote":"[]","img_path":"images/0985/224464cd5f5334d567e244e0288bd2b6bcec4693a58a8f0d901a2ac621416098.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,665,485,825]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the lower continental slope is in accordance with the taper angle measurements, lower in the upper continental slope and higher in the lower continental slope. Thus, the wedge may not be strictly homogenous, but it does not differ too much because the differences in the values obtained are small. The taper-angle controlling parameters obtained here are different from those deduced by previous authors because: a) the input data and the methodology employed here are different from those of previous authors, b) Toto and Kellogg (1992) analysis is based on five topographic profiles whereas the basal detachment dip is supposed to be a constant value, and c) Bernal-Olaya et al. (2015) employed only two sections across the belt derived from the geological interpretation of seismic profiles. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,844,468,857]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3. Temporal and spatial variations of taper angle and pore pressure ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,870,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As mentioned above, some features in the SFB such as thrusts and out-of-sequence thrusts, normal faults and related toe thrusts, and erosive unconformities are responsible for the modification of the taper angle. Nevertheless, taking into account that the basal pore pressure, the internal friction and the basal friction obtained for the upper and lower ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,665,937,824]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"continental slopes are equal, while the internal pore pressure is somewhat different (Table 1), it seems reasonable to assume that variations in internal pore pressure may have also contributed to taper angle variations. To illustrate these variations, we have constructed a graph in which the bathymetric slope is plotted versus the basal detachment dip for different internal pore pressure values (Fig. 17). The basal pore pressure, internal friction and basal friction values employed to construct the graph (0.7, 1 and 0.8 respectively) are the ones chosen in the section above for both the upper and lower continental slopes. The bathymetric slopes and detachment dips measured for the upper and lower continental slopes in each of the seismic profiles have been plotted on this graph. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,825,937,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There is a slight discrepancy, whose maximum value is 0.1 units, between the pore pressure values estimated numerically in the section above (Table 1) and the pore pressure values obtained graphically from the bathymetric slope versus basal detachment dip graph shown in Fig. 17. The numerically-estimated pore pressure for the upper continental slope is 0.6 (Table 1), whereas the graphically-estimated pore pressure is generally lower (comprised between approximately 0.5 and 0.55) (Fig. 17). The reason is that the numerically-estimated taper ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"19 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,66,636,365]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 17. Graph showing the bathymetric slope $(\\\\alpha)$ versus the basal detachment dip $(\\\\beta)$ for different values of pore pressure and fixed values of basal pore pressure, coefficient of friction and coefficient of basal friction. The values measured for the lower and upper continental slopes in the four depth-converted seismic profiles shown in Fig. 4 have been plotted on the graph. A possible future path for part of the belt is also illustrated. UCS: upper continental slope, LCS: lower continental slope. \"]","image_footnote":"[]","img_path":"images/0271/caecd2523304b0c97491cab474df4eec2fb5f9995471ee1132f7aa340dc02883.jpg","list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[55,390,485,549]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"angles are higher than the measured ones (Fig. 15), except for the south profile in which the graphically-estimated pore pressure is higher (around 0.65) because the numerically-estimated taper angle is lower than the measured one. A similar situation occurs for the lower continental slope where the numerically-estimated pore pressure is 0.7 (Table 1), whereas the graphically-estimated pore pressure is lower (it ranges between 0.65 and 0.7) (Fig. 17) in the north and center-north profiles -in this case the numerically-estimated taper angles are higher than the measured ones-, but on the contrary the numerically-estimated pore pressure in the center-south profile is lower than the graphically-estimated one (it ranges between 0.7 and 0.75) -in this case the numerically-estimated taper angle is lower than the measured one-. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,549,485,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We documented above that most structures in the lower continental slope are still active, whereas many structures in the upper continental slope are inactive (Fig. 12). Thus, if the present-day conditions remain constant, as the wedge advances seawards and involves undeformed rocks in the Colombian Basin, a new active lower continental slope may develop eastwards. As a consequence, the present-day, active, lower continental slope might become the inactive upper continental slope in the future, and the present-day, inactive, upper continental slope will become part of the continental shelf. If correct, the graph in Fig. 17 might illustrate the path of the taper angle of the present-day lower continental slope over time in each of the profiles across the belt. Except for the south section where there is no lower continental slope and most structures are inactive, and therefore, we are unable to predict its future evolution, the internal pore pressure of the wedge will decrease from values around 0.65–0.7 to values around 0.5–0.55 (black dashed arrows in Fig. 17). The manner in which pore pressure decreases will be related to the wedge geometry is different along strike. The internal pore pressure decrease in the central part of the wedge will be high (approximately from 0.15 to 0.2 units) and will be accompanied by a decrease in the seafloor slope and an increase in the basal detachment dip. The internal pore pressure decrease in the north portion of the wedge will be small (0.1 unit) and will go along with a decrease in the seafloor slope while the basal detachment dip will remain constant. As a result, both the taper angle and the internal pore pressure of the different along-strike regions of the SFB will become more similar. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,878,485,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Three types of regions are recognized in the SFB continental slope based on the spatial variations of the taper angle (Fig. 14) and the internal pore pressure (Fig. 18). a) A region with relatively high values of taper angle and internal pore pressure is restricted to the lower ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,390,939,537]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"continental slope in the center-south part of the SFB. b) Two regions with intermediate values of taper angle and internal pore pressure occupy the lower continental slope in the north and center-north part, as well as the upper continental slope in the south part of the belt. c) A region with relatively low values of taper angle and internal pore pressure is restricted to most of the upper continental slope except for the southernmost part. The maps in Figs. 14 and 18 show that the differences between the taper angle and internal pore pressure in the upper continental slope and those in the lower continental slope are maxima in the center-south part of the belt and decrease northwards where both values approximate each other. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,554,887,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.4. Relationships between pore pressure and sediment thickness ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,580,937,658]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As we will see below, some structural and bathymetric differences have been recognized in the SFB continental slope from north to south, however, the greatest difference corresponds to the sediment thickness (Fig. 4 in Rodríguez et al., 2021). This is why we suggest that sediment thickness may be one important controlling parameter of pore pressure variations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,659,937,829]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The pore pressure in the lower continental slope is higher than in the upper continental slope (Figs. 17 and 18). Thus, the degree of compaction of the sediments in the upper continental slope is greater, because the greater grain packaging the larger fluid loss and the larger pore pressure reduction. This is consistent with the fact that the stratigraphic succession prior to the SFB formation, as well as the succession coeval to the SFB formation, is substantially thicker in the upper continental slope than in the lower continental slope (Fig. 4 in Rodríguez et al., 2021) (Fig. 10). Perhaps the fact that the structures in the upper continental slope are generally older than those developed in the lower continental slope (Fig. 12), has favored an additional compaction due to tectonic load, which has taken place to a much lesser extent in the lower continental slope (Fig. 10). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,831,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The pore pressure in the upper continental slope is similar in the north, center-north and center-south profiles, whereas it is higher in the south profile (Figs. 17 and 18). The main along-strike stratigraphic difference in the upper continental slope is the lesser thickness of strata deposited before the development of the SFB in the southern part (Fig. 4 in Rodríguez et al., 2021) which probably suffered little compaction, i.e., the pores were hardly modified and little fluid was expelled. The high and fast sediment supply in this region during the SFB development ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[490,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"19","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"20 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[124,65,870,672]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 18. Map of pore pressure variation in the SFB continental slope for fixed values of basal pore pressure, coefficient of friction and coefficient of basal friction. The map has been constructed by interpolating values obtained from the four depth-converted seismic profiles approximately perpendicular to the SFB shown in Fig. 4. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \"]","image_footnote":"[]","img_path":"images/0011/3eb8b9081a2c7915b66f2ccf318f058c4571800404fdea36c02ef67b2ecfac23.jpg","list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,733,485,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(Fig. 4 in Rodríguez et al., 2021) may have caused a load increase on uncompacted sediments with open pores preventing fluid scape (e.g., Saffer and Bekins, 2006; Shi and Wang, 1985) leading to a pore pressure increase. The presence of more mud diapirs in the south portion of the upper continental slope (Fig. 3) supports the hypothesis of a higher pore pressure. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,813,485,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The pore pressure in the lower continental slope is similar in the north and center-north profiles, whereas it is much higher in the center-south profile (Figs. 17 and 18). The main along-strike stratigraphic difference in the lower continental slope is the extremely thinner sedimentary succession in the center-south profile with respect to the rest of profiles (Fig. 4 in Rodríguez et al., 2021). Similarly to the southern part of the upper continental slope, the thin sedimentary succession previous to the SFB formation probably suffered little compaction. Thus, the fast deposition of sediments synchronous to the SFB formation above poorly ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,733,937,761]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"compacted sediments caused a notable increase in pore pressure in the center-south region. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,778,766,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.5. Discussion on the taper angle analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,804,937,896]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The taper angle analysis performed above assumes an approximate homogeneous wedge, with basal pore pressure, and coefficients of internal and basal friction being constant everywhere, and admits that the variation in pore pressure in the wedge relative to the basal pore pressure can reach a $10\\%$ . No significant differences between the pore pressure in the wedge and the pore pressure at the detachment have been considered due to the reasons below. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,910,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"a) The equality between pore pressures in the wedge and at the detachment is supported by measurements taken in some wedges ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,42,142,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodriguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,937,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[490,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"20","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"21 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[78,65,487,143]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"such as Taiwan (Suppe and Wittke, 1977), as well as by successful analyses of the taper angle in Taiwan (Davis et al., 1983; Dahlen, 1990; Dahlen et al., 1984), Barbados (Davis et al., 1983; Dahlen, 1990), and other belts such as the Himalayas, Japan, Peru, Java, Sunda, Guatemala, Aleutians, Oregon, and Makran (Davis et al., 1983). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,145,485,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"b) In all the analyses of the SFB taper angle carried out up to date (Toto and Kellogg, 1992; Bernal-Olaya et al., 2015) the pore pressures in the wedge and at the detachment are considered to be equal. Thus, we have followed this assumption suggested by other authors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,211,485,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Nevertheless, we are aware that, for example, in the Nankai accretionary wedge, the fluid pressure in the wedge is lower than at the basal detachment. Thus, the pore pressure measured within the wedge is 0.58 (Kitajima et al., 2017), whereas the pore pressure near the megathrust fault at the base the wedge reaches approximately 0.85 (Kitajima and Saffer, 2012), so that its variation is slightly greater than $30\\%$ . Thus, in order to explore more possibilities in the SFB, we have relaxed the conditions; we have eliminated the limits to the difference between the values of pore pressure in the wedge and at detachment, and between the values of the coefficient of friction in the wedge and at detachment, as long as the theory is fulfilled, i.e., the wedge pore pressure must be equal to or less than the detachment pore pressure, and the wedge coefficient of friction must be equal to or greater than the detachment coefficient of friction. We have looked for those combinations of values whose: a) taper angle obtained is equal to that measured in the seismic profiles or whose difference is less than $0.838^{\\circ}$ and $0.867^{\\circ}$ in the lower and upper continental slope respectively, b) the basal detachment strength and the wedge strength obtained for the lower continental slope are equal to the values obtained using Suppe (2007) best-fit function or their difference is less than 0.04 and 0.3 respectively, and c) the values of the pore pressure and coefficients of friction obtained for the lower and upper continental slopes are as similar as possible. The result obtained is the same as with the more restrictive conditions. This means that the results obtained in relation to these parameters do not depend on the starting assumptions used regarding the limits imposed to the difference between the pore pressures at the wedge and at the detachment, and the coefficients of friction at the wedge and at the detachment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,580,485,633]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to estimate the pore pressure, friction and strength values from the taper angle analysis, we have assumed that the four cross sections presented have reached a critical taper state. However, this might not be the case in the particular situations listed below. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,645,485,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"a) According to our results there is higher pore pressure in the lower continental slope relative to the upper slope in the center-south, center-north and north profiles across the belt (Figs. 17 and 18). Another possibility is that the lower continental slope is subcritical and has not reached the critical taper yet. Consistent with this is the fact that this is the area of active deformation with thrusts breaching the seafloor (Fig. 12), and therefore, thickening this part of the wedge. \",\"b) Our results point out that the pore pressure in the upper continental slope is higher in the south profile than in the rest of profiles (Figs. 17 and 18). This region is the least deformed (Fig. 4), however, one would expect the opposite considering the higher pore pressure. As mentioned in a section above, the occurrence of a thick Pliocene-Quaternary succession all along the south profile may suggest an increased sediment supply by the Atrato River. Because of increased sediment, the taper could be maintained, or even be supercritical, without internal tectonic thickening. This could explain why this section is less deformed despite having a higher pore pressure. \"]","page_idx":"21","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[58,897,354,909]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11. Aseismic subduction and trench absence ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[78,923,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The SFB has been interpreted as the front of the westernmost portion ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,143]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of an accretionary prism, known as South Caribbean Deformed Belt, developed as a consequence of the subduction of the Caribbean tectonic plate underneath the South American tectonic plate. This region exhibits at least two peculiarities with respect to other subduction zones: low seismicity related to the subduction zone and absence of a trench near the deformation front. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,143,937,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"According to available earthquake catalog compiled by the Arcila Rivera (2018), there have been very few earthquakes in the study area from 1610 to 2014, and their hypocenters are located at depths relatively close to the boundary between the subducting and the overriding plates. Given that the SFB slip rate calculated above is small (average shortening rate in the overriding plate from 3 to $5\\mathrm{mm / yr}$ and average rate of basal detachment displacement from 6 to $17\\mathrm{mm / yr}$ ) and that young sediments (Pliocene and Quaternary), probably under-compacted and with a high porosity, subduct, this may prevent brittle shear localization. This probably reduces the width of the seismogenic zone resulting in aeismic subduction (e.g., Byrne et al., 1988; Toto and Kellogg, 1992; Zhang et al., 1993). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,303,937,474]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The geological interpretation of the seismic profiles shows no trench separating the subducting and overriding tectonic plates (Fig. 4). The absence of a trench could be explained as the result of a very slight bending of the subducting plate as shown by the gentle dips of Colombian Basin reflectors in this region (Fig. 4). The reason for this gentle bending is that the Caribbean Plate subducts with a very low dip under the South American Plate (e.g., Bernal-Olaya et al., 2015). Moreover, very few normal faults were active in the Colombian Basin during the development of the SFB (Fig. 3) and their displacement was very small indicating a small amount of extension. Assuming that these faults developed as a consequence of the flexure in the outer part of the lithospheric flexure hinge, this also supports a gentle bending of the subducting plate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,489,705,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12. Morphostructural zoning ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,515,670,528]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.1. Across strike regions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,540,937,659]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study area displays variations from northwest to southeast, i.e., perpendicularly to the SFB trend, in terms of bathymetry, stratigraphy and tectonics. Thus, apart from the portion of the Colombian Basin adjacent to the SFB, three regions have been identified within the SFB: a) the lower continental slope, b) the upper continental slope, and c) the continental shelf. The principal characteristics of these zones are illustrated in Fig. 19 and mentioned in Table 2, and their main differential features are described below from the outer to innermost zones using our own data and data from Rodríguez et al. (2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,673,726,684]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.1.1. Colombian Basin versus SFB ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,686,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Colombian Basin, developed in the abyssal plain, is located in front of the SFB. The SFB deformation front, which coincides with a slope change, separates it from the SFB, developed in the continental slope, the continental shelf and the onshore area (Figs. 3, 4, 11 and 13). The seafloor in the Colombian Basin is sub-horizontal to gently inclined to the NW $(0.3 - 1.4^{\\circ})$ and very regular because only few isolated faults and folds exhibit bathymetric expression, while the seafloor in the SFB reaches greater dips and may be very irregular (Figs. 4, 11 and 13). The Colombian Basin is constituted by a thin succession of Cretaceous and Cenozoic strata over Jurassic rocks, whose thickness increases towards the SFB, while the SFB is made up of a thicker Cenozoic succession which also thickens landwards (Fig. 4). In general, most of the Cenozoic strata are undeformed in the Colombian Basin, while they are quite deformed in the SFB (Fig. 4). Normal faults developed during Cretaceous-Paleocene time, some of them affecting Eocene, Oligocene and Miocene strata, and some of them reactivated as normal faults during recent times, are the most common structures in the Colombian Basin (Figs. 3-5). On the contrary, thrusts and related folds, tear faults, different types of normal faults and mud diapirs occur within the SFB. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[490,950,507,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"21","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"22 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[127,65,872,501]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 19. Idealized section across the SFB and part of the Colombian Basin showing the across-strike zones, the predominant structures in each zone and the main features of the most significant parameters. See Table 2 for a summary of the main features. \"]","image_footnote":"[]","img_path":"images/0392/d61f22f5a965d9318372ad0e22ea02d45e2fb47ea8c5bb7a710b9df6fa97a5cf.jpg","list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[58,583,937,858]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0775/68d9215f89fea250f6e3b3d14bc41e0d65acb0918209b43cba37b4fedf42d20b.jpg","list_items":null,"page_idx":"22","sub_type":null,"table_body":"<table><tr><td></td><td>SFB LOWER CONTINENTAL SLOPE</td><td>SFB UPPER CONTINENTAL SLOPE</td><td>SFB CONTINENTAL SHELF</td></tr><tr><td>SEAFLOOR DIP</td><td>2 to >7° to the NW</td><td><1-4° to the NW</td><td>0 to 0.1-1.2° to the NW</td></tr><tr><td>ACTIVE STRUCTURES</td><td>Fault-related folds</td><td>Some fault-related folds</td><td>A few mud diapirs</td></tr><tr><td>STRATIGRAPHIC THICKNESS</td><td>2 km of Cenozoic (increases from deformation front to upper-lower continental slope boundary)</td><td>5 km of Cenozoic (increases from upper-lower continental slope boundary to shelf break)</td><td>5 to >7 km of Cenozoic (increases from shelf break landwards)</td></tr><tr><td>AVERAGE THRUST SPACING</td><td>3-5 km (decreases from deformation front to upper-lower continental slope boundary)</td><td>>1-3 km (decreases from upper-lower continental slope boundary to shelf break)</td><td>>5 km</td></tr><tr><td>DETACHMENT DIP</td><td>>1 to >3° to the SE</td><td>>3 to <4° to the SE</td><td>>3 to <4° to the SE</td></tr><tr><td>DETACHMENT DEPTH</td><td>>5 km (increases from deformation front to upper-lower continental slope boundary)</td><td><10 km (increases from upper-lower continental slope boundary to shelf break)</td><td>9 to >10 km (increases from shelf break landwards)</td></tr><tr><td>WEDGE VERTICAL THICKNESS</td><td>>2 km (increases from deformation front to upper-lower continental slope boundary)</td><td><10 km (increases from upper-lower continental slope boundary to shelf break)</td><td>>8 to >10 km (increases from shelf break landwards)</td></tr><tr><td>VERTICAL THICKNESS/ STRATIGRAPHIC THICKNESS</td><td>1-1.3 (increases from deformation front to upper-lower continental slope boundary)</td><td><1.3 (increases from upper-lower continental slope boundary to shelf break)</td><td>1.3-1.4</td></tr><tr><td rowspan=\"3\">TECTONIC SUBSIDENCE - UPLIFT</td><td>Fast subsidence (Paleocene)</td><td>Fast subsidence (Paleocene)</td><td>Fast subsidence (Paleocene)</td></tr><tr><td>Slow subsidence (Eocene, Oligocene, Miocene)</td><td>Slow subsidence (Eocene, Oligocene, Miocene)</td><td>Moderate subsidence (Eocene, Oligocene, Miocene)</td></tr><tr><td>0.2 km of slow subsidence to 0.6 km of slow uplift increasing from deformation front to upper-lower continental slope boundary (Pliocene-Quaternary)</td><td>Slow uplift increasing from upper-lower continental slope boundary to shelf break (Pliocene-Quaternary)</td><td>2.2-3 km of rapid uplift (Pliocene-Quaternary)</td></tr><tr><td>TAPER ANGLE</td><td>7 to >8°</td><td>>5 to >7°</td><td></td></tr><tr><td>PORE PRESSURE</td><td>0.65-0.73</td><td>0.51-0.66</td><td></td></tr></table>","table_caption":"[\"Table 2 Main features of the three SFB zones defined across strike illustrated in Fig. 19. The data presented in this table comes from ourselves and from Rodriguez et al. (2021). \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[57,876,487,929]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tectonic subsidence was fast during Paleocene both in the Colombian Basin and in the SFB, and slow during Eocene, Oligocene, and Miocene, although it increases towards the SFB (Fig. 9a, 9b, 9c and 9d). Moderate tectonic subsidence occurred during Pliocene and Quaternary in the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,876,937,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Colombian Basin, while slow tectonic subsidence and fast tectonic uplift occurred in the SFB. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,952,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"22","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"23 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[58,66,268,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.1.2. SFB lower continental slope ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,79,485,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The lower continental slope is the most external zone of the SFB. A slope change constitutes the boundary between the lower continental slope and the upper continental slope (Figs. 3, 11 and 13). In this area, the seafloor is the most inclined and irregular of the entire SFB, because many structures are still active (Figs. 11-13). This region is formed by the thinnest Cenozoic succession of the SFB (Figs. 4 and 10). Structures such as backthrusts and related folds, continental-slope normal faults with associated toe thrusts, and normal faults reactivated as reverse faults including related folds only occur in this domain (Figs. 3 and 4). The average thrust spacing is intermediate between that of the upper continental slope and that of the continental shelf. Both the thrust dip and displacement are the smallest ones of the entire SFB. The Pliocene-Quaternary piggy-back, syn-tectonic basins related to fold growth and thrust emplacement are the shallowest and narrowest. The dip of the basal detachment, where thrusts branch at depth forming an imbricate thrust system, the depth to the basal detachment, the wedge vertical thickness and the vertical tectonic thickness compared to the original stratigraphic thickness are the smallest of the whole SFB (Figs. 4, 10 and 13). The slowest Eocene-Miocene and Pliocene-Quaternary tectonic subsidence and the slowest Pliocene-Quaternary tectonic uplift of the whole SFB occurred in this region (Fig. 9e, 9f, 9g and 9h). Both the taper angle and the internal pore pressure are the highest of the entire SFB (Figs. 14, 15, 17 and 18, and Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,395,268,408]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.1.3. SFB upper continental slope ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,409,485,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The upper continental slope is the intermediate zone of the SFB. The shelf break, which is a slope change, separates the upper continental slope from the continental shelf (Figs. 3, 11 and 13). The seafloor dips less and exhibits less irregularities than the lower continental slope but it dips more and is more irregular than the continental shelf, since some structures developed near the upper-lower continental slope boundary are still active (Figs. 11-13). The Cenozoic strata that constitute this region exhibit intermediate thicknesses between those of the lower continental slope strata and those of the continental shelf strata (Figs. 4 and 10). The most important out-of-sequence thrusts occur in this region and constitute the boundary between the upper and the lower continental slopes. The average thrust spacing is the smallest one of the study area (Figs. 3 and 4). Both the thrust dip and displacement are the highest ones. The depth and width of the Pliocene-Quaternary piggy-back, syntectonic basins related to folds and thrusts are intermediate in between those of the lower continental slope and those in the continental shelf. The thrusts branch at depth with the basal detachment forming an imbricate thrust system, and the dip of the detachment is the steepest one. The depth to detachment, the wedge vertical thickness, and the vertical tectonic thickness versus the stratigraphic thickness are intermediate values in between those of the lower continental slope and those of the continental shelf (Figs. 4, 10 and 13). Intermediate Eocene-Miocene tectonic subsidence and intermediate Pliocene-Quaternary tectonic uplift between those of the lower continental slope and those of the continental shelf occurred in this region. The taper angle and the internal pore pressure are the smallest of the SFB (Figs. 14, 15, 17 and 18, and Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,778,233,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.1.4. SFB continental shelf ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,790,485,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The continental shelf is the most internal zone of the SFB (Figs. 3, 11 and 13). The seafloor is the less inclined and most regular of the SFB, since most structures are inactive (Figs. 11-13). This domain is made up by the thickest Cenozoic succession of the SFB (Fig. 4). Most the mud diapirs and shale cored anticlines with crestal normal faults, and continental-shelf normal faults, some of them reactivated as reverse faults or as normal faults several times, only occur in this domain (Figs. 3 and 4). The average thrust spacing is the largest one. The Pliocene-Quaternary basins filled in with young syn-tectonic strata are the deepest and widest of the entire SFB. The dip of the basal detachment, from which thrusts emanate, the depth to the basal detachment, the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"wedge vertical thickness, and the vertical tectonic thickness versus the stratigraphic thickness are the greatest of the entire SFB (Figs. 4 and 13). The fastest Eocene-Miocene tectonic subsidence and the fastest Pliocene and Quaternary tectonic uplift of the entire SFB occurred in this region (Fig. 9i, 9j, 9k and 9l). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,146,663,158]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.2. Along strike regions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,172,937,317]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Apart from variations from the external to the internal zones of the belt, there are also along-strike changes, i.e., from southwest to northeast, in terms of characteristics of the structures, as well as stratigraphic and bathymetric features. The belt could be divided into three different regions: a) a south region, which is the south salient under the influence of the Uramita Fault; b) a central region, which is the proper SFB s.s.; and c) a north region under the influence of the Magdalena Fan and Canoas Oblique Ramp. The most important characteristics of these zones are illustrated in Fig. 20 and presented in Table 3, and their main differential features are described below from south to north using our own information plus Rodríguez et al. (2021) data. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,330,823,343]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.2.1. South salient influenced by the Uramita Fault ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,343,937,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This region corresponds to the south part of the SFB; an entrant separates it from the SFB s.s. to the north, and the Uramita Fault separates it from the North Panama Belt to the south (Figs. 3 and 20 and Table 3). This portion of the belt is narrower than the SFB s.s. but similar to the north region. Unlike the rest of zones, only upper continental slope occurs in this region. The dip of the seafloor in the continental shelf is the lowest of the entire SFB, whereas that of the portion of the Colombian Basin just in front of this region is the highest (Table 3). The bathymetry of the continental slope is the most regular of the belt suggesting almost no recent tectonic activity (Figs. 11 and 12). The Cretaceous-Miocene strata exhibit an intermediate thickness in the frontal part and the highest near the shelf break, so that the $2\\mathrm{km}$ difference between both thicknesses is intermediate (Figs. 4 and 10), whereas the sedimentary succession that fills in piggy-back basins is the thickest one. The vertical thickness of the wedge in the deformation front is the highest, whereas in the shelf break is the lowest, and therefore, the vertical thickness in the shelf break is almost 1.5 times that of the deformation front, i.e., the lowest of the entire SFB (Figs. 4 and 13), and the vertical tectonic thickening, i.e., the vertical thickness minus the stratigraphic sequence thickness, is also the lowest. The basal detachment exhibits the highest dip beneath the upper continental slope (Figs. 4 and 13). The depth to detachment beneath the deformation front is intermediate and the depth to detachment beneath the shelf break is the lowest, thus the depth to detachment beneath the shelf break is slightly more than 1 time that beneath the deformation front, being the lowest ratio of the entire SFB. Thrusts and thrust-related folds exhibit an approximately N-S strike, and their average spacing in the deformation front is the lowest together with that of the SFB s.s., whereas in the shelf break is the highest (Fig. 3). The variation between the thrust spacing in the deformation front and in the shelf break, as well as the number of thrusts, is the smallest one of the whole SFB. An intermediate number of tear faults and mud diapirs with related crestal normal faults and folds occur in this region, while the number of continental-shelf normal faults is the lowest (Fig. 3). The deformation front in the south salient is made up of large detachment folds and a few, minor WNW-directed thrust faults emanating from the basal detachment (seaward-vertent structures) (Fig. 4). The shortening measured here is the smallest of the entire SFB. Pliocene-Quaternary tectonic uplift in the deformation front occurred in this region in contrast to the tectonic subsidence occurred in the other regions; the uplift in the continental shelf is an intermediate value. Thus, this region exhibits the most similar behavior between the deformation front and the shelf break in terms of subsidence/uplift because uplift has taken place at both sites (Fig. 9). The taper angle measured in the upper continental slope (Figs. 14 and 15) and the pore pressure value estimated in the upper continental slope are the highest ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[490,950,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"23","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"24 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[161,65,836,578]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 20. Idealized map of the SFB showing the along-strike zones and the predominant structures in each zone. See Table 3 for a summary of the main features. \"]","image_footnote":"[]","img_path":"images/0616/a0984626019e5063e0179cb31da751f5f98389893a38972173bf71d204a86101.jpg","list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,616,304,629]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ones of the whole belt (Figs. 17 and 18). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,643,154,654]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.2.2. SFB s.s ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,656,485,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This region is the central portion of the SFB separated by a gradual boundary with the north part of the belt, and by an inlet from the south salient (Figs. 3 and 20 and Table 3). The SFB s.s. is the widest portion of the belt. The ratio between the width of the upper continental slope and that of the lower continental slope is extremely variable from less than 1 to 6 times the width of the lower continental slope. The dip of the lower continental slope seafloor may be up to 4 times that of the upper continental slope. The dip of the continental shelf is intermediate between that of the north and south regions, and that of the Colombian Basin in front of this region is the lowest (Table 3). The degree or irregularity of the bathymetry of the continental slope is intermediate in between that of the north and south regions (Figs. 11 and 12). The thickness of the Cretaceous-Miocene strata in the frontal part is the lowest and it is intermediate near the shelf break, so that the difference between both thicknesses from 3 to $5\\mathrm{km}$ is the highest one of the whole SFB (Figs. 4 and 10), whereas the succession that fills in piggy-back basins is the thinnest one of the whole SFB. The wedge vertical thickness in the deformation front is the lowest and is intermediate in the shelf break, and therefore, the wedge vertical thickness in the shelf break ranges from almost 2.5 to slightly more than 3 times that of the deformation front, and is the most pronounced ratio of the entire SFB (Figs. 4 and 13), ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,616,937,931]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and the vertical tectonic thickening is intermediate. The basal detachment dip beneath the lower continental slope is the lowest one of the entire SFB, but increases to the highest values beneath the upper continental slope (Figs. 4 and 13). The depth to detachment beneath the deformation front is the lowest and the depth beneath the shelf break is intermediate; the depth to detachment beneath the shelf break is from almost 1.5 times to almost 2 times higher than that beneath the deformation front, being the highest ratio of the entire SFB. The strike of the thrusts and related folds is NNE-SSW, and their average spacing around the deformation front is the lowest together with that of the south region, whereas in the shelf break is the lowest (Fig. 3). The $1 - 2\\mathrm{km}$ difference between the average thrust spacing in the deformation front versus the one at the shelf break, as well as the number of thrusts, are the highest ones of the whole SFB. The largest number of tear faults, mud diapirs with related crestal normal faults and shale cored anticlines, and continental-shelf normal faults occur in this region (Fig. 3). The deformation front in the SFB s.s. consists of a symmetrical triangular zone made up of SE-directed thrusts (backthrusts) (landward-vergent structures) in the outer part, and NW-directed thrusts (seaward-vergent structures) in the inner part, all of them emanating from the basal detachment. In some portions of the SFB s.s., the deformation front is a poorly developed triangular zone formed by an imbricate thrust system with sporadic backthrusts (Fig. 4). The shortening measured is the highest of the entire SFB. The maximum amount of tectonic subsidence ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,142,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,952,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"24","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"25 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[58,116,485,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0677/81c24818af2453166727534643f2153f7be9a9fbde9f54c6bac7897e150accef.jpg","list_items":null,"page_idx":"25","sub_type":null,"table_body":"<table><tr><td></td><td>SOUTH SALIENT INFLUENCED BY THE URAMITA FAULT</td><td>SINÜ FOLD BELT s.s.</td><td>REGION INFLUENCED BY THE MAGDALENA FAN/CANOAS OBLIQUE RAMP</td></tr><tr><td>BELT WIDTH</td><td>Upper continental slope: 17-33 km TOTAL: 100 km</td><td>Lower continental slope: 6-26 km Upper continental slope: 24-38 km Continental slope: 24-38 km TOTAL: 130 km</td><td>Lower continental slope: 13-14 km Upper continental slope: 33-37 km Continental slope: 47-50 km TOTAL: 100 km</td></tr><tr><td>STRATIGRAPHIC THICKNESS</td><td>Cret-Mio (deformation front) < 4 km Cret-Mio (shelf break): 6 km Plio-Quat < 2 km TOTAL: 6-8 km</td><td>Cret-Mio (deformation front): 1-3 km Cret-Mio (shelf break): 5-6 km Plio-Quat: 0.5-1 km TOTAL: 1.5-7 km</td><td>Cret-Mio (deformation front): 4.5 km Cret-Mio (shelf break): 5 km Plio-Quat: 1-2 km TOTAL: 5.5-7 km</td></tr><tr><td>ORIENTATION OF LONGITUDINAL STRUCTURES</td><td>N-S</td><td>NNE-SSW</td><td>NE-SW</td></tr><tr><td>AVERAGE THRUST SPACING</td><td>Deformation front: 3-4 km Shelf break: 3-4 km</td><td>Deformation front: 3-4 km Shelf break: 2-3 km</td><td>Deformation front: 4.5 km Shelf break: 3 km</td></tr><tr><td>DEFORMATION FRONT STYLE</td><td>Detachment folds</td><td>Symmetrical triangular zone</td><td>Triangular zone</td></tr><tr><td>SHORTENING</td><td>13.8 ± 0.7 km</td><td>15.7 ± 0.4-23.9 ± 0.5 km</td><td>19.0 ± 0.4 km</td></tr><tr><td>SEAFLOOR DIP</td><td>Colombian Basin: 1.4° Upper continental slope: 2.5-4° Continental shelf >0.1°</td><td>Colombian Basin: 0.3-0.4° Lower continental slope: 3-6° Upper continental slope: 1.5-3° Continental shelf: 0.1-0.3°</td><td>Colombian Basin: 0.4° Lower continental slope: 5-7° Upper continental slope: 2° Continental shelf: 1.2°</td></tr><tr><td>DETACHMENT DIP</td><td>Upper continental slope: 3.8°</td><td>Lower continental slope: 1.5-2.8° Upper continental slope: 3.6-3.8°</td><td>Lower continental slope: 3° Upper continental slope: 3°</td></tr><tr><td>DETACHMENT DEPTH</td><td>Deformation front: 7.6 km Shelf break: 8.7 km</td><td>Deformation front: 5.4-6.8 km Shelf break: 9.1-9.7 km</td><td>Deformation front: 7.5 km Shelf break: 10 km</td></tr><tr><td>WEDGE VERTICAL THICKNESS</td><td>Deformation front: 6 km Shelf break: 8 km</td><td>Deformation front: 3-3.5 km Shelf break: 8.5-9.5 km</td><td>Deformation front: 5 km Shelf break: 10 km</td></tr><tr><td>TAPER ANGLE</td><td>Upper continental slope: 7.2°</td><td>Lower continental slope: 8.4° Upper continental slope: 5.5-5.7°</td><td>Lower continental slope: 6.9° Upper continental slope: 5.7°</td></tr><tr><td>PORE PRESSURE</td><td>Upper continental slope: 0.7</td><td>Lower continental slope: 0.7 Upper</td><td>Lower continental slope: 0.7 Upper continental slope: 0.5</td></tr></table>","table_caption":"[\"Table 3 Main features of the three SFB zones defined along strike illustrated in Fig. 20. The data presented in this table comes from ourselves and from Rodriguez et al. (2021). \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[512,79,937,170]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0825/5760bb9a6cb51972d2908e7881ce5b9c3bf9fd13591ce8078c807730e55445dc.jpg","list_items":null,"page_idx":"25","sub_type":null,"table_body":"<table><tr><td>SOUTH SALIENT INFLUENCED BY THE URAMITA FAULT</td><td>SINÜ FOLD BELT s.s.</td><td>REGION INFLUENCED BY THE MAGDALENA FAN/CANOAS OBLIQUE RAMP</td></tr><tr><td></td><td>continental slope: 0.5</td><td></td></tr></table>","table_caption":"[\"Table 3 (continued) \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[507,187,937,331]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"25","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"during Pliocene-Quaternary times in the deformation front occurred in this region together with the north region, and the maximum amount of tectonic uplift in the continental shelf also occurred in this region. Therefore, this region is where the behavior of these two sites in terms of tectonic subsidence/uplift is the most different (Fig. 9). The taper angle in both the upper and the lower continental slopes are the lowest, and the $1.4^{\\circ} - 2.7^{\\circ}$ difference between both taper angles is the highest one of the entire SFB (Figs. 14 and 15). The value of pore pressure in the upper continental slope is the lowest and is the highest in the lower continental slope; thus, the 0.15–0.2 difference between both values is the highest one of the whole SFB (Figs. 17 and 18). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,345,927,358]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"25","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12.2.3. Region influenced by the Magdalena Fan/Canoas Oblique Ramp ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,359,937,925]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"25","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This region is the northern part of the SFB, whose boundary to the north is the Magdalena Fan and the Canoas Oblique Ramp, while its southern boundary with the SFB s.s. is diffuse (Figs. 3 and 20 and Table 3). The width of this part of the belt is smaller than that of the SFB s.s. but similar to that of the south salient. The width of the upper continental slope is more than 2.5 times that of the lower continental slope. The dip of the lower continental slope seafloor is from 2.5 to 3.5 times that of the upper continental slope. The dip of the continental shelf is the highest of the whole SFB, whereas that of the Colombian Basin in front of this region is intermediate (Table 3). The bathymetry of the continental slope is the most irregular of the SFB suggesting a lot of recent tectonic activity (Figs. 11 and 12). The thickness of the Cretaceous-Miocene sedimentary pile is the highest in the frontal part and the lowest in the shelf break, and therefore, the $0.5\\mathrm{km}$ difference between both thicknesses is the lowest one of the whole SFB (Figs. 4 and 10), whereas the thickness of the strata that fill in piggy-back basins is intermediate. The wedge vertical thickness in the deformation front is intermediate and is the highest in the shelf break, and thus, the wedge vertical thickness in the shelf break is 2 times that of the deformation front, which is an intermediate value between that of the SFB s.s. and that of the south salient (Figs. 4 and 13), and the vertical tectonic thickening is the highest of the SFB. The basal detachment exhibits the highest dip underneath the lower continental slope which becomes the lowest underneath the upper continental slope (Figs. 4 and 13). The depth to detachment beneath the deformation front is intermediate and that beneath the shelf break is the highest, and therefore, the depth to detachment beneath the shelf break is almost 1.5 times that beneath the deformation front, being this an intermediate value. The strike of the thrusts and related folds is approximately NE-SW, and their average spacing measured near the deformation front is the highest, whereas around the shelf break is intermediate (Fig. 3). The $1.5\\mathrm{km}$ difference between the thrust spacing in the deformation front and in the shelf break, as well as the number of thrusts, are intermediate values. Tear faults are almost non-existent. The lowest number of mud diaps including crestal normal faults and folds, and an intermediate number of continental-shelf normal faults, occur in this region. Several structures branch northwards with the Canoas Oblique Ramp (Fig. 3). The deformation front is an asymmetrical triangular zone because the outermost part of the deformation front consists of a SE-directed thrust (backthrust) and a thrust that branches with the backthrust forming a pop-up, whereas the innermost part of the deformation front is made up of NW-directed thrusts (seaward-vertent structures), all of them emanating from the basal detachment (Fig. 4). The shortening measured is an ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"25","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodriguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"25","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,952,505,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"25","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"26 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[57,65,485,238]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"intermediate value. The maximum amount of tectonic subsidence during Pliocene-Quaternary in the deformation front occurred in this region together with the SFB s.s. region, whereas the minimum amount of tectonic uplift in the continental shelf occurred here as well. Thus, the behavior of the deformation front compared to that of the shelf break in terms of tectonic subsidence/uplift is intermediate (Fig. 9). The taper angle measured in the upper continental slope is intermediate, whereas in the lower continental slope is the lowest, and thus, the $1.3^{\\circ}$ difference between taper angles is the smallest one of the entire SFB (Figs. 14 and 15). The value of estimated pore pressure in the upper continental slope is intermediate and is the lowest in the lower continental slope; the 0.1 difference between both values is the smallest one of the whole SFB (Figs. 17 and 18). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[58,250,171,263]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13. Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,277,485,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The post-Jurassic evolution of the Colombian Basin adjacent to the SFB consisted of a Cretaceous-Paleocene extensional event with considerable tectonic subsidence, followed by a slower subsidence event of Eocene-Miocene age during which some normal faults were still active. During Pliocene-Quaternary, the SFB development caused a lithospheric flexure of the Caribbean Plate, accompanied by normal reactivation of previous faults (i.e., flexural extension), which induced high tectonic subsidence in the Colombian Basin. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,383,487,736]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The SFB was initiated by the beginning of Pliocene in the study area and is still active today at a rate of several millimeters per year. The SFB resulted mostly from horizontal motion, mainly displacement along the basal detachment as well as some overriding plate shortening, accompanied by a minor component of vertical motion responsible for tectonic uplift and thickening. The number of active thrusts and related folds increases from the trailing part of the belt to the deformation front supporting a forward propagation sequence. It also varies along strike from the almost inactive salient in the south portion of the belt to the active continental slope in the north part, suggesting a possible slight clockwise rotation of the subducting Caribbean Plate or a possible increased sediment influx due to the Atrato River in the south part of the belt inhibiting structure activity. The SFB can be considered as an approximately homogeneous wedge whose basal pore pressure, and coefficients of internal and basal friction are roughly constant everywhere, whereas the pore pressure is lower in the upper continental slope causing a lower taper angle in the upper continental slope than in the lower continental slope. The small motion rate of the belt and the subduction of highly porous sediments caused an aseismic subduction, and the gentle flexure of the subducting plate prevented the development of a trench. The longitudinal and transversal variations in terms of bathymetry, stratigraphy and structure have allowed us to divide the SFB in three morpho-structural regions across strike: lower continental slope, upper continental slope and continental shelf, and three regions along strike: north region influenced by the Magdalena Fan/Canoas Oblique Ramp, SFB s.s. and south salient influenced by the Uramita Fault. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,738,485,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Interpreting seismic profiles across the SFB from the geological point of view with the aid of well logs, quantifying amounts of shortening and basal detachment displacement, carrying out a backstripping analysis in order to quantify tectonic subsidence/uplift and vertical tectonic thickening, relating the morphological features to the underlying structure, quantifying the taper angle and their causal parameters in different portions of the belt, as well as establishing a SFB zoning both along and across strike, have proven to be efficient strategies to gain insight into the large-scale structure and evolution of the SFB. These aspects are not only important from the purely scientific point of view but also from the industry point of view because they may be a valuable tool to improve the exploration and exploitation of hydrocarbons recently reactivated in his region (see Reuber et al., 2021). For instance, the large-scale analysis of the SFB carried out here, especially with regard to tectonic subsidence/uplift and tectonic thickening, may be ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,65,937,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"useful in obtaining burial data, and therefore, could help in establishing the hydrocarbon generation and migration. In addition, the large-scale history of SFB presented here may serve as analogue for other submarine regions developed under a similar tectonic setting but whose available data are scarcer or of poorer quality. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,148,732,162]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Declaration of competing interest ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,176,937,216]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,230,638,242]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,255,939,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We thank the editor Tiago Alves, Christopher Connors and an anonymous reviewer for their useful comments and suggestions, as well as J. Gallastegui and D. Pedreira for their help regarding geophysical issues. I. Rodríguez work has been supported by the research contract CN-016-15 (\"Convenio especialto para la realizacion de una tesis doctoral en la linea de investigacion en Geologia y Geosistemas del programa dedoctorado en Biogeociencias\") under the framework agreement between Repsol Exploracion S.A. and the University of Oviedo, Spain. We acknowledge the Colombian Agencia Nacional de Hidrocarburos (ANH) and Repsol Exploracion S.A. for providing us the data and for the research stay at Repsol (Madrid) offices of I. Rodriguez. We thank G. Zamora and B. Amigo for their help with the data and with the Repsol-Universidad de Oviedo contract. We would like to acknowledge financial support by research project CGL 2015-66997-R (\"Aplacion del analisis del plegamento a la investigacion de recursos geologicos\" -AAPLIREGE-) funded by the Spanish Ministry for Economy and Competitiveness and the European Fund for Regional Development (FEDER), research project PID2021-126357NB-100 (Cenozoic uplift of the N-Iberian margin at different scales: influence on seismic activity, relief, emerged/submerged lands and underground aquifers -CUNIMS-) funded by the Spanish Ministry for Science and Innovation, Spain, and research project FC-GRUPIN-IDI/2018/000216 (\"Ayudas a organismos Públicos de investigacion para apoyar la actividad que desarrollen sus grupos de investigacion en el Principado de Asturias en el periodo 2018-2020\") funded by the Principado de Asturias. We thank Schlumberger for permission to use the software Petrel, IHS Markit for permission to use the software Kingdom Suite, Petroleum Exploration Experts-Midland Valley for permission to use the software Move, and J. G. Antuna for maintaining the equipment. We would like to dedicate this article to our colleague, recently deceased, Alberto Marcos, professor at the University of Oviedo. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,679,586,691]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"26","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,704,934,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Aleman, A., 1983. Geology and hydrocarbon evolution of the Northwest Colombia. 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Seismic evidence for widespread possible gas hydrate horizons on continental slopes and rises. AAPG (Am. Assoc. Pet. Geol.) Bull. 63, 2204-2213. https://doi.org/10.1306/2F91890A-16CE-11D7-8645000102C1865D. \",\"Sigurdsson, H., Leckie, R.M., Acton, G.D., 1997. Caribbean volcanism, Cretaceous/ Tertiary impact, and ocean climate history: synthesis of Leg 165. Proc. Ocean Drill. Progr. - Initial Rep. 165, 377-402. \",\"Suppe, J., 2007. Absolute fault and crustal strength from wedge tapers. Geology 35 (12), 1127-1130. https://doi.org/10.1130/G24053A.1. \",\"Suppe, J., Wittke, J.H., 1977. Abnormal pore-fluid pressures in relation to stratigraphy and structure in the active foreland-thrust belt of northwestern Taiwan. Petrol. Geol. Taiwan 14, 11-24. \"]","page_idx":"28","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[512,66,934,327]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Toto, E., Kellogg, J.N., 1992. Structure of the Sinu-San Jacinto fold belt - an active accretionary prism in northern Colombia. J. S. Am. Earth Sci. 5, 211-222. https://doi.org/10.1016/0895-9811(92)90039-2. \",\"Trenkamp, R., Kellogg, J., Freymueller, J., Mora, H., 2002. Wide plate margin deformation, southern Central America and northwestern South America, CASA GPS observations. J. S. Am. Earth Sci. 15, 157-171. https://doi.org/10.1016/S0895-9811(02)00018-4. \",\"Vargas, C.A., Mann, P., 2013. Tearing and breaking off of subducted slabs as the result of collision of the Panama Arc-Indenter with Northwestern South America. Bull. Seismol. Soc. Am. 103 (3), 2025-2046. https://doi.org/10.1785/0120120328. \",\"Vernette, G., 1986. La plateforme continentale de Caraibe de Colombia (du debouché du Magdalena au Golfe de Morrosquillo): importance du diapirism argilleux sur la morphologie et la sedimentation. PhD Thesis. Université de Bordeaux, p. 387. \",\"Vernette, G., Mauffret, A., Bobier, C., Briceno, L., Gayet, J., 1992. Mud diapirism, fan sedimentation and strike-slip faulting, Caribbean Colombian Margin. Tectonophysics 202, 335-349. https://doi.org/10.1016/0040-1951(92)90118-. \",\"Vinnels, J.S., Butler, R.W.H., McCaffrey, W.D., Paton, D.A., 2010. Depositional processes across the Sinú accretionary prism, offshore Colombia. Mar. Petrol. Geol. 29, 794-809. https://doi.org/10.1016/j.marpetgeo.2009.12.008. \",\"Vitali, C., Mauffret, A., Kenyon, N., Renard, V., 1985. Panamanian and Columbian deformed belts: an integrated study using Gloria and seabeam transits and seismic profiles. In: Muscle, A., Biju-Duval, B., Blanchet, B., Stephan, J.F. (Eds.), Geodynamique des Caraibes. Technip, Paris, pp. 451-460. \",\"Zhang, J., Davis, D.M., Wong, T.F., 1993. The brittle-ductile transition in porous sedimentary rocks: geological implications for accretionary wedge aeismicity. J. Struct. Geol. 15 (7), 819-830. https://doi.org/10.1016/0191-8141(93)90178-D. \"]","page_idx":"28","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[58,42,144,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"28","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. Rodríguez et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[699,42,939,52]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"28","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Marine and Petroleum Geology 143 (2022) 105780 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,952,507,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"28","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"29 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[57,206,776,271]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Horizontal/vertical motion and wedge geometry of the Sinú Fold Belt, South-Caribbean accretionary prism, NW Colombia: Implications for a morphostructural zoning \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[838,185,890,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0881/6b3e5aceba9ef8ae9ff455372c8723e2b5b80e64382db015ed59e5296bb8781c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,283,781,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Indira Rodríguez a, Josep Poblet a,\\\\*, Mayte Bulnes a, Joan Flinch b,\\\\*, Massimiliano Masini b \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,308,563,332]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"$^{a}$ Departamento de Geología, Universidad de Oviedo, C/Jesús Arias de Velasco s/n, 33005, Oviedo, EU, Spain \\\",\\\"b Repsol, C/ Mendez Álvaro 44, 28045, Madrid, EU, Spain \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[58,360,194,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ARTICLEINFO \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,385,109,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,395,127,406]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Sinu fold belt \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,407,157,417]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accretionary wedge \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,418,115,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Shortening \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,428,157,438]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tectonic subsidence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,440,126,448]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Critical taper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,450,142,460]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Morphostructure \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[334,360,435,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ABSTRACT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[332,384,939,566]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Sinú Fold Belt, located in the southwestern part of the South Caribbean Deformed Belt, northwest Colombia, has been interpreted as the outer portion of an accretionary wedge resulting from the subduction of the Caribbean Plate under the South American Plate. Several geological sections, across and along the offshore portion of the Sinú Fold Belt, have been constructed through geological interpretation of 2D seismic sections constrained by a few exploration wells. Their analysis has allowed us to quantify the amount of horizontal motion (shortening responsible for the structures and basal detachment displacement) and vertical motion (tectonic subsidence/uplift and wedge vertical thickening) undergone by the belt over time; unravel its recent evolution consisting of almost no active structures in the south edge and a large amount of active structures northwards; quantify its pore pressure, coefficient of friction and strength using its wedge geometry consisting of high taper angles in the lower continental slope near the deformation front and lower taper angles in the upper continental slope away from it; and understand the aseismic and trench-lacking character of the belt. These observations have been crucial to identify the main features of the morphostructural zones across the belt (Colombian Basin, lower continental slope, upper continental slope and continental shelf) and establish a new along-strike zoning (north region influenced by the Magdalena Fan/Canoas Oblique Ramp, Sinú Fold Belt s.s., and south salient influenced by the Uramita Fault). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,602,164,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,629,487,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Sinú Fold Belt (SFB), located mostly offshore northwest Colombia, together with the San Jacinto Fold Belt, located onshore northwest Colombia, are the leading and trailing parts respectively of a NE-SW trending accretionary wedge developed to the south of the Colombian Basin (Fig. 1a and b). This NW-directed accretionary wedge resulted from eastwards, low-angle subduction of oceanic rocks and sediments belonging to the Caribbean Plate under arc terranes along the northwest edge of the South American continent that belong to the South American Plate (e.g., Ladd and Truchan, 1983; Ladd et al., 1984) (Fig. 1c). In this paper we will focus on the offshore part of the SFB between the Uramita Fault to the south and the Magdalena Fan to the north. This part of the belt is exceptionally well imaged in high quality \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,604,591,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"seismic data. \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,616,939,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Most of the knowledge on the large-scale structure of the SFB come from geological interpretation of seismic reflection profiles, which has allowed the construction of geological sections (e.g., Toto and Kellogg, 1992; Bernal-Olaya et al., 2015) as well as structural maps (e.g., Vitali et al., 1985; Cediel and Caceres, 2000; Flinch et al., 2003b; Cediel, 2011; Martínez et al., 2015; Rodríguez et al., 2021) of the belt, and their integration into lithosphere-scale transects from the Colombian Basin, across the Sinú-San Jacinto belt, to the San Jorge Basin (included in the Lower Magdalena Basin), to the mountain range (Central and Eastern Cordillera) (e.g., Flinch et al., 2003a; Mantilla-Pimiento, 2007; Bernal-Olaya et al., 2015; Flinch and Castillo, 2015; Mora-Bohórquez et al., 2017) (Fig. 1c), or even to the foreland basin developed eastwards of the mountain range (e.g., Vargas and Mann, 2013). Thus, the SFB has been \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[357,42,640,55]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[58,74,164,163]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ELSEVIER \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[379,75,621,88]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Contents lists available at ScienceDirect \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[334,105,667,127]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[319,145,680,160]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"journal homepage: www.elsevier.com/locate/marpetgeo \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[838,66,937,160]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,818,203,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"* Corresponding author. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[63,832,564,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"** Corresponding author. Independent Geoscience & Energy Consultant, Madrid, EU, Spain. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[58,844,937,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E-mail addresses: indira@geol.uniovi.es (I. Rodríguez), jpoblet@geol.uniovi.es (J. Poblet), maite@geol.uniovi.es (M. Bulnes), flinchjoan@gmail.com (J. Flinch), massimiliano.masini@repsol.com (M. Masini). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[58,877,337,889]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1016/j.marpetgeo.2022.105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,890,552,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received 10 January 2022; Received in revised form 16 May 2022; Accepted 6 June 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,902,226,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Available online 11 June 2022 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[58,912,934,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"0264-8172/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[55,65,485,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the subject of many studies, not only because of its scientific interest, but because of its hydrocarbon potential explored from the sixties to present day by many oil companies. However, in our opinion some interesting large-scale issues still need to be fully understood. Some refer to the belt kinematics, i.e., belt shortening, basal detachment displacement and vertical subsidence/uplift, whereas others refer to its geometry, i.e., taper angle, morphology, relief and thickness. Likewise, the interrelationships between its geometry and kinematics, and how these elements influence each other spatially and through time, must be established. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,197,485,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Regarding horizontal movements of the SFB, some studies have quantified the shortening responsible for the SFB (e.g., Ruiz et al., 2000; Kellogg et al., 2005; Bernal-Olaya et al., 2015) and the magnitude of tectonic plate motion (e.g., Freymueller et al., 1993; Kellogg and Vega, 1995; Trenkamp et al., 2002), however, neither the amount of displacement along the accretionary-prism basal detachment nor its relationship with the belt shortening and plate motion have been analyzed. As regards vertical movements of the SFB, we are aware of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,276]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"only one study on the subsidence/uplift in a Colombian Basin section adjacent to the SFB (Sánchez et al., 2019), but there have been no studies of the SFB up to date. With respect to the taper angle, two analyses have been carried out (Toto and Kellogg, 1992; Bernal-Olaya et al., 2015), but the new data available allow for more detailed measurements of the taper angle, as well as for quantification of its across- and along-strike variations and the parameters that control it. Regarding the SFB relief, recent sedimentation/erosion processes have been documented in detail (Vinnels et al., 2010), however, this information has not been correlated yet with the activity and kinematics of the underlying structures. Transversal and longitudinal variations in elements such as the SFB morphology, taper angle and crustal thickness have been documented (e.g., Toto and Kellogg, 1992; Vinnels et al., 2010; Bernal-Olaya et al., 2015), however, the relationship between these variations and the belt kinematics has not been examined, and no zoning of the belt has been established yet. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,277,937,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To address these issues, we have carried out a geological interpretation of six regional, depth-converted 2D seismic profiles, with the help \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,327,937,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. a) Satellite image of the Caribbean region showing the main tectonic elements, the ODP well (yellow circle) and the region enlarged in b) (red rectangle). b) Satellite image of the Caribbean margin of northwest Colombia showing the major structural units and faults, as well as the study area in the offshore portion of the SFB (red dashed polygon), the seismic lines illustrated here (white lines) and wells (yellow circles), and the location of the section depicted in c) (pink line). Figures a) and b) modified from Case and Holcombe (1980) and Cediel et al. (2003), and base maps from GEBCO Digital Atlas by GIS map services. We are not allowed to show the location of all the interpreted seismic profiles due to confidentiality agreements with the owning companies. c) Vertically exaggerated crustal section illustrating the Sinu and San Jacinto fold belts (modified from Mantilla-Pimento, 2007). SJFB: San Jacinto Fold Belt, SJB: San Jorge Basin. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0424/d3bdd37fc549e15e10b17e0858b23658f5feac85c40e8614058e49ef978a60b0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,145]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of a few well-logs and a high-density grid of 2D time seismic profiles. The data obtained have been employed to characterize and quantify large-scale aspects of the SFB, such as horizontal/vertical motion, taper and morphology, and their variations, together with variations in the structural style, have allowed us to define different morphostructural regions both across and along strike. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,158,200,171]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Geological setting \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,184,487,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The South Caribbean Deformed Belt, developed along the Colombian and Venezuelan coasts, is an accretionary wedge that runs along the convergent margin between the Caribbean and South American tectonic plates (Fig. 1a). The Caribbean-Plate relative motion towards ESE since Late Miocene (e.g., Minster and Jordan, 1978; Trenkamp et al., 2002; Pindell and Kennan, 2007) caused different tectonic regimes depending on the shape of the South American Plate boundary. Motion almost parallel to the coastline gave rise to a strike-slip regime in north Colombia and Venezuela, however, motion mainly perpendicular to the coastline produced a compressional setting in the northwestern Colombian coast. The South Caribbean Deformed Belt in northwest Colombia consists of a NE-SW trending double belt called Sinú-San Jacinto Fold Belt (Fig. 1b), which resulted from a two-stage development (e.g., Galindo and Lonegan, 2013). Thus, the San Jacinto Fold Belt is the innermost portion of the accretionary belt formed by dextral-transpressional collision/accretion between the Caribbean and South American tectonic plates from Paleocene to Oligocene (e.g., Flinch, 2003a, 2003b), whereas the SFB is the outermost part of the accretionary belt and reflects a Late Miocene to Recent compressive stage related to the Andean orogeny (e.g., Duque-Caro, 1979; Ruiz et al., 2000). This complex scenario was caused by the clockwise rotation of the Caribbean Plate from Cretaceous to the present (e.g., Escalona and Mann, 2011; Ardila and Diaz, 2015). The Sinú-San Jacinto Fold Belt is bounded to the west by the Uramita Fault which separates it from the North Panama Fold Belt (Fig. 1b); to the south it is bounded by the Western and Central cordilleras; to the east, the Romeral Fault Zone \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,939,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"separates it from the San Jorge and Plato basins; it is bounded to the north by the Magdalena Fan; to the northeast, it is separated from the Santa Marta Massif by the Santa Marta-Bucaramanga Fault; and to the northwest, the deformation front is responsible for its thrusting over the Colombian Basin. The Sinú Fault Zone is the eastern boundary of the SFB and the western boundary of the San Jacinto Fold Belt. The SFB developed over a subducting Mesozoic basement (e.g., Toto and Kellogg, 1992; Ruiz et al., 2000; Alfaro and Holz, 2014b) and comprises a Cenozoic sedimentary cover mainly made up of shales with sporadic cherts, sandstones, conglomerates and limestones (Duque-Caro, 1979) (Fig. 2). The most important structure is an imbricate system of W-directed thrusts and related folds (Fig. 3), as well as piggy-back basins filled with thick sequences of syn-tectonic strata (Kolla et al., 1984; Toto and Kellogg, 1992; Flinch et al., 2003a; Vinnels et al., 2010). The thrusts emanate from a deep main detachment located within deep over-pressed shales, which are the source for mud diapirs and related ductile deformation in the host sediments (Shepard et al., 1968; Ramirez, 1969; Shepard, 1973; Duque-Caro, 1979, 1984; Vernette, 1986; Vernette et al., 1992; Briceno and Vernette, 1992; Ruiz et al., 2000). These diapirs, together with normal faults, are mainly developed in the trailing part of the belt (Flinch et al., 2003a,b; Mantilla-Pimiento, 2007). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,356,633,369]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Data employed \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,380,939,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Six pre-stack depth migrated seismic lines have been interpreted from the geological point of view although only four are shown here (Fig. 1b). The chosen four lines are approximately perpendicular to the belt, i.e., NW-SE, have an average length of $100\\\\mathrm{km}$ and reach a depth of around $22\\\\mathrm{km}$ . The spacing between them ranges from 35 to $60\\\\mathrm{km}$ . Two additional seismic lines are approximately parallel to the belt, i.e., NE-SW, are more than $800\\\\mathrm{km}$ long but we have interpreted around $250\\\\mathrm{km}$ , and reach a depth of $22\\\\mathrm{km}$ . The spacing between these two lines ranges from 30 to $70\\\\mathrm{km}$ . Nowadays, pre-stack depth migration is considered the most accurate method to perform depth conversions of time seismic lines, and that guarantees the precision of the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,554,934,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 2. Stratigraphic section of the study area including additional information on the seismic stratigraphy and tectonics-sedimentation relationships, constructed using our own data, wells, an idealized stratigraphic column built by Alfaro and Holz (2014a, b) based on various studies (Duque-Caro, 1979, 1984, 1990; Aleman, 1983; Duque-Caro et al., 1996; Guzmán, 2007), and Vinnels et al. (2010) data. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0901/fcf9b221e7a2cbe70a9075aeb2c23cfc645c77293aecdbc50843c854417485ff.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,65,872,742]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3. Structural map of the SFB constructed by drawing the traces of the emergent structures and plotting vertically the fault tips and the fold hinges of the buried structures. Colombian-Basin normal faults developed during Cretaceous-Paleocene, reactivated as normal faults during Pliocene-Quaternary, are also shown in the west part of the study area. The location of the seismic profiles displayed in Fig. 4 is shown. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0000/9ae484d3743930052445a3e157bc56395330548317f45c27f36b4a56c4ce2aab.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,803,485,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"measurements of angles and distances taken in the depth-converted seismic lines. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,829,485,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition, we have interpreted sixty-one 2D time seismic lines acquired in eight different surveys. These seismic lines exhibit two predominant directions: NW-SE, i.e., approximately perpendicular to the SFB, and NE-SW, i.e., approximately parallel to the SFB. This dataset covers an area of approximately $17,000\\\\mathrm{km}^2$ , the length of the time seismic sections ranges from $23\\\\mathrm{km}$ to more than $400\\\\mathrm{km}$ , although most of them exhibit a length in between 50 and $150\\\\mathrm{km}$ , and reach two-way travel times from 6 to 8 s. The spacing between the time seismic lines \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,803,937,854]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ranges from 1.5 to $5\\\\mathrm{km}$ . Both the depth-converted and the time seismic lines were acquired by the oil companies BP-Amoco, BP Exploration, Intercol, Ecopetrol and Gulf Oil Corporation from 1967 to 2004 and were supplied to us by the company Repsol. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,854,937,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data from six wells has been employed: a) the Ocean Drilling Project (ODP) Site 999 (Sigurdsson et al., 1997), located in the Caribbean Sea approximately $400\\\\mathrm{km}$ to the northwest of the SFB deformation front, that penetrates more than $1\\\\mathrm{km}$ of Upper Cretaceous-Upper Pleistocene strata (Fig. 1a); and b) five exploration wells, located in the continental shelf about $20\\\\mathrm{km}$ from the Colombian coast, that penetrate up to $4.5\\\\mathrm{km}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,118]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of Neogene-Quaternary strata (Fig. 1b). The exploration wells in the continental shelf were drilled by the companies Colombian Gulf Oil, Provincia Petroleum, Citco Colombia Petroleum Corporation and Phillips Petroleum from 1969 to 1979 and were supplied to us by Repsol. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,118,485,224]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Up to nine stratigraphic units have been defined based on the amplitude, frequency, continuity and geometry of the seismic reflectors (Figs. 2 and 4). The software Petrel E&P (Schlumberger), Kingdom Suite (IHS Markit) and Move (Midland Valley-Petroleum Exploration Experts) have been used to carry out the geological interpretation of the seismic data and subsequent data analysis. The specific methodology used to decipher each of the different issues discussed below is explained at the beginning of each section. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,237,258,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Main stratigraphic features \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,263,487,368]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study area is made up by a Jurassic to present-day succession (Fig. 2). The Cretaceous to present-day succession is mainly siliciclastic and approximately coarsening upwards (from shales in the lower part to shales, sandstones and some conglomerates in the upper part), as well as shallowing upwards (from deep water sediments evolving upwards to shallow water/transitional environments). Perpendicularly to the Colombian coast, the thickness of the Cretaceous-Miocene succession increases from the abyssal plain (less than $1\\\\mathrm{km}/$ more than $3\\\\mathrm{km}$ ) to the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"continental shelf (5 km/almost 6 km) (Fig. 4). Approximately parallel to the Colombian coast in the continental slope, the Mesozoic-Neogene succession increases from the center-south part of the SFB (Fig. 4c) towards the northeast and southwest, whereas in the continental shelf, it reaches its maximum thickness in the south part (Fig. 4d) and decreases northwards. Although the thickness of the Pliocene-Quaternary sequence is quite variable, approximately perpendicular to the Colombian coast it thickens from the continental slope (approximately $1 - 2\\\\mathrm{km}$ ) to the continental shelf (almost $3 - 4\\\\mathrm{km}$ ), i.e., similarly to the pre-Miocene sequence. Approximately parallel to the Colombian coast, the Pliocene-Quaternary succession is thin in the south-central part of the belt and thickens both to the northeast and to the southwest. The different stratigraphic units mapped in the seismic lines are bounded by unconformities. In some localities they become angular unconformities that truncate underlying beds and may be onlapped by overlaying beds. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,263,937,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the Colombian Basin, the Cretaceous and Paleocene successions are syn-rift strata (Fig. 2), although a few normal faults cut and offset Eocene, Oligocene and Miocene strata. Occasionally, the uppermost Pliocene and Quaternary strata are coeval to the normal reactivation of these older faults. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,329,937,368]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Paleocene, Eocene, Oligocene and Miocene strata that constitute the SFB, as well as older underlying rocks, are pre-tectonic with respect to the SFB structures, i.e., they are pre-growth strata (Fig. 2). The \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[124,392,863,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0543/5b63d436d99303df36f6fd811def32be202814ac08113a78b3a2c69fc41ae102.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,506,801,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0160/6afa1f13a07c779bb2cd5c5ed7e48b7006008f6d0b210be827957a0d9c02fc20.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,631,860,733]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0730/71242ddba1544f26b1f64f204fd74b6f285aa5dff0cb35d535ecb77604ac7ae9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,744,868,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 4. Geological interpretation of four depth-converted seismic profiles across the SFB from north (a) to south (b) showing thrusts and related folds, normal faults and mud diapirs. The pin (left part of the seismic profiles) and loose (right part of the seismic profiles) lines employed to measure the shortening in the four profiles are shown. See Figs. 1b and 3 for location. The stratigraphic sections used to infer the tectonic subsidence curves depicted in Fig. 9 are located at the left border of the seismic profiles (Fig. 9a, 9b, 9c and 9d - Colombian Basin), to the right of the pin line (Fig. 9e, 9f, 9g and 9h - SFB Deformation Front) and at the right border of the seismic profiles (Fig. 9i, 9j, 9k and 9l - SFB Continental Shelf). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0301/b4decedd6904c80cab6faef2ab1d694f77369819a0b94a5afe3ee9100f8518da.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,952,502,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,182]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pliocene and Quaternary strata exhibit a number of features diagnostic of syn-tractonic deposition associated with faults, folds and diapirs, and therefore, they are interpreted as growth strata. Nevertheless, the lower part of the Pliocene-Quaternary sequence can be also considered pregrowth or growth, while the upper part can be growth or post-growth strata, so that the stratigraphic position of the boundary between these sequences vary from one structure to another because faults, folds and diapirs developed in the SFB are diachronic (Rodríguez et al., 2021, 2022a; 2022b). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,197,315,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5. Main structural elements of the SFB \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,223,485,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The SFB is a NE-SW trending fold and thrust belt, more than $200\\\\mathrm{km}$ long and around $130\\\\mathrm{km}$ wide in its widest part, developed mainly in the continental slope and in the continental shelf offshore northwest Colombia (Fig. 1b). In map view it is a curved belt convex to the northwest (seawards) and it is slightly asymmetric, so that it is wider in the central-north part, and a minor recess and salient occur towards the south (Fig. 3). A NNE-SSW trending and approximately rectilinear fault, named Sinú Fault Zone, separates the SFB trailing part from the San Jacinto Fold Belt (Figs. 1c and 3). The SFB leading part is separated from the Colombian Basin by the deformation front defined by a frontal thrust or a triangle zone. It exhibits a stepped morphology along strike caused by faults that disrupt its continuity, and is the belt tectonic element that best reflects the belt curved shape (Fig. 3). The SFB is covered by the Magdalena Fan towards the northeast, whereas it ends against the NNW-SSE trending Uramita fault towards the southwest (Fig. 1b). In profile view, the SFB is a wedge bounded by a submarine topography gently inclined to the NW and by a basal detachment gently dipping to the SE (Fig. 4). The wedge apex is located seawards, while the thickest part of the wedge, which may reach more than $10\\\\mathrm{km}$ of vertical thickness in the study area, is located landwards. Ductile structures, such as folds and mud diapirs, as well as fragile structures apparently developed under contractional (thrusts), extensional (normal faults) and strike-slip (strike-slip faults) tectonic regimes, occur within the SFB. Some of these structures, such as thrusts, folds, mud diapirs and some normal faults, are longitudinal with respect to the belt, and some of them are transverse, such as tear faults and strike-slip faults (Rodriguez, 2020; Rodríguez et al., 2021) (Fig. 3). A brief description of these structures is presented below. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,607,228,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.1. Contractional structures \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,633,485,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thrusts, together with related folds, are the most abundant longitudinal structures, particularly in the continental slope. Their strike bends from approximately N-S in the south portion of the SFB to NE-SW in the north (Fig. 3). Most thrusts exhibit a listric geometry and form an imbricate thrust system that emanates from a SE gently dipping basal detachment located within Paleocene strata (Fig. 4). Although NW-directed thrusts are the most common structures, a few SE-directed thrusts, i.e., backthrusts, occur. Pop-ups and triangular zones developed in those regions where thrusts and backthrusts coexist. Growth ramp folds, in the form of single-hinge anticlines, box-fold type anticlines and anticlinal monoclines, make up the hangingwall of these thrusts (Fig. 4a, 4b and 4c). Two large anticlines and a syncline, interpreted as growth detachment folds, developed in the SFB south salient (Fig. 4d). The imbricate thrust system and related folds developed according to a roughly forward propagation sequence (piggy-back) from southeast to northwest, both at the scale of a few structures and at the scale of the whole SFB (Rodríguez et al., 2021, 2022a). Sporadic out-of-sequence thrusts are recognized, such as those in the transition from the upper continental slope to the lower continental slope. The basins filled in with Pliocene to present-day growth strata, located above the folds in between thrusts, are piggy-back basins (Fig. 4). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,910,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An E-W trending fault oblique to the trend of the longitudinal structures, named Canoas fault (Vernette et al., 1992; Ruiz et al., 2000), \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"has been mapped in the north part of the SFB (Fig. 3). The thrusts and related folds developed in the south fault block exhibit different morphologies and are much more abundant than those developed in the north fault block, where there are almost no structures. This fault, developed during recent times, is interpreted as an oblique thrust ramp. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,145,660,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.2. Strike-slip structures \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,171,937,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Several faults, sub-perpendicular to the longitudinal structures, i.e., transverse structures, have been identified in the continental slope (Fig. 3). Their strike ranges from WNW-ese in the south part of the belt to NW-SE in the north part and they are usually sub-vertical. While the strike of the thrusts and related folds cut by these faults is approximately the same in both fault blocks, the number, spacing and geometry of the thrusts and related folds are different in both fault blocks, and therefore, they have been interpreted as tear faults. The activity of some of these faults ended before the deposition of the youngermost sediments, whereas others are active in recent times. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,303,937,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Rosario Fault (Vernette et al., 1992; Ruiz et al., 2000) is a large fault oblique to the trend of the longitudinal structures, i.e., a transverse structure, developed in the north part of the SFB and in part of the Colombian Basin (Fig. 3). It is a right-lateral, steep fault whose average strike is E-W, and it cuts and offsets thrusts and related folds as well as a tear fault. Its activity is relatively young. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,395,670,408]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.3. Extensional structures \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,422,937,617]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Small-scale normal faults, involving shallow sediments, developed above the steepest limbs of some anticlines that show bathymetric expression in the continental slope. These faults are longitudinal structures, whose average strike is NNE-SSW in the central part of the SFB and NE-SW in the northern area. Most of them are listric, with dips from moderately to gently to the W and NW (Figs. 3, 4a, 4b and 4c). Some of these NW-directed normal faults branch at depth with a gently NW-dipping detachment, which may be the Bottom Simulating Reflector (BSR), i.e., the base of the gas hydrate stability zone (Shipley et al., 1979), forming imbricate normal fault systems. NW-directed, listric thrusts, whose dip varies from gently to moderately to the ESE and SE, emanate from the leading edge of the detachment forming toe thrusts. These normal faults and their associated toe thrusts developed in recent times, and are from simultaneous to younger than the thrusts and related folds. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,620,937,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Large listric normal faults, dipping both to the NW and to the SE, have been mapped in the continental shelf (Fig. 3). The average strike of these longitudinal structures ranges from NNE-SSW to NE-SW. Gentle rollover anticlines and sets of second-order normal faults occur in the hangingwall of these normal faults. Some faults root into the basal detachment, whereas others are shallower faults that become horizontal at intermediate depths and become toe thrusts. Some of these normal faults were reactivated as reverse and normal faults, remaining inactive in between fault reactivation periods. These normal faults cut and offset the thrusts and related folds, and some toe thrusts related to these normal faults resulted from reactivation of a portion of previous thrusts. These normal faults developed approximately during middle Pliocene time, and their reactivation took place up to present-day. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,805,630,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5.4. Mud structures \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,831,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Diapirs are longitudinal structures developed mainly in the continental shelf. They exhibit an elongated shape in map view and their main elongation axis ranges from N-S to NE-SE (Fig. 3). In general, the sidewalls of the diapirs are steeply inclined to vertical (Fig. 4a, 4b and 4d). Some overburden sediments located above the crests of the diapirs and the sediments pierced by the diapirs exhibit anticline geometries caused by the intrusion of the diapirs. Crestal-collapse normal faults developed above some mud diapirs. Mud diapirs occur in the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"hangingwall and foot wall of thrusts, and in the core of some hangingwall anticlines related to thrusts, so that they probably initiated slightly before or synchronously to the thrusts and related folds from Pliocene to present-day. Some mud diapirs are located close to listric normal faults with related rollover anticlines. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,143,394,157]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6. Main structural features of the Colombian basin \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,170,485,327]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Colombian Basin is a large elongated basin located offshore northwest of Colombia (Fig. 1a). Only the south part of the basin adjacent to the SFB has been studied here. It is filled in by sub-horizontal Cenozoic strata on top of Cretaceous and Jurassic sedimentary and igneous rocks (Fig. 4). All these rocks are involved in a basement high developed in the south part of the study area (Fig. 5). In addition, horsts and grabens bounded by NE-SW faults, that dip from moderately to steeply both to the SE and to the NW, occur (Figs. 3 and 5). These normal faults were active mainly during Cretaceous and Paleocene times, however, some normal faults also cut and offset Eocene, Oligocene and part of the Miocene strata. Some of these normal faults propagated up section in recent times and were active as normal faults. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,341,327,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7. Amount of horizontal tectonic motion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,369,164,380]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7.1. Plate motion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,395,485,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The shortening responsible for the SFB formation in the study area started in the Pliocene and is still active today according to the age of the syn-contractional strata (Rodriguez, 2020; Rodriguez et al., 2021, 2022a); this means that this region has been shortened approximately during the last 5.3 Myr. The present-day rates of convergence between the Caribbean and South American tectonic plates for this region, estimated by taking GPS measurements during 25 years, are $10\\\\mathrm{mm / yr}$ (Freymueller et al., 1993), $10 - 15\\\\mathrm{mm / yr}$ (Kellogg and Vega, 1995) and $20\\\\pm 2\\\\mathrm{mm / yr}$ (Trenkamp et al., 2002). Assuming that these plate motion rates (from 10 to $20\\\\mathrm{mm / yr}$ ) remained constant during the whole 5.3 Myr of SFB development, and that the South American tectonic plate remained stationary with respect to the Caribbean tectonic plate, then the Caribbean tectonic plate would have moved approximately from 53 km to $106\\\\mathrm{km}$ from Early Pliocene to present-day. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,580,485,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Some NE-SW normal faults developed during Mesozoic and/or Paleogene-early Neogene in the south portion of the Colombian Basin adjacent to the SFB deformation front (Fig. 3), reactivated as normal faults during Pliocene-Quaternary time, may furnish information on the rates of SFB development. Thus, we propose that the Caribbean tectonic plate bended as it subducted under the South American tectonic plate and supported the weight of the overlying SFB while it was being emplaced. This lithospheric flexure probably induced extension in the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,939,540]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"outer portion of the lithosphere flexure hinge resulting in normal faulting, i.e., flexural extension. This extension was not accommodated by new normal faults in the Colombian Basin but by reactivation of old normal faults with favorable orientation, such as the NE-SW faults mapped in the west part of the study area (Figs. 3 and 6b) whose strike may be sub-parallel to the flexure hinge. As the Caribbean tectonic plate subducted, the flexure hinge probably migrated away from the continent at a similar rate to that of the SFB advance seawards (Fig. 6a). This would explain why one of the normal faults located closer to the continent (Cretaceous-Paleocene fault reactivated during Pliocene, intersected by section lines C-C' and D-D' in Fig. 3) ceased to be active by the end of the Pliocene, while the normal fault located farther away from the continent (Cretaceous-Paleocene fault reactivated during Quaternary, intersected by section line C-C' in Fig. 3) ended its activity in recent times. Assuming that the lithospheric flexure hinge migrated from southeast to northwest, the distance between these two normal faults measured perpendicularly to their traces depicted on the map in Fig. 3 could reflect the spatial migration of the lithospheric flexure hinge. This distance divided by the time elapsed between the termination of activity of both normal faults might give us an approximate rate of the lithospheric-flexure hinge migration from the end of the Pliocene to the present-day. Since the distance measured between these two faults is $29\\\\mathrm{km}$ and the approximate time difference between the termination of activity of both faults is $2.58\\\\mathrm{Myr}$ , the rate obtained is $11\\\\mathrm{mm / yr}$ . If we assume that the rate of lithospheric-flexure hinge migration is approximately equivalent to the rate of advance of the SFB deformation front, then the rate of advance of the SFB deformation front from Pliocene to Present, obtained using flexure-related normal faults, is in full agreement with the $10 - 20\\\\mathrm{mm / yr}$ rate of convergence between the Caribbean and South American tectonic plates for the study area, estimated during 25 years using GPS measurements (Freymueller et al., 1993; Kellogg and Vega, 1995; Trenkamp et al., 2002). Obviously, the rate of lithospheric-flexure hinge migration estimated should be taken with caution since precise ages of the strata are not available and some assumptions may not be totally correct, such as the direction of migration of the lithospheric flexure hinge. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,562,699,576]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7.2. Overriding plate shortening \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,588,937,694]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Pliocene to present-day shortening responsible for the SFB has been measured in the continental slope and in part of the continental shelf using the four depth-converted seismic profiles sub-perpendicular to the SFB trend (Fig. 4). The boundary between the pre- and syncontractional sequences has been used to estimate the shortening. This is an easy identifiable, well imaged and continuous reflector, and its age is approximately Lower Pliocene, although it may vary across the belt. The shortening has been estimated as the difference between the length \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[161,709,836,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5. Geological interpretation of a time seismic profile within the Colombian Basin showing a basement high as well as normal faults. See Fig. 1b for location. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0008/1109ffd8822f2d65ecba3d8e5d0cc7732921838be6b1069a634e6a7d88389fa9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[233,66,700,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0327/76db41e337dbb3b3244db652d2103787dc84f1c2b1df6e8d2323ed4054474a74.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[290,191,700,284]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0020/b7697a38333b308ae6d112deee251c8850049f63c2d3ce9aefd257beebed0d7f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[290,292,700,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0025/ed789147a3e8a9eaf4fd773e3de29866a90adab928efb98089c83e004540d006.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[161,395,836,568]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 6. a) Cartoon illustrating the advance of the SFB from older (upper part of the figure) to younger (lower part of the figure) times and the development of normal faults in the hinge of the lithospheric flexure suffered by the subducting Caribbean Plate. We have assumed that the dip of the subducting plate remains constant over time for simplicity. Black normal faults: active normal faults, grey normal faults: inactive normal faults. b) Geological interpretation of a depth-converted seismic profile across the Colombian Basin showing normal faults. See Fig. 1b for location. The stratigraphic sections used to infer the tectonic subsidence curves depicted in Fig. 8a and b are located at the overthrow hangingwall and at the uplifted foot wall of the northwesternmost normal fault. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0626/e45d779ba5cff73400aaa856dd715e2956c62c540eba6c8a088b4ee17a12eac1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[60,663,489,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of the folded/faulted reflector and the cross-section width in between the sub-vertical pin lines located in the Colombian Basin and the subvertical loose lines in the continental shelf (Fig. 4). The shortening has been underestimated because: a) strain is likely to have occurred in the shale succession but it has not been accounted for because the measurement method employed assumes constant bed length, b) the shortening has been only estimated in the continental slope and in a portion of the continental shelf adjacent to the continental slope since we do not have depth-converted seismic profiles across the portion of the continental shelf closest to the coast and on land, and c) the significant amount of sediment volume loss due to water expel during accretion (Moore et al., 2011) has not been considered in our estimations. The shortening obtained using the four seismic sections ranges from $11.3\\\\mathrm{km}$ to $22.8\\\\mathrm{km}$ . These shortening values are apparent values because the seismic profiles are oblique to the tectonic transport vector. They have been converted to true shortening values using Cooper (1983) equations and taking into account the angle between the direction of the seismic lines and the tectonic transport vector (approximately from N110E to N120E, i.e., WNW-ESE according to Rodriguez, 2020; Rodriguez et al., 2021). The true shortening values range from $13.82 \\\\pm 0.71\\\\mathrm{km}$ to 23.9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,669,939,854]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\pm 0.53 \\\\mathrm{~km}$ , i.e., from almost $19\\\\% - 30\\\\%$ shortening. These values must be taken with caution due to possible errors made in their measurement, in the geological interpretation of the seismic data and in the depth conversion. Our shortening values are lower than those obtained by Ruiz et al. (2000) and Kellogg et al. (2005) based on the analysis of folds and faults depicted in cross sections, which are $60 - 65 \\\\mathrm{~km}$ ( $40\\\\%$ ) and more than $50 \\\\mathrm{~km}$ ( $40\\\\%$ ) respectively; the reason is that our depth-converted sections do not cover the whole SFB from the deformation front to the boundary with the San Jacinto Belt. However, our shortening values are relatively similar to those obtained by Bernal-Olaya et al. (2015) which range from 27.6 to $31.4 \\\\mathrm{~km}$ ( $27 - 32\\\\%$ ). Taking into account that the estimated shortening has been produced during 5.3 Myr and assuming a constant shortening rate, the average shortening rates range from 2.5 to $4.5 \\\\mathrm{~mm} / \\\\mathrm{yr}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,870,623,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7.3. Interplate slip \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,897,939,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The consistency between the average rates of tectonic plate motion (measured during 25 years) and those of lithospheric-flexure hinge migration (derived from data covering the last 2.58 Myr), both \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,146,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,568]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"estimated using different methods, makes it reasonable to assume that: a) the plate motion rates measured using GPS during the last 25 years remained approximately constant during the last 2.58 Myr, and perhaps during the whole 5.3 Myr of SFB development, and b) much of the motion of the Caribbean and South American plates has been accommodated at the edge of the plates with not much intraplate deformation. At subduction plate boundaries, strains accumulate within the overriding plate in response to motion of the down-going plate. To a first approximation, the sum of the margin interplate slip and the shortening in the overriding plate is equivalent to the total plate convergence (Nicol and Beavan, 2003) (Fig. 7). Therefore, margin interplate slip can be estimated by subtracting the shortening in the overriding plate from the total plate convergence. Assuming that the motion rate of the Caribbean tectonic plate has been approximately constant from 10 to $20\\\\mathrm{mm / yr}$ over the last 5.3 Myr, then the overriding plate shortening values obtained from the seismic lines represent from $13\\\\%$ to $45\\\\%$ of the total Pliocene-Quaternary movement of the Caribbean tectonic plate estimated above. These percentages are minimum values that would increase if considering the strain, plus the sum of all the SFB shortening from the deformation front to the trailing part of the SFB (Sinu Fault Zone), plus possible mistakes derived from measurements, interpretation and processing. Thus, the remaining $55 - 87\\\\%$ of plate convergence would be the maximum values accommodated by margin interplate slip, i.e., slip on the subduction thrust. This means that the maximum displacement along the basal detachment would range from 29.15 to $92.22\\\\mathrm{km}$ . Taking into account that the shortening has been produced during 5.3 Myr and assuming a constant rate of basal detachment displacement, the average rates of basal detachment displacement range from 5.5 to $17.5\\\\mathrm{mm / yr}$ . If the Caribbean-Plate motion rate in the past had been less than the current one and/or part of the plate movement would have been accommodated by intraplate deformation, then the displacement along the basal detachment would be less. Apparently, the percentage of basal detachment displacement seems very high with respect to the plate convergence, however, similar values have been obtained in other regions, such as the Hikurangi margin located in the boundary between the Pacific and Australian tectonic plates, where $\\\\geq 80\\\\%$ of the convergent component of relative plate motion was accommodated by interplate slip (Nicol and Beavan, 2003). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,582,310,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8. Amount of vertical tectonic motion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,607,240,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8.1. Tectonic subsidence/uplift \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,634,487,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A backstripping analysis has been carried out to estimate the tectonic component of subsidence in both the SFB and the Colombian Basin. The thickness of the stratigraphic units has been measured in the depth-converted seismic profiles. The ages in million years of the stratigraphic tops have been taken from the International Stratigraphic Chart v 2019/05 (International Commission on Stratigraphy, 2019). Although \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,939,408]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the different stratigraphic units are separated by unconformities, we have assumed that no hiatuses occur between them, because no accurate information about their ages is available. We have used the same exponential function of porosity variation with depth for all the stratigraphic units, being the c coefficient equal to 0.5 and the porosity at zero depth equal to $50\\\\%$ , because no porosity well logs are available and all the stratigraphic units are mainly made up of shales. We have assumed that the water depth at the time of sedimentation of the different stratigraphic units was the current water depth in the Colombian Basin, because they are interpreted to be deposited in similar deep-water environments. However, since the deposition of the Pliocene and Quaternary sediments was approximately coeval to the SFB formation, we have assumed that the water depth during their deposition in the SFB was the same as it is at their current location. Standard values of density equal to $3.3~\\\\mathrm{g/cm^3}$ for the asthenosphere and $1.0~\\\\mathrm{g/cm^3}$ for water have been used. Thus, the numerical values obtained for the tectonic subsidence may not be reliable, however, the trend of the functions obtained probably is. The purposes of this analysis are: a) decipher whether tectonic subsidence or uplift occurred in the different regions and at different times, b) identify variations in the tectonic subsidence/uplift patterns across strike (Colombian Basin-deformation front-continental shelf) and along strike (south part-central part-north part), c) estimate rates and values of tectonic subsidence/uplift due to the Pliocene-Quaternary SFB development, and d) link the tectonic subsidence/uplift patterns to geodynamic phenomena derived from the SFB development. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,409,939,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Firstly, we have compared two tectonic subsidence curves (Fig. 8a and b), derived from two stratigraphic columns located in two different structural positions within the Colombian Basin (Fig. 8c). These columns are located in the southwestern part of one depth-converted seismic profile approximately parallel to the SFB trend; one in the downthrown hangingwall and the other in the uplifted foot wall of a normal fault that bounds the graben mapped in the northwest part of the seismic section depicted in Fig. 6b. These two columns have helped us to figure out small-scale variations in the tectonic subsidence pattern in the Colombian Basin. All the stratigraphic units from Cretaceous to present-day occur in the downthrown fault-block column, whereas the Eocene and Oligocene are absent in the uplifted fault-block column due to a hiatus or eroded section. The tectonic subsidence was moderate in both columns from Cretaceous to Paleocene when normal faulting with relatively high displacement took place in the Colombian Basin; null in the uplifted fault block and slow in the downthrown fault block during the Eocene, Oligocene and Miocene, when sporadic normal faults with relatively small displacement still developed in the Colombian Basin; and very fast during Pliocene and Quaternary in both columns when the development of the SFB caused lithospheric flexuring in the Colombian Basin. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,672,939,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Secondly, we have compared twelve tectonic subsidence curves (Fig. 9), derived from stratigraphic columns located in three different structural positions along the four depth-converted seismic profiles \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[211,730,788,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 7. Sketch showing that plate motion at convergent margins is accommodated by belt shortening plus slip along the basal detachment (modified from Nicol and Beavan, 2003). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0304/3615c0c2509a92b0ccde75a96d984040d5747fd4f031cfa4ab201a5c413b15ec.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[494,950,504,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[60,68,339,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0315/d29a40a857aeb7bdb5cf84c2185e19db1678ace25d68b8aaf9499d7c6611d4e3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[357,66,636,426]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 8. Depth versus time graphs illustrating two tectonic subsidence curves constructed in the Colombian Basin in: a) the downthrow fault block and b) in the uplifted fault block of a normal fault that bounds a graben. c) Structural sketch of the SFB and Colombian Basin showing the location of the tectonic subsidence curves shown in a) (black stars) and in Fig. 9 (black circles). The thin black lines indicate the position of the seismic profiles where the tectonic subsidence curves are located. See also caption of Fig. 6 for location. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0409/45dfed5a0ec1f10575bf728b3b2ea8e0334003ef829d2f21b6dc1eed137c02ae.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,455,485,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"approximately perpendicular to the SFB trend (Fig. 4). Three columns have been built in each profile: one in the Colombian Basin, one in the continental slope adjacent to the SFB deformation front, and one in the continental shelf adjacent to the SFB shelf break (Fig. 7c). Thus, we have obtained four tectonic subsidence curves in the Colombian Basin, four in the deformation front and four in the trailing part of the belt. Our purpose is to characterize large-scale variations, both along and across strike, in the tectonic subsidence pattern as a result of the SFB development. The path of the tectonic subsidence curves derived from the four columns located in the Colombian Basin is very similar (Fig. 9a, 9b, 9c and 9d). Similarly, the tectonic subsidence pattern obtained for the four columns located in the continental slope is similar (Fig. 9e, 9f, 9g and 9h), and the tectonic subsidence pattern obtained for the four columns located in the continental shelf is almost identical (Fig. 9i, 9j, 9k and 9l). Thus, there are no significant differences along strike. According to the twelve curves, the tectonic subsidence is fast during Paleocene, and slow during Eocene, Oligocene, and Miocene, although it increases from the Colombian Basin to the continental shelf. The main differences occur during Pliocene and Quaternary. In the Colombian Basin, the Pliocene-Quaternary tectonic subsidence increases with respect to the Eocene-Oligocene-Miocene tectonic subsidence (Fig. 9a, 9b, 9c and 9d). In the continental slope, the Pliocene-Quaternary tectonic subsidence is similar to the tectonic subsidence during the Eocene-Oligocene-Miocene except for the southernmost profile where uplift occurs (Fig. 9e, 9f, 9g and 9h). In the continental shelf, a pronounced uplift occurs during the Pliocene-Quaternary (Fig. 9i, 9j, 9k and 9l). We believe the Colombian Basin suffered a remarkable tectonic subsidence during Pliocene and Quaternary times because it is located on the Caribbean subducting plate that sank below the South-American overriding plate and supported the SFB tectonic and sedimentary load. The Pliocene-Quaternary subsidence near the SFB deformation front was partially compensated by the belt uplift, and therefore, there was little tectonic subsidence or even some small tectonic uplift. A noticeable tectonic uplift took place in the continental shelf during Pliocene and Quaternary due to the SFB development. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,916,485,929]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although the numerical values derived from the tectonic subsidence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,455,939,759]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"curves are not reliable, the comparison between values obtained in different times and in different regions might be significant. Thus, we have estimated tectonic subsidence/uplift values during the SFB development by subtracting the tectonic subsidence values obtained at the end of the Miocene from the values obtained during the Pliocene-Quaternary. While there has been tectonic uplift of approximately 0.6 km in the southern part of the SFB deformation front (Fig. 9e), in the central and northern parts of the deformation front there has been about 0.2 km of tectonic subsidence (Fig. 9f, g and 9h). In the continental shelf the tectonic uplift ranges from 2.6 km in the southern part of the belt (Fig. 9i), to 2.7–3 km in the central part (Fig. 9j and k), to slightly more than 2.2 km in the northern part (Figure 9l). Thus, the most similar behavior between the deformation front and the continental shelf in terms of subsidence/uplift has occurred in the southern portion of the belt where uplift has taken place at both sites. On the contrary, in the central portion of the belt, the behavior has been dramatically different with slight subsidence in the deformation front and large uplift in the continental shelf. The behavior has been intermediate in the northern portion of the belt with slight subsidence in the deformation front and moderate uplift in the continental shelf. Since these figures were achieved during a time span of approximately 5.3 Myr, the average rates of tectonic uplift inferred in the most uplifted region, i.e., the continental shelf, range from 0.4 to 0.6 mm/yr. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,778,700,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8.2. Vertical tectonic thickening \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,804,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The wedge vertical thickness has been estimated at different localities in the four depth-converted seismic profiles approximately perpendicular to the SFB (Fig. 4) and a map of iso-contours of wedge vertical thickness in the continental slope has been constructed by interpolating the available data (Fig. 10). The wedge vertical thickness near the deformation front, measured from the seafloor to the basal detachment, is less than $4\\\\mathrm{km}$ in the central profiles across the belt and increases to almost $6\\\\mathrm{km}$ in the southern profile, and to more than $5\\\\mathrm{km}$ in the northern profile (Fig. 10). The wedge vertical thickness near the shelf break is $10\\\\mathrm{km}$ in the northern profile and decreases progressively \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,507,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[164,66,196,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0761/28cf81d3ab874a55671bfa7877f8a1a5aabe2594b3ec6b2d0585ccc13d93907c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,100,321,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"COLOMBIAN BASIN \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0664/f691a80acc3d4f9f5ba866b0c699e5d4fbaf01a7c992e0d189a21a732ac43933.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n 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\"[699,100,870,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0940/aa0af62fe04beb80e3171325ceca8f0fc97f8aa9191df7e4149ddbbdd15b2884.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,341,321,557]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0610/37d119e9415bdae54fec9e33b4d76b1b2472b8512ae3216fcfc41ce3a1e5e38f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[334,325,507,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0239/42c5fae7e931a56025f8be9386dc83c83f2a281b2904ee7e267fe0e3446e0361.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[517,341,687,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0880/85caa72fc1d3f614ae5efc02d9538d5eb96fd711c9b54ba5a3a26f6025b7f7fc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[700,341,870,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0992/c7d13252e134e1e420cb95cedb633bad287546d28f6f3da9df17ac9a1d7a1cd5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[124,582,321,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0122/3c09f5fa34b82b95a221030399c27545f59123ae13e17beed38c194896f010bb.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[334,567,505,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0114/ab223762140a31a63d1e155ead2b03432db18b5359418ea6eda895942025ebfa.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[515,582,687,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0151/0a70179a9c37f5bfd525817496bcac15dc8be8408129c8b9652b4fead041c1ac.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[699,582,870,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 9. Depth versus time graphs illustrating twelve tectonic subsidence curves for: a), b), c) and d) the Colombian Basin; e), f), g) and h) the SFB deformation front; and i), j), k) and l) the continental shelf. C: Cretaceous, P: Paleocene, E: Eocene, O: Oligocene, M: Miocene, PQ: Pliocene-Quaternary. See Fig. 8c and caption of Fig. 4 for location. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0366/44ea758e33cc091e15c7cedc51aa7afc4b9f15350365ec62cdbdc801da21506f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,873,487,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"to approximately $9\\\\mathrm{km}$ towards the southern profile. Thus, the difference between the wedge vertical thickness measured in the deformation front and in the continental shelf break is maximum in the central profiles across the belt, minimum in the southern profile, and intermediate in the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,873,613,886]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"northern profile. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,887,937,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The orthogonal thickness of the whole stratigraphic sequence has been measured at different localities in the four depth-converted seismic profiles approximately perpendicular to the SFB (Fig. 4) and an isopach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,146,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[171,65,823,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 10. Map of isopachs and iso-contours of wedge vertical thickness of the SFB continental slope from the deformation front to the shelf break. The data used to construct this figure come from values measured in the depth-converted seismic lines shown in Fig. 4. The location of the seismic profiles displayed in Fig. 4 is shown. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0284/71eb8847b04e6067900c835287a0a10008d89849749bad21818a5f4e9c87c2fa.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,786,485,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"map has been constructed by interpolating the available data (Fig. 10). The amount of vertical tectonic thickening has been estimated by subtracting the orthogonal thickness of the stratigraphic sequence from the wedge vertical thickness at each locality. As expected, the amount of vertical tectonic thickening increases from the deformation front, where it is 0, to values around $0.5 - 2.1\\\\mathrm{km}$ in the shelf break area. The stratigraphic thickness contours and the wedge vertical-thickness contours (Fig. 10) are not strictly parallel but intersect each other more than once. This indicates that the sedimentary basin infilling did not fully control the SFB structure, so that variations occurred along strike. The greatest difference between the magnitude of the isopachs and that of the wedge \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,786,937,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"vertical thickness occurs at the central part of the belt, indicating a greater vertical tectonic thickening in this region. The minimum tectonic thickening occurs in the south part of the belt and an intermediate tectonic thickening occurs in the north part. Taking into account that this thickening occurred during a time span of approximately 5.3 Myr, the average rate of vertical tectonic thickening in the most thickened regions has been $0.4\\\\mathrm{mm / yr}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,878,937,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The absolute values of horizontal tectonic motion estimated in the section above have been compared with the values of vertical tectonic movement estimated in this section. The total horizontal motion has been estimated as the sum of the SFB shortening and the displacement \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodriguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"along the SFB basal detachment. The vertical motion has been estimated as the maximum tectonic uplift. The horizontal component of motion is far greater than the vertical one; thus, the horizontal motion component reaches percentages higher than $90\\\\%$ , whereas less than $10\\\\%$ has been accommodated as vertical motion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,146,179,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9. Recent motion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,172,186,186]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9.1. Morphostructure \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,199,485,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The SFB reaches around $130\\\\mathrm{km}$ in width in its central portion, measured from the Sinú Fault Zone to the deformation front, decreasing towards both edges to approximately $95\\\\mathrm{km}$ to the north and $110\\\\mathrm{km}$ so the south (Figs. 3 and 11a). The width of the continental shelf and its adjacent land, measured from the shelf break to the Sinú Fault Zone, reaches its maximum value (around $75\\\\mathrm{km}$ ) in the south part of the belt decreasing progressively to approximately $45\\\\mathrm{km}$ in the north. The continental slope can be divided into upper continental slope, bounded by the shelf break and a slope break within the continental slope, and lower continental slope, that extends from this slope break within the continental slope to the deformation front (Fig. 11). The width of the whole continental slope, i.e., from the shelf break to the deformation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,157]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"front including both the upper and lower continental slopes, is maximum in the central part of the belt (almost $40\\\\mathrm{km}$ wide the upper continental slope and almost $30\\\\mathrm{km}$ wide the lower continental slope) and decreases both to the north (almost $30\\\\mathrm{km}$ wide the upper continental slope and almost $15\\\\mathrm{km}$ wide the lower continental slope) and to the south (slightly more than $15\\\\mathrm{km}$ wide the upper continental slope and $0\\\\mathrm{km}$ wide the lower continental slope). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,157,937,316]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The dip of the seafloor in the continental shelf and in the abyssal plain changes from less than a degree to slightly more than a degree to the NW, whereas the dip of the continental slope seafloor ranges from slightly less than $2^{\\\\circ}$ to slightly more than $7^{\\\\circ}$ to the NW (Fig. 4). The seafloor dip in the upper continental slope, from less than $2^{\\\\circ}$ to almost $4^{\\\\circ}$ , is lesser than the seafloor dip in the lower continental slope, from slightly more than $3^{\\\\circ}$ to slightly more than $7^{\\\\circ}$ . The seafloor dip in the upper and lower continental slopes increases from the central part towards both the north and south parts of the belt. The seafloor dip difference in the upper versus the lower continental slope increases from less than $2^{\\\\circ}$ in the central part of the belt up to almost $5^{\\\\circ}$ in the north and up to almost $4^{\\\\circ}$ in the south. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,316,937,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The seafloor in the continental shelf and in the abyssal plain is approximately a planar surface, but the continental slope seafloor may be either planar or irregular (Fig. 11). The width of the irregular portion \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[62,373,581,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0435/e6748ca8aabaad21fd8d907f45048d5f5b066b8509eb0c9c47d406f41ba0fa08.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[586,373,934,880]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 11. a) Slope map constructed using the interpretation of the seafloor in the available seismic profile grid showing the location of eleven bathymetric profiles displayed in b). The profiles are vertically exaggerated and their section lines are approximately perpendicular to the slope. AP: abyssal plain, LCS: lower continental slope, UCS: upper continental slope, CS: continental shelf. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0310/ed2cccee65473c336195c6f3ac0065f0fe678872c1545ecfbb2c5e3916146ac3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,170]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of continental slope seafloor increases progressively from south to north, so that almost no irregularities occur in the south part of the belt, whereas the whole continental slope seafloor is irregular in the north part of the SFB (Fig. 11b). The boundary between regular and irregular bathymetry is oblique to the boundary between the upper and lower continental slope, so that, the seafloor in the upper continental slope displays a more regular bathymetry than that of the lower continental slope. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,66,616,76]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9.2. Neotectonics \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,92,937,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The seafloor in the SFB shows evidence of recent superficial processes, such as sedimentation, channel and canyon erosion, slumping, etc. (Vinnels et al., 2010). However, these processes have not been intense enough to mask the bathymetric expression of recent thrusts and related folds, recognized as elongated hills in the case of anticlines and elongated depressions in the case of synclines. Since all the structures involve approximately the same lithologies and submarine erosion is similar throughout the entire SFB, we can assume that an irregular \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[121,214,870,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 12. Structural map of the SFB shown in Fig. 3 overlapped on the map shown in Fig. 11 to illustrate the emergent structures domain and the buried structures domain. The geometry of the boundary between both domains has been drawn taking into account not only seafloor irregularities but geological elements such as folds, thrusts and tear faults. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0761/fc5083c75e2fd6bf29e5cf635518f4ecfdc3751fccfb63ccd8c9392d6879afe4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,484,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"seafloor is due to active underlying structures, while a regular seafloor, either because of erosion or because of structures mantled by sediment fill, indicates that the underlying structures are inactive. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,105,485,235]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Many structures located in the east portion of the SFB are not topped by seafloor irregularities, whereas many structures located in the westernmost part of the belt have caused bathymetric irregularities in the seafloor (Figs. 11 and 12). This suggests that the tectonic activity responsible for the development of thrusts and related folds propagated from ESE (inactive structures at present) to WNW (active structures in recent times). This is in accordance with the forward or piggy-back sequence of propagation of thrusts and related folds deduced from growth stratal patterns (Rodriguez, 2020; Rodriguez et al., 2021, 2022b). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,238,487,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The continental slope seafloor in the south edge of the belt is approximately regular, except for the most frontal structure that constitutes the deformation front in this area; thus, only this structure may be presently active, whereas the rest of structures seem to be inactive. The irregular geometry of the whole continental slope seafloor in the north part of the belt suggests that most structures located in this region are presently active (Figs. 11 and 12). The width of the region in which the structures have bathymetric expression, the number of structures developed below the irregular area and the seafloor irregularity is much greater to the north than to the south. This suggests that the tectonic activity of the belt in recent times has been much higher in the north sector of the belt than in the south one. This along-strike variation in tectonic activity could be explained in two different ways. a) If we assume that the Caribbean tectonic plate is slightly rotating clockwise with respect to the South American tectonic plate along an axis located south of the study area, then a larger amount of Caribbean Plate would subduct below the South American Plate in the north part of the SFB than in the south part. b) In the southern profile, the Pliocene and Quaternary sediments are very thick and are distributed throughout the entire profile (Fig. 4d). This could be the result of a possible increased sediment influx during the Pliocene-Quaternary coming from the Atrato River, located south of the study area (Connors, pers. com.). Because of increased sediment, the taper in this region could be maintained (or even be supercritical) without internal tectonic thickening, i.e., without structure activity. If this hypothesis were true, one of the most remarkable consequences would be that uplift produced onshore to the south of the study area could influence the SFB development. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,592,485,750]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In outline, the boundary between regular and irregular bathymetry is not strictly parallel to the strike of the thrusts and related folds developed in the continental slope (Fig. 12). Thus, some structures with no bathymetric expression to the south exhibit bathymetric irregularities to the north, suggesting that the tectonic activity responsible for the development of these particular structures stopped before in the south (inactive part of the structure) than in the north (active part of the structure). This points out that these structures propagated according to a combined frontal and lateral propagation model (Poblet, 2020). Although the available seismic profile grid is not dense enough, it seems that the position of the boundary between active and inactive structures in some localities is controlled by tear faults. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,751,487,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A positive bathymetric relief, much higher than the adjacent reliefs, developed above a thrust-related anticline located at the boundary between the upper and lower continental slopes in the north (bathymetric profiles 1 and 2 in Fig. 11b) and south-central (bathymetric profiles 6 and 8 in Fig. 11b) parts of the SFB. It is likely that the relief height is somehow related to the amount of thrust displacement and to the age of activity cessation of the underlying structure. Assuming that the temporal factor is the most important controlling parameter, we can state that the structure located at the boundary between the upper and lower continental slopes is younger than the surrounding structures. Thus, this structure would be an out-of-sequence thrust with respect to the general piggy-back thrust sequence. This timing is in accordance with that deduced from growth strata and cross-cutting relationships between this structure and adjacent structures in the geological interpretation of the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,65,862,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"seismic profiles (Rodriguez, 2020; Rodriguez et al., 2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,92,628,105]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10. Critical taper \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,118,670,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.1. Taper measurements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,143,937,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The taper angle is the sum of the bathymetric surface slope $(\\\\alpha)$ , measured from the deformation front to remarkable slope changes within the continental slope or to the continental shelf, and the basal detachment dip $(\\\\beta)$ (Davis et al., 1983). A large number of points corresponding to the seafloor and the basal detachment have been digitized in each of the four depth-converted seismic profiles depicted in Fig. 4. These points have been adjusted by linear best-fit functions to calculate the average slope of the submarine topography and the average dip of the basal detachment. The coefficients of determination $\\\\mathbb{R}^2$ obtained for the best-fit linear functions vary between 0.8 and almost 1 in the case of the submarine topographic slope, and from 0.9 to almost 1 for the basal detachment dip. The values of these coefficients, very close to 1, guarantee that the linear functions obtained are reasonable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,316,937,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The azimuths of the four depth-converted seismic profiles are N154E for the southernmost one and from N132E to N136E for the other three (Fig. 1b). The azimuth of these seismic profiles is not strictly perpendicular to the bathymetric contours (Fig. 11a) and to the trace of the main longitudinal structures on the structural SFB map (Fig. 3). Thus, the average slope of the submarine topographic surface and the average dip of the basal detachment obtained from the four seismic profiles using best-fit functions are not true but apparent dips. The azimuth of the depth-converted seismic profiles forms an angle from $3^{\\\\circ}$ to $34^{\\\\circ}$ with the azimuth of the maximum dip line of the main thrust surfaces and that of the main fold limbs. In order to estimate the true average slope of the submarine topographic surface and the true average dip of the basal detachment from their apparent average dips in the four seismic profiles, the following equation has been used: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,509,937,523]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\varphi = \\\\arctan \\\\left(\\\\tan \\\\varphi^ {\\\\prime} / \\\\cos \\\\gamma\\\\right), \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[507,533,937,585]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\varphi$ is the true dip, $\\\\varphi^{\\\\prime}$ is the apparent dip measured on the seismic profile using a best-fit function and $\\\\gamma$ is the angle between the seismic profile azimuth and the azimuth of the maximum dip line of the longitudinal main structural elements. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,586,937,742]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition, the four sections obtained from the seismic profiles (Fig. 13) have been compared with the bathymetric profiles obtained from the bathymetric map to double check them (Fig. 11b). The average dips of the upper and lower continental slopes in the section obtained from the center-south seismic profile (Fig. 13c) are very similar, while these dips are different in the bathymetric profiles perpendicular to the bathymetric contours constructed by ourselves (bathymetric profiles 5, 6 and 8 in Fig. 11b). The center-south seismic profile is more oblique to the SFB trend than the rest of profiles. To sort this out, the geometry of the lower continental slope in this profile has been modified (Fig. 13c) according to a 3D surface generated from our bathymetry and a new true slope has been calculated. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,745,937,889]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The taper angle in the lower continental slope ranges from $6.9^{\\\\circ}$ to $8.4^{\\\\circ}$ , while it ranges from $5.5^{\\\\circ}$ to $7.2^{\\\\circ}$ in the upper continental slope (Fig. 14). The taper angle estimated in the lower continental slope decreases from the central-south portion of the SFB to the north edge. This decrease occurs because the detachment dip in the north edge increases but the dip of the lower continental slope decreases more. The taper angle in the upper continental slope remains approximately constant along strike, except for the SFB south edge where it increases. This increase is due to an increment in the dip of the upper continental slope in the south part of the belt, although the detachment dip remains approximately constant along strike. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,507,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,68,860,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 13. Four simplified profiles showing the seafloor and basal detachment extracted from the four depth-converted seismic profiles across the SFB depicted in Fig. 4. In the center-south profile (c), the continental slope and the basal detachment underneath have been reconstructed using information from the bathymetric profiles displayed in Fig. 11b and from the rest of depth-converted seismic profiles (see text for an explanation), so that the grey lines come from the original profile. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0356/e4a622803a78ec4963b770a21ce419e5f9d557c40206ad760cd11655337762ce.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,783,381,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.2. Estimations of pore pressure, friction and strength \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,808,485,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The critical angle is the equilibrium angle established at the leading edge of a wedge that can slide along a basal detachment without undergoing internal deformation (Davis et al., 1983). In the SFB, folds related to thrusts and out-of-sequence thrusts giving rise to marked seafloor irregularities in some localities of the transition zone between the lower and upper continental slope (Fig. 11b) contributed to increase the taper, while normal faults and related toe thrusting, as well as erosional unconformities, developed in some portions of the continental slope and the continental shelf (Figs. 3 and 4) contributed to reduce the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,781,937,861]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"taper angle. These observations suggest that the SFB taper angle might have been subcritical in some periods and regions, and supercritical in others. A numerical analysis of the parameters that control the taper angle has been carried out in order to gain insight into the understanding of the causes of the across- and along-strike variations of the SFB taper angle. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,862,937,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Since the critical angle theory is fulfilled for mechanically homogeneous wedges (e.g., Davis et al., 1983), we have assumed that the SFB is a homogeneous wedge, and this has allowed us to perform a simple analytical approach. The fact that variations in the bathymetric surface inclination are reflected in slight changes in the basal detachment dip \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,952,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"16 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,65,870,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 14. Map showing the taper angles measured in the SFB continental slope constructed by interpolating values measured in the four depth-converted seismic profiles approximately perpendicular to the SFB shown in Fig. 4. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0229/142f469556f88732642faf1df4bbab415de68f9bd5496756075e8a17631aa466.jpg\",\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,732,485,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Fig. 13) suggest that the SFB may be a mechanically homogeneous wedge, because in non-mechanically homogeneous wedges variations in the slope of the bathymetric surface are not associated with variations in the basal detachment dip (Suppe, 2007). Of course, the basal detachment dip is not the only determining factor to infer whether a wedge is homogeneous or heterogeneous, since, for instance, variations in the strength of the basal detachment could take place due to lithology and/or fluid pressure changes. In fact, we must keep in mind that the across- and along-strike variations described by Bernal-Olaya et al. (2015), Rodríguez (2020) and Rodríguez et al. (2021) rather suggest that the SFB is not strictly a homogeneous wedge. Thus, the results obtained should be taken with caution. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,891,485,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Since the geometry of a wedge depends on the pore pressure and internal friction (Davis et al., 1983; Dahlen, 1990), first of all, we have searched the literature for the most appropriate range of values for these \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,732,937,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"physical parameters to be applied to the SFB taking into account its characteristics. We have assumed that the pore pressure in the wedge $(\\\\lambda)$ is approximately equal to the pore pressure at the detachment $(\\\\lambda b)$ although we admit that the wedge pore pressure may be up to $10\\\\%$ lower than the detachment pore pressure, and that the friction coefficient in the wedge $(\\\\mu)$ is equal or greater than the basal friction coefficient at the detachment $(\\\\mu b)$ with a maximum difference of $30\\\\%$ between both values. The minimum pore pressure considered is 0.4, since we assume that the sediments within the wedge are close to the fracturing point, and therefore, their pore pressure must be greater than the hydrostatic pore pressure $(\\\\lambda h \\\\sim 0.4)$ . According to Hubbert and Rubey (1959), a pore pressure equal to 1.0 would correspond to a subaerial wedge in which there is no fluid in the pores. Thus, the value of 1.0 has been discarded for the SFB, but values up to 0.9 have been admitted because these values can be reached in overpressured wedges, such as the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodriguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"17 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,525]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Makran (Harms in Davis et al., 1983), Barbados (Moore and Von Huene, 1980), Aleutians (Hottman et al., 1979) and Oregon (Moore and Von Huene, 1980) wedges amongst others. The coefficients of internal friction, estimated from fracturing laboratory experiments, range from 0.6 to 1.0 (Dahlen, 1990), being 0.85 the universal value of Byerlee (1978) for most rocks; their corresponding internal friction angles $(\\\\varphi)$ are $30 - 45^{\\\\circ}$ . Since the resistance of rocks decreases in saturated samples with high clay content (Morrow et al., 1981), coefficients of friction below 0.6 (equivalent to friction angles below $30^{\\\\circ}$ ) have been also admitted because the sediments involved in the SFB include a large amount of clays. Summarizing, the range of values chosen are: a) pore pressure in the wedge $(\\\\lambda)$ and at the base of the wedge $(\\\\lambda b)$ from 0.4 to 0.9, b) coefficient of friction in the wedge $(\\\\mu)$ and at the base of the wedge $(\\\\mu b)$ from 0 to 1, and c) angle of friction $(\\\\varphi)$ (related to the coefficient of friction $\\\\mu$ ) from $10^{\\\\circ}$ to $45^{\\\\circ}$ . All the range of values for the pore pressures, coefficients of friction and friction angles, as well as the dips of the detachment measured in the four depth-converted seismic profiles approximately perpendicular to the SFB trend, have been introduced in equation (86) of Dahlen (1990) to obtain theoretical taper angles $(\\\\alpha + \\\\beta)$ , wedge strengths (W) and basal detachment strengths (F). This equation is a useful approximation for wedges with narrow taper angles, where the maximum compressional stress axis is almost horizontal and the basal detachment is very weak. The SFB accomplishes these requirements because: a) the taper angles range from 5.5 to $8.4^{\\\\circ}$ , i.e., they are small, b) thrusts and backthrusts with similar dips coexist, i.e., the maximum compressional stress axis is almost horizontal, and c) shales constitute the detachment horizon, i.e., the basal detachment is very weak. Varying the pore pressure 0.1 units and the friction angles $2^{\\\\circ}$ each time, we have obtained thousands of theoretical taper angles. These results have been compared with the actual taper values measured in the four depth-converted profiles. At first sight, the best pore pressures, coefficients of friction and strength values would be those whose resulting theoretical taper angles were more similar to the actual taper values measured in the depth-converted profiles, however, more issues need to be considered. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,527,485,698]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to determine the most appropriate pore pressure, friction and strength values for the continental slope, solutions that do not meet the following three conditions have been discarded: a) the difference between the taper angles estimated using the equation and those measured in the four seismic profiles must be as low as possible (we have assumed that less than $0.867^{\\\\circ}$ is a good approximation for the upper continental slope and less than $0.838^{\\\\circ}$ is a good approximation for the lower continental slope); b) the pore pressure, friction and strength values must be the same for the four transects because we have assumed that the wedge is approximately homogeneous; and c) the wedge pore pressure must be equal to or up to $10\\\\%$ lower than the detachment pore pressure, and the wedge friction coefficient must be equal to or up to $30\\\\%$ higher than the detachment friction coefficient. Three solutions \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,274]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"meet these conditions for the upper continental slope and four coincidences have been obtained for the lower continental slope (Table 1). We have chosen the solutions whose pore pressure, friction and strength values for the upper continental slope are more similar to those obtained for the lower continental slope following the principle that the wedge is approximately homogeneous (solutions framed by red rectangles in Table 1). The taper angle of the upper continental slope measured in the seismic profiles that differs more from the theoretically estimated taper angle is that of the south profile (underestimated by $0.86^{\\\\circ}$ ), whereas the taper angle measured in the seismic profiles that resembles more the estimated taper angle is that of the north profile (overestimated by $0.50^{\\\\circ}$ ) (Fig. 15). The greatest difference between the theoretically estimated taper angle and the measured taper angle for the lower continental slope occurs in the center-south profile (underestimated by $0.83^{\\\\circ}$ ), whereas the minimum difference occurs in the center-north profile (overestimated by $0.30^{\\\\circ}$ ) (Fig. 15). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,276,937,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To double-check the wedge strength and the basal detachment strength obtained for the active part of the SFB, i.e., mainly the lower continental slope, a technique created by Suppe (2007) has been applied. According to this author, the strength of active, mechanically-homogeneous wedges and the strength of their basal detaches can be directly determined from the linear covariation of surface slope $(\\\\alpha)$ and detachment dip $(\\\\beta)$ , without strong assumptions about the specific strength-controlling mechanisms. This strategy has been successfully applied to experimental dry sand wedges, the Niger Delta thrust belt, the Taiwan mountain belt, and a particular thrust responsible for an earthquake. The wedge strength and the basal detachment strength obtained for the lower continental slope of the SFB using the linear best-fit function and equations (3) and (4) of Suppe (2007) is 1.74 and 0.27 respectively, although we must admit that the $R^2$ coefficient is 0.4, which indicates that the fit is not very good as only three data points are available (Fig. 16). The difference between the values calculated from combining all the parameters in Dahlen (1990) equation and from the linear covariance strategy of Suppe (2007) is 0.287 for the wedge strength and 0.034 for the basal detachment strength, being always greater the values estimated using the linear covariance method. These small differences point out that the results obtained from both methods are consistent, and suggest that they could be reasonable values since they are similar and have been calculated employing methods unrelated to each other. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,593,939,699]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The values chosen in our simulation of the taper angles for the upper continental slope and for the lower continental slope are identical in terms of basal pore pressure, internal friction, basal friction and fault strength, but they differ in the internal pore pressure (0.6 for the upper continental slope and 0.7 for the lower continental slope) and in the wedge strength (1.93 for the upper continental slope and 1.45 for the lower continental slope). The fact that the calculated internal pore pressure is smaller in the upper continental slope with respect to that of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,776,939,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0935/95ec95891cd58d91ce9447174e6f359962958a899fbef15839959c6225066026.jpg\",\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>TAPER</td><td>ANGLE</td><td>(α + β)</td><td>(°)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td>Seismic</td><td>profiles</td><td></td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td></td><td></td><td>South</td><td>C-South</td><td>C-North</td><td>North</td><td>λ</td><td>λb</td><td>μ</td><td>φ</td><td>μb</td><td>F</td><td>W</td></tr><tr><td>Lower</td><td>1</td><td></td><td>7.61</td><td>7.17</td><td>7.92</td><td>0.5</td><td>0.6</td><td>0.6</td><td>32</td><td>0.5</td><td>0.200</td><td>1.127</td></tr><tr><td>continental slope</td><td>2</td><td></td><td>7.53</td><td>7.26</td><td>7.63</td><td>0.4</td><td>0.5</td><td>0.9</td><td>41</td><td>0.7</td><td>0.350</td><td>2.289</td></tr><tr><td>(dmax=0.838°)</td><td>3</td><td></td><td>7.58</td><td>7.16</td><td>7.76</td><td>0.6</td><td>0.7</td><td>0.8</td><td>37</td><td>0.7</td><td>0.210</td><td>1.209</td></tr><tr><td></td><td>4</td><td></td><td>7.54</td><td>7.16</td><td>7.69</td><td>0.7</td><td>0.7</td><td>1.0</td><td>45</td><td>0.8</td><td>0.240</td><td>1.449</td></tr><tr><td>Upper</td><td>1</td><td>6.33</td><td>6.22</td><td>6.34</td><td>5.96</td><td>0.9</td><td>0.9</td><td>0.4</td><td>22</td><td>0.4</td><td>0.040</td><td>0.120</td></tr><tr><td>continental slope</td><td>2</td><td>6.33</td><td>6.30</td><td>6.33</td><td>6.22</td><td>0.6</td><td>0.7</td><td>1.0</td><td>45</td><td>0.8</td><td>0.240</td><td>1.931</td></tr><tr><td>(dmax=0.867°)</td><td>3</td><td>6.32</td><td>6.25</td><td>6.33</td><td>6.08</td><td>0.9</td><td>0.9</td><td>1.0</td><td>45</td><td>0.8</td><td>0.080</td><td>0.483</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1 Theoretical taper angles, as well as pore pressures, coefficients of friction, friction angles and strength values, calculated for the lower and upper continental slope. The most plausible combinations of parameters are inside red rectangles. The taper angles obtained in the two most plausible solutions are represented graphically in Fig. 15. $\\\\\\\\mathbf{d}_{\\\\\\\\mathrm{max}}$ : maximum difference allowed between the measured taper angle and the theoretical one. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,507,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"18 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[208,66,786,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 15. Graphical comparison between the taper angles measured in the four depth-converted profiles approximately perpendicular to the SFB shown in Fig. 4 and the theoretical taper angles obtained, both in the lower continental slope and in the upper continental slope. The values of the taper angles measured in the seismic profiles have been extracted from Fig. 14, while the values of the theoretical taper angles have been extracted from Table 1. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0856/28766075944dbd390b5f3d34c2f0f64deb49f08c331cdd7715761b74ca480153.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[208,330,789,607]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 16. Graph showing the bathymetric slope versus the basal detachment dip, in which the values measured for the lower continental slope in three depth-converted seismic profiles shown in Fig. 4 have been plotted. The wedge strength (W) and the basal detachment strength (F) have been estimated from the linear best-fit function according to Suppe (2007) method. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0985/224464cd5f5334d567e244e0288bd2b6bcec4693a58a8f0d901a2ac621416098.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,665,485,825]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the lower continental slope is in accordance with the taper angle measurements, lower in the upper continental slope and higher in the lower continental slope. Thus, the wedge may not be strictly homogenous, but it does not differ too much because the differences in the values obtained are small. The taper-angle controlling parameters obtained here are different from those deduced by previous authors because: a) the input data and the methodology employed here are different from those of previous authors, b) Toto and Kellogg (1992) analysis is based on five topographic profiles whereas the basal detachment dip is supposed to be a constant value, and c) Bernal-Olaya et al. (2015) employed only two sections across the belt derived from the geological interpretation of seismic profiles. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,844,468,857]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3. Temporal and spatial variations of taper angle and pore pressure \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,870,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As mentioned above, some features in the SFB such as thrusts and out-of-sequence thrusts, normal faults and related toe thrusts, and erosive unconformities are responsible for the modification of the taper angle. Nevertheless, taking into account that the basal pore pressure, the internal friction and the basal friction obtained for the upper and lower \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,665,937,824]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"continental slopes are equal, while the internal pore pressure is somewhat different (Table 1), it seems reasonable to assume that variations in internal pore pressure may have also contributed to taper angle variations. To illustrate these variations, we have constructed a graph in which the bathymetric slope is plotted versus the basal detachment dip for different internal pore pressure values (Fig. 17). The basal pore pressure, internal friction and basal friction values employed to construct the graph (0.7, 1 and 0.8 respectively) are the ones chosen in the section above for both the upper and lower continental slopes. The bathymetric slopes and detachment dips measured for the upper and lower continental slopes in each of the seismic profiles have been plotted on this graph. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,825,937,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There is a slight discrepancy, whose maximum value is 0.1 units, between the pore pressure values estimated numerically in the section above (Table 1) and the pore pressure values obtained graphically from the bathymetric slope versus basal detachment dip graph shown in Fig. 17. The numerically-estimated pore pressure for the upper continental slope is 0.6 (Table 1), whereas the graphically-estimated pore pressure is generally lower (comprised between approximately 0.5 and 0.55) (Fig. 17). The reason is that the numerically-estimated taper \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"19 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,66,636,365]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 17. Graph showing the bathymetric slope $(\\\\\\\\alpha)$ versus the basal detachment dip $(\\\\\\\\beta)$ for different values of pore pressure and fixed values of basal pore pressure, coefficient of friction and coefficient of basal friction. The values measured for the lower and upper continental slopes in the four depth-converted seismic profiles shown in Fig. 4 have been plotted on the graph. A possible future path for part of the belt is also illustrated. UCS: upper continental slope, LCS: lower continental slope. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0271/caecd2523304b0c97491cab474df4eec2fb5f9995471ee1132f7aa340dc02883.jpg\",\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[55,390,485,549]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"angles are higher than the measured ones (Fig. 15), except for the south profile in which the graphically-estimated pore pressure is higher (around 0.65) because the numerically-estimated taper angle is lower than the measured one. A similar situation occurs for the lower continental slope where the numerically-estimated pore pressure is 0.7 (Table 1), whereas the graphically-estimated pore pressure is lower (it ranges between 0.65 and 0.7) (Fig. 17) in the north and center-north profiles -in this case the numerically-estimated taper angles are higher than the measured ones-, but on the contrary the numerically-estimated pore pressure in the center-south profile is lower than the graphically-estimated one (it ranges between 0.7 and 0.75) -in this case the numerically-estimated taper angle is lower than the measured one-. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,549,485,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We documented above that most structures in the lower continental slope are still active, whereas many structures in the upper continental slope are inactive (Fig. 12). Thus, if the present-day conditions remain constant, as the wedge advances seawards and involves undeformed rocks in the Colombian Basin, a new active lower continental slope may develop eastwards. As a consequence, the present-day, active, lower continental slope might become the inactive upper continental slope in the future, and the present-day, inactive, upper continental slope will become part of the continental shelf. If correct, the graph in Fig. 17 might illustrate the path of the taper angle of the present-day lower continental slope over time in each of the profiles across the belt. Except for the south section where there is no lower continental slope and most structures are inactive, and therefore, we are unable to predict its future evolution, the internal pore pressure of the wedge will decrease from values around 0.65–0.7 to values around 0.5–0.55 (black dashed arrows in Fig. 17). The manner in which pore pressure decreases will be related to the wedge geometry is different along strike. The internal pore pressure decrease in the central part of the wedge will be high (approximately from 0.15 to 0.2 units) and will be accompanied by a decrease in the seafloor slope and an increase in the basal detachment dip. The internal pore pressure decrease in the north portion of the wedge will be small (0.1 unit) and will go along with a decrease in the seafloor slope while the basal detachment dip will remain constant. As a result, both the taper angle and the internal pore pressure of the different along-strike regions of the SFB will become more similar. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,878,485,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Three types of regions are recognized in the SFB continental slope based on the spatial variations of the taper angle (Fig. 14) and the internal pore pressure (Fig. 18). a) A region with relatively high values of taper angle and internal pore pressure is restricted to the lower \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,390,939,537]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"continental slope in the center-south part of the SFB. b) Two regions with intermediate values of taper angle and internal pore pressure occupy the lower continental slope in the north and center-north part, as well as the upper continental slope in the south part of the belt. c) A region with relatively low values of taper angle and internal pore pressure is restricted to most of the upper continental slope except for the southernmost part. The maps in Figs. 14 and 18 show that the differences between the taper angle and internal pore pressure in the upper continental slope and those in the lower continental slope are maxima in the center-south part of the belt and decrease northwards where both values approximate each other. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,554,887,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.4. Relationships between pore pressure and sediment thickness \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,580,937,658]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As we will see below, some structural and bathymetric differences have been recognized in the SFB continental slope from north to south, however, the greatest difference corresponds to the sediment thickness (Fig. 4 in Rodríguez et al., 2021). This is why we suggest that sediment thickness may be one important controlling parameter of pore pressure variations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,659,937,829]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The pore pressure in the lower continental slope is higher than in the upper continental slope (Figs. 17 and 18). Thus, the degree of compaction of the sediments in the upper continental slope is greater, because the greater grain packaging the larger fluid loss and the larger pore pressure reduction. This is consistent with the fact that the stratigraphic succession prior to the SFB formation, as well as the succession coeval to the SFB formation, is substantially thicker in the upper continental slope than in the lower continental slope (Fig. 4 in Rodríguez et al., 2021) (Fig. 10). Perhaps the fact that the structures in the upper continental slope are generally older than those developed in the lower continental slope (Fig. 12), has favored an additional compaction due to tectonic load, which has taken place to a much lesser extent in the lower continental slope (Fig. 10). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,831,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The pore pressure in the upper continental slope is similar in the north, center-north and center-south profiles, whereas it is higher in the south profile (Figs. 17 and 18). The main along-strike stratigraphic difference in the upper continental slope is the lesser thickness of strata deposited before the development of the SFB in the southern part (Fig. 4 in Rodríguez et al., 2021) which probably suffered little compaction, i.e., the pores were hardly modified and little fluid was expelled. The high and fast sediment supply in this region during the SFB development \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[490,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"19\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"20 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[124,65,870,672]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 18. Map of pore pressure variation in the SFB continental slope for fixed values of basal pore pressure, coefficient of friction and coefficient of basal friction. The map has been constructed by interpolating values obtained from the four depth-converted seismic profiles approximately perpendicular to the SFB shown in Fig. 4. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0011/3eb8b9081a2c7915b66f2ccf318f058c4571800404fdea36c02ef67b2ecfac23.jpg\",\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,733,485,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(Fig. 4 in Rodríguez et al., 2021) may have caused a load increase on uncompacted sediments with open pores preventing fluid scape (e.g., Saffer and Bekins, 2006; Shi and Wang, 1985) leading to a pore pressure increase. The presence of more mud diapirs in the south portion of the upper continental slope (Fig. 3) supports the hypothesis of a higher pore pressure. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,813,485,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The pore pressure in the lower continental slope is similar in the north and center-north profiles, whereas it is much higher in the center-south profile (Figs. 17 and 18). The main along-strike stratigraphic difference in the lower continental slope is the extremely thinner sedimentary succession in the center-south profile with respect to the rest of profiles (Fig. 4 in Rodríguez et al., 2021). Similarly to the southern part of the upper continental slope, the thin sedimentary succession previous to the SFB formation probably suffered little compaction. Thus, the fast deposition of sediments synchronous to the SFB formation above poorly \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,733,937,761]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"compacted sediments caused a notable increase in pore pressure in the center-south region. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,778,766,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.5. Discussion on the taper angle analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,804,937,896]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The taper angle analysis performed above assumes an approximate homogeneous wedge, with basal pore pressure, and coefficients of internal and basal friction being constant everywhere, and admits that the variation in pore pressure in the wedge relative to the basal pore pressure can reach a $10\\\\%$ . No significant differences between the pore pressure in the wedge and the pore pressure at the detachment have been considered due to the reasons below. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,910,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"a) The equality between pore pressures in the wedge and at the detachment is supported by measurements taken in some wedges \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,42,142,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodriguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,937,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[490,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"20\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"21 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[78,65,487,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"such as Taiwan (Suppe and Wittke, 1977), as well as by successful analyses of the taper angle in Taiwan (Davis et al., 1983; Dahlen, 1990; Dahlen et al., 1984), Barbados (Davis et al., 1983; Dahlen, 1990), and other belts such as the Himalayas, Japan, Peru, Java, Sunda, Guatemala, Aleutians, Oregon, and Makran (Davis et al., 1983). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,145,485,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"b) In all the analyses of the SFB taper angle carried out up to date (Toto and Kellogg, 1992; Bernal-Olaya et al., 2015) the pore pressures in the wedge and at the detachment are considered to be equal. Thus, we have followed this assumption suggested by other authors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,211,485,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Nevertheless, we are aware that, for example, in the Nankai accretionary wedge, the fluid pressure in the wedge is lower than at the basal detachment. Thus, the pore pressure measured within the wedge is 0.58 (Kitajima et al., 2017), whereas the pore pressure near the megathrust fault at the base the wedge reaches approximately 0.85 (Kitajima and Saffer, 2012), so that its variation is slightly greater than $30\\\\%$ . Thus, in order to explore more possibilities in the SFB, we have relaxed the conditions; we have eliminated the limits to the difference between the values of pore pressure in the wedge and at detachment, and between the values of the coefficient of friction in the wedge and at detachment, as long as the theory is fulfilled, i.e., the wedge pore pressure must be equal to or less than the detachment pore pressure, and the wedge coefficient of friction must be equal to or greater than the detachment coefficient of friction. We have looked for those combinations of values whose: a) taper angle obtained is equal to that measured in the seismic profiles or whose difference is less than $0.838^{\\\\circ}$ and $0.867^{\\\\circ}$ in the lower and upper continental slope respectively, b) the basal detachment strength and the wedge strength obtained for the lower continental slope are equal to the values obtained using Suppe (2007) best-fit function or their difference is less than 0.04 and 0.3 respectively, and c) the values of the pore pressure and coefficients of friction obtained for the lower and upper continental slopes are as similar as possible. The result obtained is the same as with the more restrictive conditions. This means that the results obtained in relation to these parameters do not depend on the starting assumptions used regarding the limits imposed to the difference between the pore pressures at the wedge and at the detachment, and the coefficients of friction at the wedge and at the detachment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,580,485,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to estimate the pore pressure, friction and strength values from the taper angle analysis, we have assumed that the four cross sections presented have reached a critical taper state. However, this might not be the case in the particular situations listed below. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,645,485,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"a) According to our results there is higher pore pressure in the lower continental slope relative to the upper slope in the center-south, center-north and north profiles across the belt (Figs. 17 and 18). Another possibility is that the lower continental slope is subcritical and has not reached the critical taper yet. Consistent with this is the fact that this is the area of active deformation with thrusts breaching the seafloor (Fig. 12), and therefore, thickening this part of the wedge. \\\",\\\"b) Our results point out that the pore pressure in the upper continental slope is higher in the south profile than in the rest of profiles (Figs. 17 and 18). This region is the least deformed (Fig. 4), however, one would expect the opposite considering the higher pore pressure. As mentioned in a section above, the occurrence of a thick Pliocene-Quaternary succession all along the south profile may suggest an increased sediment supply by the Atrato River. Because of increased sediment, the taper could be maintained, or even be supercritical, without internal tectonic thickening. This could explain why this section is less deformed despite having a higher pore pressure. \\\"]\",\n \"page_idx\": \"21\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[58,897,354,909]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11. Aseismic subduction and trench absence \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,923,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The SFB has been interpreted as the front of the westernmost portion \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of an accretionary prism, known as South Caribbean Deformed Belt, developed as a consequence of the subduction of the Caribbean tectonic plate underneath the South American tectonic plate. This region exhibits at least two peculiarities with respect to other subduction zones: low seismicity related to the subduction zone and absence of a trench near the deformation front. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,143,937,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"According to available earthquake catalog compiled by the Arcila Rivera (2018), there have been very few earthquakes in the study area from 1610 to 2014, and their hypocenters are located at depths relatively close to the boundary between the subducting and the overriding plates. Given that the SFB slip rate calculated above is small (average shortening rate in the overriding plate from 3 to $5\\\\mathrm{mm / yr}$ and average rate of basal detachment displacement from 6 to $17\\\\mathrm{mm / yr}$ ) and that young sediments (Pliocene and Quaternary), probably under-compacted and with a high porosity, subduct, this may prevent brittle shear localization. This probably reduces the width of the seismogenic zone resulting in aeismic subduction (e.g., Byrne et al., 1988; Toto and Kellogg, 1992; Zhang et al., 1993). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,303,937,474]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The geological interpretation of the seismic profiles shows no trench separating the subducting and overriding tectonic plates (Fig. 4). The absence of a trench could be explained as the result of a very slight bending of the subducting plate as shown by the gentle dips of Colombian Basin reflectors in this region (Fig. 4). The reason for this gentle bending is that the Caribbean Plate subducts with a very low dip under the South American Plate (e.g., Bernal-Olaya et al., 2015). Moreover, very few normal faults were active in the Colombian Basin during the development of the SFB (Fig. 3) and their displacement was very small indicating a small amount of extension. Assuming that these faults developed as a consequence of the flexure in the outer part of the lithospheric flexure hinge, this also supports a gentle bending of the subducting plate. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,489,705,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12. Morphostructural zoning \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,515,670,528]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.1. Across strike regions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,540,937,659]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study area displays variations from northwest to southeast, i.e., perpendicularly to the SFB trend, in terms of bathymetry, stratigraphy and tectonics. Thus, apart from the portion of the Colombian Basin adjacent to the SFB, three regions have been identified within the SFB: a) the lower continental slope, b) the upper continental slope, and c) the continental shelf. The principal characteristics of these zones are illustrated in Fig. 19 and mentioned in Table 2, and their main differential features are described below from the outer to innermost zones using our own data and data from Rodríguez et al. (2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,673,726,684]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.1.1. Colombian Basin versus SFB \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,686,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Colombian Basin, developed in the abyssal plain, is located in front of the SFB. The SFB deformation front, which coincides with a slope change, separates it from the SFB, developed in the continental slope, the continental shelf and the onshore area (Figs. 3, 4, 11 and 13). The seafloor in the Colombian Basin is sub-horizontal to gently inclined to the NW $(0.3 - 1.4^{\\\\circ})$ and very regular because only few isolated faults and folds exhibit bathymetric expression, while the seafloor in the SFB reaches greater dips and may be very irregular (Figs. 4, 11 and 13). The Colombian Basin is constituted by a thin succession of Cretaceous and Cenozoic strata over Jurassic rocks, whose thickness increases towards the SFB, while the SFB is made up of a thicker Cenozoic succession which also thickens landwards (Fig. 4). In general, most of the Cenozoic strata are undeformed in the Colombian Basin, while they are quite deformed in the SFB (Fig. 4). Normal faults developed during Cretaceous-Paleocene time, some of them affecting Eocene, Oligocene and Miocene strata, and some of them reactivated as normal faults during recent times, are the most common structures in the Colombian Basin (Figs. 3-5). On the contrary, thrusts and related folds, tear faults, different types of normal faults and mud diapirs occur within the SFB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[490,950,507,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"21\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"22 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[127,65,872,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 19. Idealized section across the SFB and part of the Colombian Basin showing the across-strike zones, the predominant structures in each zone and the main features of the most significant parameters. See Table 2 for a summary of the main features. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0392/d61f22f5a965d9318372ad0e22ea02d45e2fb47ea8c5bb7a710b9df6fa97a5cf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[58,583,937,858]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0775/68d9215f89fea250f6e3b3d14bc41e0d65acb0918209b43cba37b4fedf42d20b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td>SFB LOWER CONTINENTAL SLOPE</td><td>SFB UPPER CONTINENTAL SLOPE</td><td>SFB CONTINENTAL SHELF</td></tr><tr><td>SEAFLOOR DIP</td><td>2 to >7° to the NW</td><td><1-4° to the NW</td><td>0 to 0.1-1.2° to the NW</td></tr><tr><td>ACTIVE STRUCTURES</td><td>Fault-related folds</td><td>Some fault-related folds</td><td>A few mud diapirs</td></tr><tr><td>STRATIGRAPHIC THICKNESS</td><td>2 km of Cenozoic (increases from deformation front to upper-lower continental slope boundary)</td><td>5 km of Cenozoic (increases from upper-lower continental slope boundary to shelf break)</td><td>5 to >7 km of Cenozoic (increases from shelf break landwards)</td></tr><tr><td>AVERAGE THRUST SPACING</td><td>3-5 km (decreases from deformation front to upper-lower continental slope boundary)</td><td>>1-3 km (decreases from upper-lower continental slope boundary to shelf break)</td><td>>5 km</td></tr><tr><td>DETACHMENT DIP</td><td>>1 to >3° to the SE</td><td>>3 to <4° to the SE</td><td>>3 to <4° to the SE</td></tr><tr><td>DETACHMENT DEPTH</td><td>>5 km (increases from deformation front to upper-lower continental slope boundary)</td><td><10 km (increases from upper-lower continental slope boundary to shelf break)</td><td>9 to >10 km (increases from shelf break landwards)</td></tr><tr><td>WEDGE VERTICAL THICKNESS</td><td>>2 km (increases from deformation front to upper-lower continental slope boundary)</td><td><10 km (increases from upper-lower continental slope boundary to shelf break)</td><td>>8 to >10 km (increases from shelf break landwards)</td></tr><tr><td>VERTICAL THICKNESS/ STRATIGRAPHIC THICKNESS</td><td>1-1.3 (increases from deformation front to upper-lower continental slope boundary)</td><td><1.3 (increases from upper-lower continental slope boundary to shelf break)</td><td>1.3-1.4</td></tr><tr><td rowspan=\\\"3\\\">TECTONIC SUBSIDENCE - UPLIFT</td><td>Fast subsidence (Paleocene)</td><td>Fast subsidence (Paleocene)</td><td>Fast subsidence (Paleocene)</td></tr><tr><td>Slow subsidence (Eocene, Oligocene, Miocene)</td><td>Slow subsidence (Eocene, Oligocene, Miocene)</td><td>Moderate subsidence (Eocene, Oligocene, Miocene)</td></tr><tr><td>0.2 km of slow subsidence to 0.6 km of slow uplift increasing from deformation front to upper-lower continental slope boundary (Pliocene-Quaternary)</td><td>Slow uplift increasing from upper-lower continental slope boundary to shelf break (Pliocene-Quaternary)</td><td>2.2-3 km of rapid uplift (Pliocene-Quaternary)</td></tr><tr><td>TAPER ANGLE</td><td>7 to >8°</td><td>>5 to >7°</td><td></td></tr><tr><td>PORE PRESSURE</td><td>0.65-0.73</td><td>0.51-0.66</td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2 Main features of the three SFB zones defined across strike illustrated in Fig. 19. The data presented in this table comes from ourselves and from Rodriguez et al. (2021). \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[57,876,487,929]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tectonic subsidence was fast during Paleocene both in the Colombian Basin and in the SFB, and slow during Eocene, Oligocene, and Miocene, although it increases towards the SFB (Fig. 9a, 9b, 9c and 9d). Moderate tectonic subsidence occurred during Pliocene and Quaternary in the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,876,937,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Colombian Basin, while slow tectonic subsidence and fast tectonic uplift occurred in the SFB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,952,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"22\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"23 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[58,66,268,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.1.2. SFB lower continental slope \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,79,485,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The lower continental slope is the most external zone of the SFB. A slope change constitutes the boundary between the lower continental slope and the upper continental slope (Figs. 3, 11 and 13). In this area, the seafloor is the most inclined and irregular of the entire SFB, because many structures are still active (Figs. 11-13). This region is formed by the thinnest Cenozoic succession of the SFB (Figs. 4 and 10). Structures such as backthrusts and related folds, continental-slope normal faults with associated toe thrusts, and normal faults reactivated as reverse faults including related folds only occur in this domain (Figs. 3 and 4). The average thrust spacing is intermediate between that of the upper continental slope and that of the continental shelf. Both the thrust dip and displacement are the smallest ones of the entire SFB. The Pliocene-Quaternary piggy-back, syn-tectonic basins related to fold growth and thrust emplacement are the shallowest and narrowest. The dip of the basal detachment, where thrusts branch at depth forming an imbricate thrust system, the depth to the basal detachment, the wedge vertical thickness and the vertical tectonic thickness compared to the original stratigraphic thickness are the smallest of the whole SFB (Figs. 4, 10 and 13). The slowest Eocene-Miocene and Pliocene-Quaternary tectonic subsidence and the slowest Pliocene-Quaternary tectonic uplift of the whole SFB occurred in this region (Fig. 9e, 9f, 9g and 9h). Both the taper angle and the internal pore pressure are the highest of the entire SFB (Figs. 14, 15, 17 and 18, and Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,395,268,408]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.1.3. SFB upper continental slope \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,409,485,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The upper continental slope is the intermediate zone of the SFB. The shelf break, which is a slope change, separates the upper continental slope from the continental shelf (Figs. 3, 11 and 13). The seafloor dips less and exhibits less irregularities than the lower continental slope but it dips more and is more irregular than the continental shelf, since some structures developed near the upper-lower continental slope boundary are still active (Figs. 11-13). The Cenozoic strata that constitute this region exhibit intermediate thicknesses between those of the lower continental slope strata and those of the continental shelf strata (Figs. 4 and 10). The most important out-of-sequence thrusts occur in this region and constitute the boundary between the upper and the lower continental slopes. The average thrust spacing is the smallest one of the study area (Figs. 3 and 4). Both the thrust dip and displacement are the highest ones. The depth and width of the Pliocene-Quaternary piggy-back, syntectonic basins related to folds and thrusts are intermediate in between those of the lower continental slope and those in the continental shelf. The thrusts branch at depth with the basal detachment forming an imbricate thrust system, and the dip of the detachment is the steepest one. The depth to detachment, the wedge vertical thickness, and the vertical tectonic thickness versus the stratigraphic thickness are intermediate values in between those of the lower continental slope and those of the continental shelf (Figs. 4, 10 and 13). Intermediate Eocene-Miocene tectonic subsidence and intermediate Pliocene-Quaternary tectonic uplift between those of the lower continental slope and those of the continental shelf occurred in this region. The taper angle and the internal pore pressure are the smallest of the SFB (Figs. 14, 15, 17 and 18, and Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,778,233,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.1.4. SFB continental shelf \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,790,485,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The continental shelf is the most internal zone of the SFB (Figs. 3, 11 and 13). The seafloor is the less inclined and most regular of the SFB, since most structures are inactive (Figs. 11-13). This domain is made up by the thickest Cenozoic succession of the SFB (Fig. 4). Most the mud diapirs and shale cored anticlines with crestal normal faults, and continental-shelf normal faults, some of them reactivated as reverse faults or as normal faults several times, only occur in this domain (Figs. 3 and 4). The average thrust spacing is the largest one. The Pliocene-Quaternary basins filled in with young syn-tectonic strata are the deepest and widest of the entire SFB. The dip of the basal detachment, from which thrusts emanate, the depth to the basal detachment, the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"wedge vertical thickness, and the vertical tectonic thickness versus the stratigraphic thickness are the greatest of the entire SFB (Figs. 4 and 13). The fastest Eocene-Miocene tectonic subsidence and the fastest Pliocene and Quaternary tectonic uplift of the entire SFB occurred in this region (Fig. 9i, 9j, 9k and 9l). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,146,663,158]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.2. Along strike regions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,172,937,317]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Apart from variations from the external to the internal zones of the belt, there are also along-strike changes, i.e., from southwest to northeast, in terms of characteristics of the structures, as well as stratigraphic and bathymetric features. The belt could be divided into three different regions: a) a south region, which is the south salient under the influence of the Uramita Fault; b) a central region, which is the proper SFB s.s.; and c) a north region under the influence of the Magdalena Fan and Canoas Oblique Ramp. The most important characteristics of these zones are illustrated in Fig. 20 and presented in Table 3, and their main differential features are described below from south to north using our own information plus Rodríguez et al. (2021) data. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,330,823,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.2.1. South salient influenced by the Uramita Fault \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,343,937,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This region corresponds to the south part of the SFB; an entrant separates it from the SFB s.s. to the north, and the Uramita Fault separates it from the North Panama Belt to the south (Figs. 3 and 20 and Table 3). This portion of the belt is narrower than the SFB s.s. but similar to the north region. Unlike the rest of zones, only upper continental slope occurs in this region. The dip of the seafloor in the continental shelf is the lowest of the entire SFB, whereas that of the portion of the Colombian Basin just in front of this region is the highest (Table 3). The bathymetry of the continental slope is the most regular of the belt suggesting almost no recent tectonic activity (Figs. 11 and 12). The Cretaceous-Miocene strata exhibit an intermediate thickness in the frontal part and the highest near the shelf break, so that the $2\\\\mathrm{km}$ difference between both thicknesses is intermediate (Figs. 4 and 10), whereas the sedimentary succession that fills in piggy-back basins is the thickest one. The vertical thickness of the wedge in the deformation front is the highest, whereas in the shelf break is the lowest, and therefore, the vertical thickness in the shelf break is almost 1.5 times that of the deformation front, i.e., the lowest of the entire SFB (Figs. 4 and 13), and the vertical tectonic thickening, i.e., the vertical thickness minus the stratigraphic sequence thickness, is also the lowest. The basal detachment exhibits the highest dip beneath the upper continental slope (Figs. 4 and 13). The depth to detachment beneath the deformation front is intermediate and the depth to detachment beneath the shelf break is the lowest, thus the depth to detachment beneath the shelf break is slightly more than 1 time that beneath the deformation front, being the lowest ratio of the entire SFB. Thrusts and thrust-related folds exhibit an approximately N-S strike, and their average spacing in the deformation front is the lowest together with that of the SFB s.s., whereas in the shelf break is the highest (Fig. 3). The variation between the thrust spacing in the deformation front and in the shelf break, as well as the number of thrusts, is the smallest one of the whole SFB. An intermediate number of tear faults and mud diapirs with related crestal normal faults and folds occur in this region, while the number of continental-shelf normal faults is the lowest (Fig. 3). The deformation front in the south salient is made up of large detachment folds and a few, minor WNW-directed thrust faults emanating from the basal detachment (seaward-vertent structures) (Fig. 4). The shortening measured here is the smallest of the entire SFB. Pliocene-Quaternary tectonic uplift in the deformation front occurred in this region in contrast to the tectonic subsidence occurred in the other regions; the uplift in the continental shelf is an intermediate value. Thus, this region exhibits the most similar behavior between the deformation front and the shelf break in terms of subsidence/uplift because uplift has taken place at both sites (Fig. 9). The taper angle measured in the upper continental slope (Figs. 14 and 15) and the pore pressure value estimated in the upper continental slope are the highest \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[490,950,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"23\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"24 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[161,65,836,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 20. Idealized map of the SFB showing the along-strike zones and the predominant structures in each zone. See Table 3 for a summary of the main features. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0616/a0984626019e5063e0179cb31da751f5f98389893a38972173bf71d204a86101.jpg\",\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,616,304,629]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ones of the whole belt (Figs. 17 and 18). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,643,154,654]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.2.2. SFB s.s \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,656,485,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This region is the central portion of the SFB separated by a gradual boundary with the north part of the belt, and by an inlet from the south salient (Figs. 3 and 20 and Table 3). The SFB s.s. is the widest portion of the belt. The ratio between the width of the upper continental slope and that of the lower continental slope is extremely variable from less than 1 to 6 times the width of the lower continental slope. The dip of the lower continental slope seafloor may be up to 4 times that of the upper continental slope. The dip of the continental shelf is intermediate between that of the north and south regions, and that of the Colombian Basin in front of this region is the lowest (Table 3). The degree or irregularity of the bathymetry of the continental slope is intermediate in between that of the north and south regions (Figs. 11 and 12). The thickness of the Cretaceous-Miocene strata in the frontal part is the lowest and it is intermediate near the shelf break, so that the difference between both thicknesses from 3 to $5\\\\mathrm{km}$ is the highest one of the whole SFB (Figs. 4 and 10), whereas the succession that fills in piggy-back basins is the thinnest one of the whole SFB. The wedge vertical thickness in the deformation front is the lowest and is intermediate in the shelf break, and therefore, the wedge vertical thickness in the shelf break ranges from almost 2.5 to slightly more than 3 times that of the deformation front, and is the most pronounced ratio of the entire SFB (Figs. 4 and 13), \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,616,937,931]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and the vertical tectonic thickening is intermediate. The basal detachment dip beneath the lower continental slope is the lowest one of the entire SFB, but increases to the highest values beneath the upper continental slope (Figs. 4 and 13). The depth to detachment beneath the deformation front is the lowest and the depth beneath the shelf break is intermediate; the depth to detachment beneath the shelf break is from almost 1.5 times to almost 2 times higher than that beneath the deformation front, being the highest ratio of the entire SFB. The strike of the thrusts and related folds is NNE-SSW, and their average spacing around the deformation front is the lowest together with that of the south region, whereas in the shelf break is the lowest (Fig. 3). The $1 - 2\\\\mathrm{km}$ difference between the average thrust spacing in the deformation front versus the one at the shelf break, as well as the number of thrusts, are the highest ones of the whole SFB. The largest number of tear faults, mud diapirs with related crestal normal faults and shale cored anticlines, and continental-shelf normal faults occur in this region (Fig. 3). The deformation front in the SFB s.s. consists of a symmetrical triangular zone made up of SE-directed thrusts (backthrusts) (landward-vergent structures) in the outer part, and NW-directed thrusts (seaward-vergent structures) in the inner part, all of them emanating from the basal detachment. In some portions of the SFB s.s., the deformation front is a poorly developed triangular zone formed by an imbricate thrust system with sporadic backthrusts (Fig. 4). The shortening measured is the highest of the entire SFB. The maximum amount of tectonic subsidence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,142,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,952,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"24\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"25 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[58,116,485,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0677/81c24818af2453166727534643f2153f7be9a9fbde9f54c6bac7897e150accef.jpg\",\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td>SOUTH SALIENT INFLUENCED BY THE URAMITA FAULT</td><td>SINÜ FOLD BELT s.s.</td><td>REGION INFLUENCED BY THE MAGDALENA FAN/CANOAS OBLIQUE RAMP</td></tr><tr><td>BELT WIDTH</td><td>Upper continental slope: 17-33 km TOTAL: 100 km</td><td>Lower continental slope: 6-26 km Upper continental slope: 24-38 km Continental slope: 24-38 km TOTAL: 130 km</td><td>Lower continental slope: 13-14 km Upper continental slope: 33-37 km Continental slope: 47-50 km TOTAL: 100 km</td></tr><tr><td>STRATIGRAPHIC THICKNESS</td><td>Cret-Mio (deformation front) < 4 km Cret-Mio (shelf break): 6 km Plio-Quat < 2 km TOTAL: 6-8 km</td><td>Cret-Mio (deformation front): 1-3 km Cret-Mio (shelf break): 5-6 km Plio-Quat: 0.5-1 km TOTAL: 1.5-7 km</td><td>Cret-Mio (deformation front): 4.5 km Cret-Mio (shelf break): 5 km Plio-Quat: 1-2 km TOTAL: 5.5-7 km</td></tr><tr><td>ORIENTATION OF LONGITUDINAL STRUCTURES</td><td>N-S</td><td>NNE-SSW</td><td>NE-SW</td></tr><tr><td>AVERAGE THRUST SPACING</td><td>Deformation front: 3-4 km Shelf break: 3-4 km</td><td>Deformation front: 3-4 km Shelf break: 2-3 km</td><td>Deformation front: 4.5 km Shelf break: 3 km</td></tr><tr><td>DEFORMATION FRONT STYLE</td><td>Detachment folds</td><td>Symmetrical triangular zone</td><td>Triangular zone</td></tr><tr><td>SHORTENING</td><td>13.8 ± 0.7 km</td><td>15.7 ± 0.4-23.9 ± 0.5 km</td><td>19.0 ± 0.4 km</td></tr><tr><td>SEAFLOOR DIP</td><td>Colombian Basin: 1.4° Upper continental slope: 2.5-4° Continental shelf >0.1°</td><td>Colombian Basin: 0.3-0.4° Lower continental slope: 3-6° Upper continental slope: 1.5-3° Continental shelf: 0.1-0.3°</td><td>Colombian Basin: 0.4° Lower continental slope: 5-7° Upper continental slope: 2° Continental shelf: 1.2°</td></tr><tr><td>DETACHMENT DIP</td><td>Upper continental slope: 3.8°</td><td>Lower continental slope: 1.5-2.8° Upper continental slope: 3.6-3.8°</td><td>Lower continental slope: 3° Upper continental slope: 3°</td></tr><tr><td>DETACHMENT DEPTH</td><td>Deformation front: 7.6 km Shelf break: 8.7 km</td><td>Deformation front: 5.4-6.8 km Shelf break: 9.1-9.7 km</td><td>Deformation front: 7.5 km Shelf break: 10 km</td></tr><tr><td>WEDGE VERTICAL THICKNESS</td><td>Deformation front: 6 km Shelf break: 8 km</td><td>Deformation front: 3-3.5 km Shelf break: 8.5-9.5 km</td><td>Deformation front: 5 km Shelf break: 10 km</td></tr><tr><td>TAPER ANGLE</td><td>Upper continental slope: 7.2°</td><td>Lower continental slope: 8.4° Upper continental slope: 5.5-5.7°</td><td>Lower continental slope: 6.9° Upper continental slope: 5.7°</td></tr><tr><td>PORE PRESSURE</td><td>Upper continental slope: 0.7</td><td>Lower continental slope: 0.7 Upper</td><td>Lower continental slope: 0.7 Upper continental slope: 0.5</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3 Main features of the three SFB zones defined along strike illustrated in Fig. 20. The data presented in this table comes from ourselves and from Rodriguez et al. (2021). \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[512,79,937,170]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0825/5760bb9a6cb51972d2908e7881ce5b9c3bf9fd13591ce8078c807730e55445dc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>SOUTH SALIENT INFLUENCED BY THE URAMITA FAULT</td><td>SINÜ FOLD BELT s.s.</td><td>REGION INFLUENCED BY THE MAGDALENA FAN/CANOAS OBLIQUE RAMP</td></tr><tr><td></td><td>continental slope: 0.5</td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3 (continued) \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[507,187,937,331]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"during Pliocene-Quaternary times in the deformation front occurred in this region together with the north region, and the maximum amount of tectonic uplift in the continental shelf also occurred in this region. Therefore, this region is where the behavior of these two sites in terms of tectonic subsidence/uplift is the most different (Fig. 9). The taper angle in both the upper and the lower continental slopes are the lowest, and the $1.4^{\\\\circ} - 2.7^{\\\\circ}$ difference between both taper angles is the highest one of the entire SFB (Figs. 14 and 15). The value of pore pressure in the upper continental slope is the lowest and is the highest in the lower continental slope; thus, the 0.15–0.2 difference between both values is the highest one of the whole SFB (Figs. 17 and 18). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,345,927,358]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12.2.3. Region influenced by the Magdalena Fan/Canoas Oblique Ramp \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,359,937,925]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This region is the northern part of the SFB, whose boundary to the north is the Magdalena Fan and the Canoas Oblique Ramp, while its southern boundary with the SFB s.s. is diffuse (Figs. 3 and 20 and Table 3). The width of this part of the belt is smaller than that of the SFB s.s. but similar to that of the south salient. The width of the upper continental slope is more than 2.5 times that of the lower continental slope. The dip of the lower continental slope seafloor is from 2.5 to 3.5 times that of the upper continental slope. The dip of the continental shelf is the highest of the whole SFB, whereas that of the Colombian Basin in front of this region is intermediate (Table 3). The bathymetry of the continental slope is the most irregular of the SFB suggesting a lot of recent tectonic activity (Figs. 11 and 12). The thickness of the Cretaceous-Miocene sedimentary pile is the highest in the frontal part and the lowest in the shelf break, and therefore, the $0.5\\\\mathrm{km}$ difference between both thicknesses is the lowest one of the whole SFB (Figs. 4 and 10), whereas the thickness of the strata that fill in piggy-back basins is intermediate. The wedge vertical thickness in the deformation front is intermediate and is the highest in the shelf break, and thus, the wedge vertical thickness in the shelf break is 2 times that of the deformation front, which is an intermediate value between that of the SFB s.s. and that of the south salient (Figs. 4 and 13), and the vertical tectonic thickening is the highest of the SFB. The basal detachment exhibits the highest dip underneath the lower continental slope which becomes the lowest underneath the upper continental slope (Figs. 4 and 13). The depth to detachment beneath the deformation front is intermediate and that beneath the shelf break is the highest, and therefore, the depth to detachment beneath the shelf break is almost 1.5 times that beneath the deformation front, being this an intermediate value. The strike of the thrusts and related folds is approximately NE-SW, and their average spacing measured near the deformation front is the highest, whereas around the shelf break is intermediate (Fig. 3). The $1.5\\\\mathrm{km}$ difference between the thrust spacing in the deformation front and in the shelf break, as well as the number of thrusts, are intermediate values. Tear faults are almost non-existent. The lowest number of mud diaps including crestal normal faults and folds, and an intermediate number of continental-shelf normal faults, occur in this region. Several structures branch northwards with the Canoas Oblique Ramp (Fig. 3). The deformation front is an asymmetrical triangular zone because the outermost part of the deformation front consists of a SE-directed thrust (backthrust) and a thrust that branches with the backthrust forming a pop-up, whereas the innermost part of the deformation front is made up of NW-directed thrusts (seaward-vertent structures), all of them emanating from the basal detachment (Fig. 4). The shortening measured is an \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. Rodriguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,952,505,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"25\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"26 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[57,65,485,238]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"intermediate value. The maximum amount of tectonic subsidence during Pliocene-Quaternary in the deformation front occurred in this region together with the SFB s.s. region, whereas the minimum amount of tectonic uplift in the continental shelf occurred here as well. Thus, the behavior of the deformation front compared to that of the shelf break in terms of tectonic subsidence/uplift is intermediate (Fig. 9). The taper angle measured in the upper continental slope is intermediate, whereas in the lower continental slope is the lowest, and thus, the $1.3^{\\\\circ}$ difference between taper angles is the smallest one of the entire SFB (Figs. 14 and 15). The value of estimated pore pressure in the upper continental slope is intermediate and is the lowest in the lower continental slope; the 0.1 difference between both values is the smallest one of the whole SFB (Figs. 17 and 18). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[58,250,171,263]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13. Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,277,485,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The post-Jurassic evolution of the Colombian Basin adjacent to the SFB consisted of a Cretaceous-Paleocene extensional event with considerable tectonic subsidence, followed by a slower subsidence event of Eocene-Miocene age during which some normal faults were still active. During Pliocene-Quaternary, the SFB development caused a lithospheric flexure of the Caribbean Plate, accompanied by normal reactivation of previous faults (i.e., flexural extension), which induced high tectonic subsidence in the Colombian Basin. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,383,487,736]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The SFB was initiated by the beginning of Pliocene in the study area and is still active today at a rate of several millimeters per year. The SFB resulted mostly from horizontal motion, mainly displacement along the basal detachment as well as some overriding plate shortening, accompanied by a minor component of vertical motion responsible for tectonic uplift and thickening. The number of active thrusts and related folds increases from the trailing part of the belt to the deformation front supporting a forward propagation sequence. It also varies along strike from the almost inactive salient in the south portion of the belt to the active continental slope in the north part, suggesting a possible slight clockwise rotation of the subducting Caribbean Plate or a possible increased sediment influx due to the Atrato River in the south part of the belt inhibiting structure activity. The SFB can be considered as an approximately homogeneous wedge whose basal pore pressure, and coefficients of internal and basal friction are roughly constant everywhere, whereas the pore pressure is lower in the upper continental slope causing a lower taper angle in the upper continental slope than in the lower continental slope. The small motion rate of the belt and the subduction of highly porous sediments caused an aseismic subduction, and the gentle flexure of the subducting plate prevented the development of a trench. The longitudinal and transversal variations in terms of bathymetry, stratigraphy and structure have allowed us to divide the SFB in three morpho-structural regions across strike: lower continental slope, upper continental slope and continental shelf, and three regions along strike: north region influenced by the Magdalena Fan/Canoas Oblique Ramp, SFB s.s. and south salient influenced by the Uramita Fault. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,738,485,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Interpreting seismic profiles across the SFB from the geological point of view with the aid of well logs, quantifying amounts of shortening and basal detachment displacement, carrying out a backstripping analysis in order to quantify tectonic subsidence/uplift and vertical tectonic thickening, relating the morphological features to the underlying structure, quantifying the taper angle and their causal parameters in different portions of the belt, as well as establishing a SFB zoning both along and across strike, have proven to be efficient strategies to gain insight into the large-scale structure and evolution of the SFB. These aspects are not only important from the purely scientific point of view but also from the industry point of view because they may be a valuable tool to improve the exploration and exploitation of hydrocarbons recently reactivated in his region (see Reuber et al., 2021). For instance, the large-scale analysis of the SFB carried out here, especially with regard to tectonic subsidence/uplift and tectonic thickening, may be \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,65,937,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"useful in obtaining burial data, and therefore, could help in establishing the hydrocarbon generation and migration. In addition, the large-scale history of SFB presented here may serve as analogue for other submarine regions developed under a similar tectonic setting but whose available data are scarcer or of poorer quality. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,148,732,162]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Declaration of competing interest \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,176,937,216]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,230,638,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,255,939,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We thank the editor Tiago Alves, Christopher Connors and an anonymous reviewer for their useful comments and suggestions, as well as J. Gallastegui and D. Pedreira for their help regarding geophysical issues. I. Rodríguez work has been supported by the research contract CN-016-15 (\\\"Convenio especialto para la realizacion de una tesis doctoral en la linea de investigacion en Geologia y Geosistemas del programa dedoctorado en Biogeociencias\\\") under the framework agreement between Repsol Exploracion S.A. and the University of Oviedo, Spain. We acknowledge the Colombian Agencia Nacional de Hidrocarburos (ANH) and Repsol Exploracion S.A. for providing us the data and for the research stay at Repsol (Madrid) offices of I. Rodriguez. We thank G. Zamora and B. Amigo for their help with the data and with the Repsol-Universidad de Oviedo contract. We would like to acknowledge financial support by research project CGL 2015-66997-R (\\\"Aplacion del analisis del plegamento a la investigacion de recursos geologicos\\\" -AAPLIREGE-) funded by the Spanish Ministry for Economy and Competitiveness and the European Fund for Regional Development (FEDER), research project PID2021-126357NB-100 (Cenozoic uplift of the N-Iberian margin at different scales: influence on seismic activity, relief, emerged/submerged lands and underground aquifers -CUNIMS-) funded by the Spanish Ministry for Science and Innovation, Spain, and research project FC-GRUPIN-IDI/2018/000216 (\\\"Ayudas a organismos Públicos de investigacion para apoyar la actividad que desarrollen sus grupos de investigacion en el Principado de Asturias en el periodo 2018-2020\\\") funded by the Principado de Asturias. We thank Schlumberger for permission to use the software Petrel, IHS Markit for permission to use the software Kingdom Suite, Petroleum Exploration Experts-Midland Valley for permission to use the software Move, and J. G. Antuna for maintaining the equipment. We would like to dedicate this article to our colleague, recently deceased, Alberto Marcos, professor at the University of Oviedo. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,679,586,691]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,704,934,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Aleman, A., 1983. Geology and hydrocarbon evolution of the Northwest Colombia. In: Report of Central Exploration Technology Center. Gulf Oil Exploration and Production Company, p. 66. \\\",\\\"Alfaro, E., Holz, M., 2014a. Review of the chronostratigraphic charts in the Sinu-San Jacinto basin based on new seismic stratigraphic interpretations. J. S. Am. Earth Sci. 56, 139-169. https://doi.org/10.1016/j.jsames.2014.09.004. \\\",\\\"Alfaro, E., Holz, M., 2014b. Stratigraphic relationships between the Colombian, Sinu Offshore and Sinu-San Jacinto basins based on seismic stratigraphy. Braz. J. Genet. 44 (4), 607-625. https://doi.org/10.5327/Z2317-4889201400040008. \\\",\\\"Arcila Rivera, M.M., 2018. Nueva evaluacion de la amenaza sismica de Colombia. Estrategias para su incorporation en las normas de diseño sismo resistente. Jornadas XVII Geotecnicas y XX Estructurales. Servicio Geologico Colombiano, Bogota, pp. 1-90. \\\",\\\"Ardila, L.E., Diaz, L., 2015. Terrane accretion and transpiration created new exploration frontiers in northwestern South America. In: Bartolini, C., Mann, P. 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AAPG Memoir, pp. 295-322. https://doi.org/10.1306/13531941M1083645. \\\"]\",\n \"page_idx\": \"26\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[58,42,144,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"26\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. 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Tectonic assembly of the northern Andean block. In: Bartolini, C., Buffler, R.T., Blickwede, J. (Eds.), The Circum-Gulf of Mexico and the Caribbean: Hydrocarbon Habitats, Basin Formation and Plate Tectonics, vol. 79. AAPG Memoir, pp. 815-848. https://doi.org/10.1306/M79877C37. \\\",\\\"Cooper, M.A., 1983. The calculation of bulk strain in oblique and inclined balanced sections. J. Struct. Geol. 5 (2), 161-165. https://doi.org/10.1016/0191-8141(83)90041-X. \\\",\\\"Dahlen, F.A., 1990. Critical taper model of fold-and-thrust belts and accretionary wedges. Annu. Rev. Earth Planet Sci. 18 (1), 55-99. https://doi.org/10.1146/annurev.ea.18.050190.000415. \\\",\\\"Dahlen, F.A., Suppe, J., Davis, D., 1984. Mechanics of fold-and-thrust belts and accretionary wedges: cohesive Coulomb theory. J. Geophys. Res. Solid Earth 89 (B12), 10087-10101. https://doi.org/10.1029/JB089iB12p10087. \\\",\\\"Davis, D.M., Suppe, J., Dahlen, F.A., 1983. Mechanics of fold-and-thrust belts and accretionary wedges. 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Earth Sci. 3 (1), 71-84. https://doi.org/10.1016/0895-9811(90)90019-W. \\\",\\\"Duque-Caro, H., Guzmán, G., Hernández, R., 1996. Mapa geológico de la plancha 38 Carmen de Bolívar. Instituto Nacional de Investigaciones Geológico-Mineras, Ingeominas, p. 45. \\\",\\\"Escalona, A., Mann, P., 2011. Tectonics, basin subsidence mechanisms, and paleogeography of the Caribbean-South American plate boundary zone. Mar. Petrol. Geol. 28 (1), 8-39. https://doi.org/10.1016/j.marpetgeo.2010.01.016. \\\",\\\"Flinch, J., 2003. Structural evolution of the Sinu-Lower Magdalena Area (Northern Colombia). The circum-Gulf of Mexico and the Caribbean: hydrocarbon habitats, basin formation, and plate tectonics. In: Bartolini, C., Buffler, R.T., Blickwede, J. (Eds.), The Circum-Gulf of Mexico and the Caribbean: Hydrocarbon Habitats, Basin Formation, and Plate Tectonics, vol. 79. AAPG Memoir, pp. 776-796. https://doi.org/10.1306/M79877C35. \\\",\\\"Flinch, J., Castillo, V., 2015. Record and constraints of the eastward advance of the Caribbean Plate in northern South America. In: Bartolini, C., Mann, P. (Eds.), Petroleum Geology and Potential of the Colombian Caribbean Margin, vol. 108. AAPG Memoir, pp. 1-10. https://doi.org/10.1306/13531930M1082957. \\\",\\\"Flinch, J., Amaral, J., Doulcet, A., Mouly, B., Osorio, C., Pince, J., 2003a. Structure of the offshore Sinu accretionary wedge. Northern Colombia. In: 8th Simposio Bolivariano-Exploracion Petrolera en las Cuencias Subandinas, pp. 76-83. Cartagena (Colombia). \\\",\\\"Flinch, J., Amaral, J., Doulet, A., Mouly, B., Osorio, C., Pince, J., 2003b. Onshore offshore structure of the northern Colombia accretionary complex. In: AAPG International Conference, p. 5. Barcelona. \\\",\\\"Freymueller, J.T., Kellogg, J.N., Vega, V., 1993. Plate motions in the north Andean region. J. Geophys. Res. 98 (B12) https://doi.org/10.1029/93JB00520, 21,853-21,863. \\\",\\\"Galindo, P., Lonegan, L., 2013. Evolution of the Bahia basin: evidence for vertical-axis block rotation and basin inversion at the Caribbean Plate margin offshore northern Colombia. In: AAPG International Conference and Exhibition. Cartagena (Colombia). \\\",\\\"Guzmán, O.G., 2007. Stratigraphy and Sedimentary Environment and Implications in the Plato Basin and the San Jacinto Belt Northwestern Colombia. PhD Thesis. Université de Liege, p. 275. \\\",\\\"Hottman, C.E., Smith, J.H., Purcell, W.R., 1979. Relationship among earth stresses, pore pressure, and drilling problems, offshore Gulf of Alaska. J. Petrol. Technol. 31, 1477-1484. https://doi.org/10.2118/7501-PA. \\\",\\\"Hubbert, M.K., Rubey, W.W., 1959. Role of fluid pressure in mechanics of overthrust faulting. Bull. Geol. Soc. Am. 70, 115-166. https://doi.org/10.1130/0016-7606 (1959)70%5B115:ROFPIM%5D2.0.CO;2. \\\",\\\"International Commission on Stratigraphy, 2029. https://stratigraphy.org.chart. \\\",\\\"Kellogg, J.N., Vega, V., 1995. 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Elevated pore pressure and anomalously low stress in regions of low frequency earthquakes along the Nankai Trough subduction megathrust. Geophys. Res. Lett. 39, L23301 https://doi.org/10.1029/2012GL053793. \\\",\\\"Kitajima, H., Saffer, D., Sone, H., Tobin, H., Hirose, T., 2017. In situ stress and pore pressure in the deep interior of the Nankai accretionary prism, integrated ocean drilling program site C0002. Geophys. Res. Lett. 44 (19), 9644-9652. https://doi.org/10.1002/2017GL075127. \\\",\\\"Kolla, V., Buffler, R.T., Ladd, J.W., 1984. Seismic stratigraphy and sedimentation of the Magdalena fan, southern Colombian basin, Caribbean Sea. AAPG (Am. Assoc. Pet. Geol.) Bull. 68 (3), 316-332. https://doi.org/10.1306/AD460A1C-16F7-11D7-8645000102C1865D. \\\",\\\"Ladd, J.W., Truchan, M., 1983. Compressional features across the caribbean margin of Columbia. In: Bally, A.W. (Ed.), Seismic Expression of Structural Styles. AAPG Studies In Geology, pp. 163-166. \\\",\\\"Ladd, J.W., Truchan, M., Talwani, M., Stoffa, P.L., Buhl, P., Houtz, R., Maufiret, A., Westbrook, G., 1984. Seismic reflection profiles across the southern margin of the Caribbean. In: Bonini, W., Hargraves, R.B., Shagam, R. (Eds.), The Caribbean-South American Plate Boundary and Regional Tectonics, vol. 162. GSA Memoirs, pp. 153-159. https://doi.org/10.1130/MEM162-p153. \\\",\\\"Mantilla-Pimiento, A., 2007. Crustal Structure of the Southwestern Colombian Caribbean Margin. Friedrich-Schiller-University Jena, p. 121. PhD Thesis. \\\",\\\"Martínez, J.A., Castillo, J., Ortiz-Karpf, A., Rendon, L., Mosquera, J.C., Vega, V., 2015. Deep water untested oil-play in the Magdalena fan, Caribbean, Colombian Basin. In: Bartolini, C., Mann, P. (Eds.), Petroleum Geology and Potential of the Colombian Caribbean Margin, vol. 108. AAPG Memoir, pp. 729-748. https://doi.org/10.1306/13531955M1083658. \\\",\\\"Minster, J.B., Jordan, T.H., 1978. Present-day plate motions. J. Geophys. Res. 83 (B11), 5331-5354. https://doi.org/10.1029/JB083iB11p05331. \\\",\\\"Moore, J.C., Von Huene, R., 1980. Abnormal Pore Pressure and Hole Instability in Forearc Regions: A Preliminary Report. Report Ocean Margin Drilling Project, p. 29. Menlo Park. \\\",\\\"Moore, G.F., Saffer, D., Studer, M., Pisani, P.C., 2011. Structural restoration of thrusts at the toe of the Nankai Trough accretionary prism off Shikoku Island, Japan: implications for dewatering processes. G-cubed 12 (5), Q0AD12. https://doi.org/10.1029/2010GC003453. \\\",\\\"Mora-Bohórquez, A., Ibanez-Mejía, M., Oncken, O., De Freitas, M., Vélez, V., Mesa, A., Serna, L., 2017. Structure and age of the lower Magdalena Valley basement, northern Colombia: new reflection-seismic and U-Pb-Hf insights into the termination of the Central Andes against the Caribbean Basin. J. S. Am. Earth Sci. 74, 1-26. https://doi.org/10.1016/j.jsames.2017.01.001. \\\",\\\"Morrow, C.A., Shi, L.Q., Byerlee, J.D., 1981. Permeability and strength of san Andreas fault gouge. Geophys. Res. Lett. 8, 325-328. https://doi.org/10.1029/GL008i004p00325. \\\",\\\"Nicol, A., Beavan, J., 2003. Shortening of an overriding plate and its implications for slip on a subduction thrust, central Hikurangi Margin, New Zealand. Tectonics 22 (6), 1070. https://doi.org/10.1029/2003TC001521. \\\",\\\"Pindell, J.L., Kennan, L., 2007. Cenozoic kinematics and dynamics of oblique collision between two convergent plate margins: the Caribbean-South America collision in Eastern Venezuela, Trinidad and Barbados. In: Perkins Research Conference, pp. 458-553. Houston. \\\",\\\"Poblet, J., 2020. Cartographic pattern of terminations of simple, parallel fault-bend folds, fault-propagation folds and detachment folds. J. Struct. Geol. https://doi.org/10.1016/j.jsg.2020.104135, 104135. \\\",\\\"Ramirez, J.E., 1969. Los diapiros del mar Caribe Colombiano. Actas I Congreso Colombiano de Geologia, Bogota, pp. 31-39. \\\",\\\"Reuber, K., Goswami, A., Judd, D., Chi, S., 2021. Offshore Colombia: discovering new value in legacy data using modern workflows. GEOExPro 18 (6), 20-24. \\\",\\\"Rodriguez, I., 2020. Estructura de la parte sumergida del Cinturón de Sin y de la parte adyacente de la Cuena de Colombia (margon caribeño al NO de Colombia). PhD Thesis. Universidad de Oviedo, p. 183. \\\",\\\"Rodriguez, I., Bulnes, M., Poblet, J., Masini, M., Flinch, J., 2021. Structural style and evolution of the offshore portion of the Sinu fold belt (South Caribbean deformed belt) and adjacent part of the Colombian basin. Mar. Petrol. Geol. 125, 104862 https://doi.org/10.1016/j.marpetgeo.2020.104862. \\\",\\\"Rodriguez, I., Bulnes, M., Poblet, J., Flinch, J., Masini, M., 2022a. Chapter 8. Relationships between normal faulting, mud diapirism and thrusting in the trailing part of the Sinú Fold Belt (South Caribbean Deformed Belt), offshore northwestern Colombia. In: Zamora, G., Mora, A. (Eds.), Andean Structural Styles. A Seismic Atlas. Elsevier, Amsterdam, pp. 121-128. https://doi.org/10.1016/B978-0-323-85175-6.00008-0. \\\",\\\"Rodriguez, I., Poblet, J., Bulnes, M., Masini, M., Flinch, J., 2022b. Chapter 7. Thrust sequence in the Sinu Fold belt (South Caribbean deformed belt), offshore northwestern Colombia. In: Zamora, G., Mora, A. (Eds.), Andean Structural Styles. A Seismic Atlas. Elsevier, Amsterdam, pp. 111-119. https://doi.org/10.1016/B978-0-323-85175-6.00007-9. \\\",\\\"Ruiz, C., Davis, N., Bentham, P., Price, A., Carvajal, D., 2000. Structure and Tectonic Evolution of the South Caribbean Basin, Southern Offshore Colombia: a Progressive Accretionary Prism. 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Rodríguez et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[699,42,939,52]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"27\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Marine and Petroleum Geology 143 (2022) 105780 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,952,507,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"27\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"28 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[58,66,480,317]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"Sanchez, J., Mann, P., Carvajal-Arenas, L.C., Bernal-Olaya, R., 2019. 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G. Mazhgikhova* ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,304,667,334]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Institute of Applied Mathematics and Automation of Kabardino-Balkarian Scientific Center of RAS, 360000, Nalchik, Shortanova st., 89A, Russia ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[161,349,835,551]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract. In recent, the number of works devoted to the study of problems for fractional order differential equations is growing noticeably. The interest of researchers is due to the fact that the number of areas of science in which equations containing fractional derivatives are used varies from biology and medicine to control theory, engineering, finance, as well as optics, physics, and so on. The inclusion of delay in the fractional order equation significantly affects the course of the process described by this equation, since the unknown function is given for different values of the argument, which includes a history effect into the equation. Therefore, mathematical models containing a fractional operator and a delay argument are more accurate than models containing integer derivatives. In this paper, we study the Cauchy problem for a linear ordinary delay differential equation with the Dzhrbashyan - Nersesyan fractional differentiation operator, which is generalizing the Riemann - Liouville and Gerasimov - Caputo fractional operators. The results of the work are obtained using the methods of the theory of integer and fractional calculus, methods of the theory of delay differential equations, the method of special functions. In this paper proves a theorem on the validity of an analogue of the Lagrange formula. It is also proved that the special function $W_{\\gamma_m}(t)$ , which is defined in terms of the generalized Mittag-Leffler function (or the Prabhakar function), satisfies the equation and conditions associated with the one under study, and is the fundamental solution of the considered equation. The main result is that the existence and uniqueness theorem to the initial value problem is proved. The solution to the problem is written out in terms of the special function $W_{\\gamma}(t)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[163,557,835,582]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Key words: Dzhrbashyan - Nersesyan derivative, fractional differential equation, delay differential equation, Lagrange formula, fundamental solution, generalized Mittag - Leffler function. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,601,673,614]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 20.12.2022; Revised: 21.03.2023; Accepted: 24.03.2023; First online: 16.04.2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,768,882,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For citation. Mazhgikhova M.G. The Cauchy problem for the delay differential equation with Dzhrbashyan - Nersesyan fractional derivative. Vestnik KRAUNC. Fiz.-mat. nauki. 2023,42: 1,98-107. EDN: DMUMKE. https://doi.org/10.26117/2079-6641-2023-42-1-98-107. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,806,630,818]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding. The study was carried out without financial support from foundations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,819,717,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Competing interests. There are no conflicts of interest regarding authorship and publication. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,833,880,857]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Contribution and Responsibility. The author participated in the writing of the article and is fully responsible for submitting the final version of the article to print. 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Iycmbfynkuua f(t) npedcmaauma e sude ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[337,258,880,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nf (t) = D _ {0 t} ^ {\\gamma_ {m} - 1} g (t), \\quad g (t) \\in L (0, 1). \\tag {17}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[115,294,828,312]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To2da peuuehe 3a4u (1), (16) cyuecmeyem, euhcmeHno u uMeem bud ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[347,326,880,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nu (t) = \\sum_ {i = 0} ^ {m - 1} u _ {i} W _ {\\rho_ {i}} (t) + \\left(f * W _ {\\alpha}\\right) (t), \\tag {18}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[114,388,253,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nz \\partial e \\rho_ {i} = \\sum_ {k = 0} ^ {i} \\gamma_ {k}.\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[112,429,880,502]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ioka3aTeJIbCTBO. IokaXeM, YTO peIIeHne (18) ydoBLeTbOpReT ypaBHeHIO (1). AIA 3TOrO, yHTbIBaI OIIpeDeIeHne OIIepaTopa Dxp6aIIHa - HecceHa, IIpeCTaBLeHne f(t) (17) nΦopMyIy Apo6HOrO INHTepnPoBaHHI IO YaCTaM (12) BbIHCIM 3HaueHne BbIPAKeHnI: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[163,516,836,625]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array}{l} D _ {0 t} ^ {\\{\\gamma_ {0}, \\dots , \\gamma_ {m} \\}} u (t) = D _ {0 t} ^ {\\gamma_ {m} - 1} D _ {0 t} ^ {\\gamma_ {m} - 1} \\dots D _ {0 t} ^ {\\gamma_ {0}} \\left[ \\sum_ {i = 0} ^ {m - 1} u _ {i} W _ {\\rho_ {i}} (t) + D _ {0 t} ^ {\\gamma_ {m} - 1} g (t) * W _ {\\alpha} (t) \\right] = \\\\ = D _ {0 t} ^ {\\gamma_ {m - 1}} D _ {0 t} ^ {\\gamma_ {m - 1}} \\dots D _ {0 t} ^ {\\gamma_ {0}} \\left[ \\sum_ {i = 0} ^ {m - 1} u _ {i} W _ {\\rho_ {i}} (t) + g (t) * W _ {\\alpha - \\gamma_ {m + 1}} (t) \\right]. \\\\ \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[112,632,616,649]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aaee, HcIOb3yra CBOIcTBo (7) cyHKIIHH W(y(t) HMeem: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[121,665,926,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array}{l} D _ {0 t} ^ {\\gamma_ {m} - 1} D _ {0 t} ^ {\\gamma_ {m} - 1} \\dots D _ {0 t} ^ {\\gamma_ {0}} \\sum_ {i = 0} ^ {m - 1} u _ {i} \\left(\\lambda W _ {\\alpha + \\rho_ {i}} (t) + \\mu W _ {\\alpha + \\rho_ {i}} (t - \\tau)\\right) + \\\\ + D _ {0 t} ^ {\\gamma_ {m} - 1} \\frac {d}{d t} D _ {0 t} ^ {\\gamma_ {m - 1} - 1} \\dots D _ {0 t} ^ {\\gamma_ {0}} g (t) * W _ {\\alpha - \\gamma_ {m} + 1} (t) = \\\\ = \\sum_ {i = 0} ^ {m - 1} u _ {i} \\left(\\lambda W _ {\\rho_ {i}} (t) + \\mu W _ {\\rho_ {i}} (t - \\tau)\\right) + D _ {0 t} ^ {\\gamma_ {m} - 1} \\frac {d}{d t} g (t) * W _ {1} (t) = \\\\ = \\sum_ {i = 0} ^ {m - 1} u _ {i} \\left(\\lambda W _ {\\rho_ {i}} (t) + \\mu W _ {\\rho_ {i}} (t - \\tau)\\right) + D _ {0 t} ^ {\\gamma_ {m} - 1} g (t) + D _ {0 t} ^ {\\gamma_ {m} - 1} g (t) * \\frac {d}{d t} [ \\lambda W _ {\\alpha + 1} (t) + \\mu W _ {\\alpha + 1} (t - \\tau) ] = \\\\ = \\sum_ {i = 0} ^ {m - 1} u _ {i} \\left(\\lambda W _ {\\rho_ {i}} (t) + \\mu W _ {\\rho_ {i}} (t - \\tau)\\right) + f (t) + D _ {0 t} ^ {\\gamma_ {m} - 1} g (t) * [ \\lambda W _ {\\alpha} (t) + \\mu W _ {\\alpha} (t - \\tau) ] = \\\\ \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[115,40,255,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISSN 2079-6641 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[721,40,878,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MaXrHxOBA M.Γ. 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D _ {0 t} ^ {\\gamma_ {i} - 1} D _ {0 t} ^ {\\gamma_ {i} - 1} \\dots D _ {0 t} ^ {\\gamma_ {0}} u (t) \\right| _ {t = 0} = \\sum_ {i = 0} ^ {m - 1} u _ {i} D _ {0 t} ^ {\\gamma_ {i} - 1} D _ {0 t} ^ {\\gamma_ {i} - 1} \\dots D _ {0 t} ^ {\\gamma_ {0}} W _ {\\gamma_ {0} + \\gamma_ {1} + \\dots + \\gamma_ {i}} (t) \\Big | _ {t = 0} = \\\\ = u _ {i} W _ {1} (t) \\bigg | _ {t = 0} = u _ {i}. \\\\ \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[142,307,766,326]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PaccmOTpIM OAnOpOHyIO 3aAauy, COOTBeTcTBYIOIyIO 3aAae (1), (16) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[127,338,880,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nD _ {0 t} ^ {\\left\\{\\gamma_ {0}, \\dots , \\gamma_ {m} \\right\\}} u (t) - \\lambda u (t) - \\mu H (t - \\tau) u (t - \\tau) = 0, \\quad \\lim _ {t \\rightarrow 0} D _ {0 t} ^ {\\left\\{\\gamma_ {0}, \\dots , \\gamma_ {i} \\right\\}} u (t) = 0, \\quad i = \\overline {{0 , m - 1}}. \\tag {19}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[112,385,880,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IcnoB3yra COOTHOIIeHHe, CBaIBaIOJIee Apo6HyO IpoN3BOADHyO Ajkp6aIIHa - HepcecaHa c IpoN3BOADHO PImaHa -AynBnIa [2] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[149,435,845,480]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nD _ {0 t} ^ {\\left\\{\\gamma_ {0}, \\dots , \\gamma_ {m} \\right\\}} u (t) = D _ {0 t} ^ {\\alpha} u (t) - \\sum_ {k = 0} ^ {m - 1} \\frac {t ^ {\\rho_ {k} - \\alpha - 1}}{\\Gamma \\left(\\rho_ {k} - \\alpha\\right)} \\left[ D _ {0 t} ^ {\\left\\{\\gamma_ {0}, \\dots , \\gamma_ {k} \\right\\}} u (t) \\right] _ {t = 0}, \\quad m - 1 < \\alpha \\leq m,\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[112,495,880,512]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IyHTbBaOHOPOHbIe HaaAlbHbIe ycLOBnI, I3 3aAaN (19) IIpHXoAMK cLaeYIOJIe ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[169,525,825,552]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nD _ {0 t} ^ {\\alpha} u (t) - \\lambda u (t) - \\mu H (t - \\tau) u (t - \\tau) = 0, \\quad \\lim _ {t \\rightarrow 0} D _ {0 t} ^ {\\alpha - i} u (t) = 0, \\quad i = \\overline {{0 , m - 1}},\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[112,565,880,602]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KOTOPaI IMeET ToIbKO TpUbHaIbHoe peIIeHne [5]. 3HaHT, peIIeHne HeoAHOPOAHOJ 3aDaU (1), (16) eAnHCTBeHHO. 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MockBa: Φn3MaTANT, 2003.272 c. \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[114,40,512,57]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3aHa KaIII IypaBHeHc Apo6HoI ... ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[737,39,880,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISSN 2079-6641 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,932,515,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"105 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[114,85,882,626]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"4. Kilbas A. A., Srivastava H. M., Trujillo J. J. Theory and Applications of Factional Differential Equations. Amsterdam: Elsevier, 2006. 523 pp. \",\"5. Icxy A. B. YpaBHeHra e yacmHbIX npou3eOdbHbIX dpobHo2o nopAka. MockBa: Hayka, 2005.199 c. \",\"6. Oldham K. B., Spanier J. The fractional calculus. N.-Y. L.: Acad. press., 1974. 234 pp. \",\"7. Barrett J. H. Differential equation of non-integer order, Canad. J. Math., 1954. vol. 6, no. 4, pp. 529-541. \",\"8. Pskhu A. V. Initial-value problem for a linear ordinary differential equation of noninteger order, *Sb. Math.*, 2011. vol. 202, no. 4, pp. 571-582. \",\"9. Fedorov V. E., Plekhanova M. V., Izhberdeeva E. M. Initial value problems of linear equations with the Dzhrbashyan - Nersesyan derivative in Banach spaces, Symmetry., 2021. vol. 13, no. 6, pp. 1058. \",\"10.BoIkoBaA.P.,Ix6epAeeBaE.M.,ΦeOpOB B.E.HaHaBHeBie3aDaun AλyypaBHeHn c KOMIO3HnHeApO6HbIX IPOIN3BOAdhIX,Yen86.fo3.-MameM. hcyH.,2021.T.6,N3,C.269-277. \",\"11. BoratbpeBa $\\\\Phi$ . T.HaalbHa 3aDa aA pyaBHeHn Apo6HOra Iop4Ka c IOCToHHbIMN Ko3ΦΦHnEHTaMn, Becm. KPAVHl. $\\\\Phi u3$ -MaM. Hayku., 2016. T.16, N4-1, C. 21-26. \",\"12. Bellman R. E., Cooke K. L. Differential-Difference Equations. New York. London.: Acad. Press., 1963. 462 pp. \",\"13. Hale J. K, Lunel S. M. V. Introduction to Functional Differential Equations. New York. London.: Springer, 1993. 449 pp. \",\"14. Θλνκρολις Λ. Ε. Hopкнн C. E. BeedeHue e meopuO duφfepehuaIbHbIX ypaBHeHui c omKLOHOUouMcA apzymeHmOM. MockBa: Hayka, 1971.296 c. \",\"15. Мьшкс А.Д. Л uehble dupepehuuahbte ypaheu c 3ana3dbiearouum apzymemom. MockBa: Hayka, 1972.351 c. \",\"16. HopKIN C. E. O peIIeHnIX AInHeHOrO oHOpOaHOrO aHΦΦepeHuaIbHorO ypaBHeHn BToporo IopAka c 3aIa3DbIbAoHmApryMeHTOM, YMH, 1959. T. 14. 1, N85, C. 199-206. \",\"17. Маринова M. Г.Зада Ковд Дд ДбИКНБЕНОД ДфсpehenlaьHorо уразненя с опетахор PMmaHa-АнвILAЯ c 3aIIa3dIbAIOHm apryMeHTOM, Иseecmua KEHU PAH, 2017. T.75, N#1, C. 24-28. \",\"18. MaXrHxOBA M. Γ. HauaIbHa I KpaEBa 3aDaun AAn O6bIKHOBeHHORo AnΦΦepeHIIaIbHorO ypaBHeHnA Dpo6HOrO IopraKa C 3aIIa3bIBaIOIIIm apryMeHTOM, YenlaBuHcKu' Fusuko-Mamemamuecku Jyphal, 1968. T. 3, N#1, C. 27-37. \",\"19. Mazhgikhova M. G. Dirichlet problem for a fractional-order ordinary differential equation with retarded argument, Differential equations, 2018. T.54, N²2, C. 187-194. \",\"20. Prabhakar T. R. A singular integral equation with a generalized Mittag-Leffler function in the kernel, Yokohama Math. J., 1971. vol. 19, pp. 7-15. \",\"21. HaimapK M. A. LuneuHbte duufpepeHuuaIbHbte onepamopbl. MockBa: Hayka, 1969.528 c. \"]","page_idx":"8","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[115,673,243,781]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0728/dda61f6e01ef09a890aed28f9b9698a9208ab29b6aba9a13f368e80477d6d952.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[376,656,620,673]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HΦopMaun o6 aBTope ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[252,690,884,764]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MaohcuxoBa MaduHa TymapoeHa - MlaaHn HauHybI coTpydHnK OTaLa Apo6HOrO NcUncLeHn IHCHTyTa IIpHKlaADHO MaTeMaTHKn I aBTOMaTH3aHn KBHII PAH, HaJIbHnK, PocSna, https://orcid.org/0000-0001-7612-8850. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,40,257,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISSN 2079-6641 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[721,40,880,55]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MaXrIxAoBa M.Γ. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[482,932,515,945]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"106 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[114,82,243,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,104,880,778]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] Dzhrbashyan M. M., Nersesyan A. B. Fractional derivatives and the Cauchy problem for differential equations of fractional order, Izv. AN Arm. SSR., 1968, 36, 1, 3-29. (In Russian) \",\"[2] Pskhu A. V. The fundamental solution of a diffusion-wave equation of fractional order, Izv. Math., 2009, 73, 2, 351-392. DOI: 10.4213/im2429 \",\"[3] Nakhushev A.M. Drobnoe ischislenie i ego primenenie [Fractional calculus and its application]. Fizmatlit, Moskva, 2003, 272 (In Russian) \",\"[4] Kilbas A.A., Srivastava H.M., Trujillo J.J. Theory and Applications of Factional Differential Equations. Elsevier, Amsterdam, 2006, 523 \",\"[5] Pskhu A. V. Uravneniya v chastnykh proizvodnykh drobnogo poryadka [Fractional order partial differential equations]. Nauka, Moskva, 2005, 199. (In Russian) \",\"[6] Oldham K. B., Spanier J. The fractional calculus. N.-Y. L., Acad. press., 1974, 234. \",\"[7] Barrett J. H. Differential equation of non-integer order, Can. J. Math., 1954, 6, 4, 529-541. \",\"[8] Pskhu A. V. Initial-value problem for a linear ordinary differential equation of noninteger order, Sb. Math., 2011, 202, 4, 571-582. \",\"[9] Fedorov V. E., Plekhanova M. V., Izhberdeeva E. M. Initial value problems of linear equations with the Dzhrbashyan - Nersesyan derivative in Banach spaces, Symmetry, 2021, 13, 6, 1058. \",\"[10] Volkova A. R., IzhberdeevaE. M., Fedorov V. E. Initial value problems for equations with a composition of fractional derivatives, Chel. fiz.-mat. zh., 2021, 6, 3, 269-277. (In Russian) \",\"[11] Bogatyreva F. T. Initial value problem for fractional order equation with constant coefficients, Vest. KRAUNTs. Fiz.-mat. nauki., 2016, 16, 4-1, 21-6. (In Russian) \",\"[12] Bellman R. E., Cooke K. L. Differential-Difference Equations, N-Y., Acad. Press, 1963, 462. \",\"[13] Hale J. K, Lunel S. M. V. Introduction to Functional Differential Equations, N-Y, Springer, 1993. 449. \",\"[14] El'sgol'ts L. E. Introduction to the theory of differential equations with deviating argument. Nauka, Moskva, 1971, 296. (In Russian) \",\"[15] Myshkis A.D. Lineynye differentialsial'nye uravneniya s zapazdyvayushchim argumentom [Linear delay differential equations]. Nauka, Moskva, 1972. (In Russian) \",\"[16] Norkin S. B. On solutions of a linear homogeneous delay differential equation, UMN, 1959, 14, 1:85, 199-206. (In Russian) \",\"[17] Mazhgikhova M.G. Cauchy problem for ordinary differential equation with Riemann-Liouville operator with delay, Izvestiya KBNTs RAN, 2017, 75, 1, 24-28. (In Russian) \",\"[18] Mazhgikhova M. G. Initial and boundary value problems for ordinary differential equation of fractional order with delay, Chel. Phys. and Math. Journal, 2018, 3, 1, 27-37. (In Russian) \",\"[19] Mazhgikhova M. G. Dirichlet problem for a fractional-order ordinary differential equation with retarded argument, Differential equations, 2018, 54, 2, 187-194. (In Russian) \",\"[20] Prabhakar T. R. A singular integral equation with a generalized Mittag-Leffler function in the kernel, Yokohama Math. J., 1971, 19, 7-15. \",\"[21] Naymark M. A. Lineynye differentials'nye operatory [Linear differential operators]. Nauka, Moskva, 1969, 528. (In Russian) \"]","page_idx":"9","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[349,782,648,799]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Information about the author ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,799,243,908]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0270/74c56356ecd384164e3fc52c469722aa544baaa98986d602c105e34eb477f711.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[252,816,884,891]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Mazhgikhova Madina Gumarovna - Junior Researcher, Department of Fractional Calculus, Institute of Applied Mathematics and Automation, KBSC RAS, Nalchik, Russia, https://orcid.org/0000-0001-7612-8850. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,40,515,57]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3aHa KaIII IyapBHeHc Apo6HoI ... 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IocLeAHne DecrTHeNk KOIueCTBO pa6oT, IocBSeHbIX NCCLeDoBaHIO 3aDaU AAnFpeHuaIbHbIX ypaBHeHn Apo6Horo IpOraKa, 3aMeTHo pacteT. INTepec NccLeDoBaTee BBy3BaH TeM, YTO KoIueCTBO o6LaCTe HAYKn, B KOTOpbIX NcIOIA3yOTcY ypaBHeHn, CoepKaIIne Apo6HbIE IPOIN3BOADHe, BApbpyETcR OT 6noLOrHn IMeANIIHNbI DO TeOpHn yIpaBLaHn, INJKeHepn, FInHaICOB, a TaKKe OITIKN, FIn3IKN i TAK DaIee. BkLIOueHne 3aIIa3DbIBaHn B ypaBHeHne Apo6HOr O IpOraKaC kIeHT Ha XOD IIpoIeCa, OINCSbIBaEMORO 3TNM UpaBHeHm, TAK KaH HeIN3BeCTHa FyHKIIIN 3aJaETcR IIpI pa3AIuHbIX 3NaYeHnx aprMyEHTA YoBCNT 3ΦΦeKT IIpeBbCTOPN B ypaBHeHne. IOnToMy, MaTeMaTHueCKNe MoDeA, CoepXaIIne Apo6HbI OIepaTOP N 3aIIa3DbIBaIOII m aprMyEHT, 60Jeet ToHybl, Yem MoDeA, coepXaIIne IPOIN3BOADHbI eIeIoro IpOraKa. B DaIHHO pa6Ote NccLeAyeTcR 3aDAva KOni dA LInHeHoro 6bIKHOBEHORO AnΦΦePeHuaIaHBO rpaBHeHn C 3aIIa3DbIBaIOII m aprMyEHTOM c OIIepaTopOM Apo6Horo AnΦΦepeHuaIaHn - HpcceHa, 06o6IIaIOIIIM IN3BeCTHbIe Apo6HbI OIIepaTopBI PImaHa - AnyBnlln I EpacIMoBA - KaIyTO. PezyltaTIpa6ObTI IOnLyehbC nCIOIb3OBAHnEM MeTOOB TeOpHn I Apo6HORcNCncLEHn, MeTOOB TeOpHn AnΦΦepeHuaIaHBx UpaBHeHn C 3aIIa3DbIBaIOII m aprMyEHTOM, MeTOA cIeIIaNBbIX FyHKIIIN. B pa6Ote DOka3bIAeTcR TeOpema O cIpBaBeDAInBOCTn aHaIora fOpMyJI LArpaHxa. TaKxe DOKa3aHo, YTO cIeIIaLBhA JyHKIIIN Wym(t), KOTopA,B CBOIO OyepeB, OIIpeDeAEETcYepez 06o6IIeHHyo FyHKIIIO MHTTar - LeΦΦePa (m) FyHKIIIN IIpa6Xakapa), yOobLetBopReT ypaBHeHIO u ycLOBnM, COIPRAKeHHbIM NccLeAeyMoM, I ABIAETc FyHNDAmeHTaIBbIM peIeHNm PaccMaTpiBaEMOrO ypaBHeHn. CΦopMylnpoBaHa n DoKa3aHa TeOpema cyIeCTBOBaHHN n EAnHCtBeHHOCtN peIeHNn HauAlbHO 3aDaun. PeIeHNHe IocTaBleHHo 3aDaun BBIncaHO B TepMNHX cIeIIaNbHO FyHKIIIN W(y)(t). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[161,611,835,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KJIouebe cnoea: Ipuusbodna Ahcpaunha - Hepceca, ypaenue dpobzo no npda, ypaenue c 3ana3duaouum apzymemom, fopmyla Aaspanoica, fyhdamaehmaibhoe peuenue, oobuenna fynkuur Mummaz - Legfnepe. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,665,793,680]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Плучени: 20.12.2022; Испральень: 21.03.2023; Пионгтө: 24.03.2023; Пибүкүдү онүйн: 16.04.2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[796,860,880,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0200/5b671e82baaa8257e5c626caa19e8d2b192a768477ea06967a17b424fe6f9f17.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[137,84,855,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BecTHnK KPAVHII. Φn3.-MaT. HayKn. 2023. T. 42. N1. C.98-107. ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,768,882,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Для сиитураьн. Мжгхова M. Г. 3адаа Кошдд Урбенс c Дрбон Ппогьд HonДжрбшн - Hecceha c 3аиздывагшм aprymehTom // Becmuk KPAYHJ.Фuz.-Mam. hayku. 2023. T.42. N1. C. 98-107. EDN: DMUMKE. https://doi.org/10.26117/2079-6641-2023-42-1-98-107. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,806,670,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ΦHnHaHcnpoBaHne. IccλeOBoHne BbIIOAHLaocb 6e3 ΦHnHaHcBOI IOAdepKKn ΦOHDoB. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,819,761,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Kohkypnyoune HHTepecb. KoHΦaIKTOB HHTepecoB B OTHOIIeHHn aBTOpCTBa N Iy6aIKaIHn HeT. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,833,880,857]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ABTOpckn BkJaI N OTBeTCTBeHHocTh. ABTOp yUaCTBOBaB H aHIncaHm CtaTbN I IOAHOCTbIO HeceT OTBeTCTBeHHocTh 3a IIpeOCTaBaeHne OKOHaTeMbHO BepCm CtaTbN B NeYaTb. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,857,532,871]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{*}$ KoppeioHdEHHa: E-mail: mazhgihova.madina@yandex.ru \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,871,719,884]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Konmen ny6lukyemcna yc0eux Creative Commons Attribution 4.0 International License \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,885,297,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\odot$ MaKrxHOBa M.Γ., 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[112,898,552,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\odot$ IKNP △BO PAH, 2023 (opHnHa- MaKeT, H3aH, coCTaBaeHne) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[487,932,510,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"98 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,109,248,122]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MATHEMATICS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,128,532,143]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.26117/2079-6641-2023-42-1-98-107 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,148,240,161]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Research Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,166,265,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Full text in Russian \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,185,265,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MSC 34A12, 34K09 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[808,117,870,161]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0956/e01f122eb54f858361aca117ab055d578e896f92e141cbc70eeed17e3a2a3342.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[134,212,863,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Cauchy Problem for the Delay Differential Equation with Dzhrbashyan - Nersesyan Fractional Derivative \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[396,272,601,288]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"M. G. Mazhgikhova* \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,304,667,334]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Institute of Applied Mathematics and Automation of Kabardino-Balkarian Scientific Center of RAS, 360000, Nalchik, Shortanova st., 89A, Russia \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[161,349,835,551]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract. In recent, the number of works devoted to the study of problems for fractional order differential equations is growing noticeably. The interest of researchers is due to the fact that the number of areas of science in which equations containing fractional derivatives are used varies from biology and medicine to control theory, engineering, finance, as well as optics, physics, and so on. The inclusion of delay in the fractional order equation significantly affects the course of the process described by this equation, since the unknown function is given for different values of the argument, which includes a history effect into the equation. Therefore, mathematical models containing a fractional operator and a delay argument are more accurate than models containing integer derivatives. In this paper, we study the Cauchy problem for a linear ordinary delay differential equation with the Dzhrbashyan - Nersesyan fractional differentiation operator, which is generalizing the Riemann - Liouville and Gerasimov - Caputo fractional operators. The results of the work are obtained using the methods of the theory of integer and fractional calculus, methods of the theory of delay differential equations, the method of special functions. In this paper proves a theorem on the validity of an analogue of the Lagrange formula. It is also proved that the special function $W_{\\\\gamma_m}(t)$ , which is defined in terms of the generalized Mittag-Leffler function (or the Prabhakar function), satisfies the equation and conditions associated with the one under study, and is the fundamental solution of the considered equation. The main result is that the existence and uniqueness theorem to the initial value problem is proved. The solution to the problem is written out in terms of the special function $W_{\\\\gamma}(t)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[163,557,835,582]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Key words: Dzhrbashyan - Nersesyan derivative, fractional differential equation, delay differential equation, Lagrange formula, fundamental solution, generalized Mittag - Leffler function. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,601,673,614]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 20.12.2022; Revised: 21.03.2023; Accepted: 24.03.2023; First online: 16.04.2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,768,882,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For citation. Mazhgikhova M.G. The Cauchy problem for the delay differential equation with Dzhrbashyan - Nersesyan fractional derivative. Vestnik KRAUNC. Fiz.-mat. nauki. 2023,42: 1,98-107. EDN: DMUMKE. https://doi.org/10.26117/2079-6641-2023-42-1-98-107. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,806,630,818]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding. The study was carried out without financial support from foundations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,819,717,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Competing interests. There are no conflicts of interest regarding authorship and publication. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,833,880,857]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Contribution and Responsibility. The author participated in the writing of the article and is fully responsible for submitting the final version of the article to print. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,857,515,871]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"*Correspondence: E-mail: mazhgihova.medina@yandex.ru \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,872,778,884]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The content is published under the terms of the Creative Commons Attribution 4.0 International License \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,885,299,898]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\langle \\\\widehat{\\\\mathbb{C}}\\\\rangle$ Mazhgikhova M.G., 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,898,830,912]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\odot$ Institute of Cosmophysical Research and Radio Wave Propagation, 2023 (original layout, design, compilation) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[796,860,880,882]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0254/7fe194a690760cf701ba853e867141111f55956f3ff212126462c39b5bcc23cc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[137,84,878,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Vestnik KRAUNC. Fiz.-Mat. nauki. 2023. vol. 42. no. 1. P. 98-107. ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[485,932,510,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"99 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,83,233,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BVeIeHne \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,118,359,135]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PaccMOToPM ypaBHeHne\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[225,149,880,171]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nL u \\\\equiv D _ {0 t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\right\\\\}} u (t) - \\\\lambda u (t) - \\\\mu H (t - \\\\tau) u (t - \\\\tau) = f (t), \\\\quad t > 0, \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,185,880,224]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"rde D0t{y0,...,ym} - oIepaTOp apo6HOrO anΦpepeHnnpoBaHnA xkp6aHa - HepceCnHa [1], [2] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[268,224,880,246]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {s t} ^ {\\\\alpha} u (t) = D _ {s t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\right\\\\}} u (t) = D _ {s t} ^ {\\\\gamma_ {m} - 1} D _ {s t} ^ {\\\\gamma_ {m} - 1} \\\\dots D _ {s t} ^ {\\\\gamma_ {0}} u (t), \\\\tag {2}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,252,880,302]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\alpha = \\\\sum_{k=0}^{m} \\\\gamma_k - 1, 0 < \\\\gamma_k \\\\leq 1, \\\\gamma_0 + \\\\gamma_m > 1, H(t) - \\\\phi y_{HKIIJX} XeBncaIa, \\\\lambda, \\\\mu - \\\\Pi pOu3BOAusbHbIe$ IIOCToRHHbIe, $\\\\tau - \\\\phi uKcNpOBaHHOe$ IIOAOJHTeALbHOe YNCAo. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,304,880,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B cLyuae $\\\\gamma_0 = \\\\alpha -m + 1,\\\\gamma_k = 1,k = \\\\overline{1,m}$ IpoH3BOHaJ AJkp6aIIHa-HepceHa IIepexoHT B IpoH3BOHyIO PImaHa-ANyBnIaI \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[287,351,707,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {s t} ^ {\\\\{\\\\alpha - m + 1, 1, \\\\dots , 1 \\\\}} u (t) = D _ {s t} ^ {\\\\alpha} u (t), \\\\quad m - 1 < \\\\alpha \\\\leq m,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,390,880,426]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"a cLyuae $\\\\gamma_{k} = 1,k = \\\\overline{0,m - 1},\\\\gamma_{m} = \\\\alpha -m + 1$ IpoH3BOHaJ AKp6aIIHa-HepceHaIpeXoHT B OIIepaTOp Apo6HOrO AnΦΦepeHnIpObaHnI EpacHMoBa-KaIyTo \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[290,437,704,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {s t} ^ {\\\\{\\\\alpha - m + 1, 1, \\\\dots , 1 \\\\}} u (t) = \\\\partial_ {s t} ^ {\\\\alpha} u (t), \\\\quad m - 1 < \\\\alpha \\\\leq m.\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,476,880,513]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B IIpeIbIyIiX COOTHOIIeHnIx Apo6HbI OIIepaTOp PImaHa - IHyBnIaONpeIeJIeTcI IO φopMyIe [3, c. 9] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[221,526,880,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {s t} ^ {\\\\alpha} g (t) = \\\\left\\\\{ \\\\begin{array}{l l} \\\\frac {\\\\operatorname {s i g n} (t - s)}{\\\\Gamma (- \\\\alpha)} \\\\int_ {s} ^ {t} \\\\frac {g (\\\\xi) d \\\\xi}{| t - \\\\xi | ^ {\\\\alpha + 1}}, & \\\\alpha < 0; \\\\\\\\ g (t), & \\\\alpha = 0; \\\\\\\\ \\\\operatorname {s i g n} ^ {n} (t - s) \\\\frac {d ^ {n}}{d t ^ {n}} D _ {s t} ^ {\\\\alpha - n} g (t), & n - 1 < \\\\alpha \\\\leq n, \\\\quad n \\\\in \\\\mathbb {N}, \\\\end{array} \\\\right. \\\\tag {3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,621,880,677]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\Gamma (z)$ -ramMa $\\\\phi$ yHKIIJN 3JIepa,a IIpoIN3BOHaI TepacIMoBa - KaIpyTo (peyIapn3OBaHHaI Apo6HaI IIpoIN3BOHaI) OIIpeAeAAETcOoTHOIeHHeM paBeHCTBOM [3] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,678,880,697]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\partial_ {s t} ^ {\\\\alpha} u (t) = \\\\operatorname {s i g n} ^ {n} (t - s) D _ {s t} ^ {\\\\alpha - n} u ^ {(n)} (t), \\\\quad n - 1 < \\\\alpha \\\\leq n, \\\\quad n \\\\in \\\\mathbb {N}. \\\\tag {4}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,705,880,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CpeHMOHorpaΦH,IOCBaHHeHHbIX TeOpHn Apo6HO rCHcHcHn,OTMeTtM [4], [5], [6].IccLeOBAHnHO HauaHbHix 3aHaY dAe HΦpePeHuaHbHix ypaBHeHn Apo6HO IopAka IOCBaHHeHpa6oTBi [7],[8],[9],[10],[11]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,764,880,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TeopHH AnΦΦepeHIIaIbHbIX ypaBHeHn C 3aIIa3DbIbAIOIIM aprMyeHTOM IocBraIeHbI pa6oTbI [12], [13] [14], [15]. HaayalbHa 3aDaay AIA JINHeHOrO o6bIKHOBeHHORO AnΦΦepeHIIaIbHOrO ypaBHeHn Apo6HorO IOpJaKa C 3aIIa3DbIbAIOIIM aprMyeHTOM 6bla NCCleObHa B pa6oTe [16]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,839,880,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HaayaIbHbIe 3aIauHn I 3aauHc KpaEBbIMn ycIobHmN TIIa IIITypMa - AHyBnAIA \\nAly ypaBHeHn C IpnOu3BOADHO PImaHa - AHyBnAIA N ypaBHeHn C IpnOu3BOADHO \\nTepacIMoBa - KaIyTO c 3aIIa3DbIBaIOUIM aprYMeHTOM, KOToPbIE YBIAIOTc YaCTHBIMN \\nClyuYaAMn ypaBHeHn (1) npn $1 < \\\\alpha \\\\leq 2$ , nccIeOBAIncb B pa6oTaX [17] n [18]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,40,257,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[721,40,878,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MaXrHxOBA M.Γ. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,932,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"100 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,83,443,102]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BcHOMoRaTeJIbHaJaФyHKiIa \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,118,806,137]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PaccMOToPM $\\\\phi y_{HKIIIO}W_{\\\\nu}(t)$ ,KOTopa paHee 6bIa BBeDeHa B pa6oTe [19] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[129,148,880,193]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ {\\\\nu} (t) = W _ {\\\\nu} (t; \\\\tau , \\\\lambda , \\\\mu) \\\\equiv \\\\sum_ {s = 0} ^ {\\\\infty} \\\\mu^ {s} (t - s \\\\tau) _ {+} ^ {\\\\alpha s + \\\\gamma - 1} E _ {\\\\alpha , \\\\alpha s + \\\\nu} ^ {s + 1} (\\\\lambda (t - s \\\\tau) _ {+} ^ {\\\\alpha}), \\\\quad \\\\nu \\\\in \\\\mathbb {R}, \\\\quad t > 0, \\\\tag {5}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,204,149,217]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"rAe \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[383,216,611,261]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nE _ {\\\\alpha , \\\\beta} ^ {\\\\rho} (z) = \\\\sum_ {k = 0} ^ {\\\\infty} \\\\frac {(\\\\rho) _ {k} z ^ {k}}{\\\\Gamma (\\\\alpha k + \\\\beta) k !}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,267,880,307]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"- 06o6iEHHaeyHKIg MHTar - AeΦΦepa (yHKIIg Ipa6xaKapa) [20], $(\\\\rho)_k = \\\\frac{\\\\Gamma(\\\\rho + k)}{\\\\Gamma(\\\\rho)} - c_{MBOA} \\\\PioxrAmmepa,$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[347,319,636,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n(t - s \\\\tau) ^ {\\\\rho} = \\\\left\\\\{ \\\\begin{array}{c l} (t - s \\\\tau) ^ {\\\\rho}, & t > s \\\\tau , \\\\\\\\ 0, & t \\\\leq s \\\\tau . \\\\end{array} \\\\right.\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[142,378,784,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TaKKe, B [19] Aλγ ΦyHKΠιN Wγ(t) (5) ΑOKa3aHbI cλeDyIOΠηne CBOICTBa: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,397,880,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Haunha c HeKOTopoTo s BbipaJKeHne sT > t, IIO3Tomy pA (5) coApKHT KOHeHoe YncLo cIaRaembIX N = [t/τ] + 1. \\\",\\\"2.ДяФунки（5）IMeeT MeToΦopMyaAp6HOrO INHTeRpoAΦpeHπIpoBaHnI IopKaα∈RnV>0: \\\"]\",\n \"page_idx\": \"3\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[401,470,880,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {0 t} ^ {\\\\alpha} W _ {\\\\nu} (t) = W _ {\\\\nu - \\\\alpha} (t). \\\\tag {6}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[142,499,566,516]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. ΦyHKIIa W(t) ydoBlaTeBopraTe ypaBHeHIO: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[258,527,880,565]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ {\\\\nu} (t) = \\\\lambda W _ {\\\\nu + \\\\alpha} (t) + \\\\mu W _ {\\\\nu + \\\\alpha} (t - \\\\tau) + \\\\frac {t ^ {\\\\nu - 1}}{\\\\Gamma (\\\\nu)}, \\\\quad \\\\nu \\\\in \\\\mathbb {R}. \\\\tag {7}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[142,579,603,596]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4.ДяФункииWk(t) cIIpaBeAUNBO COOTHOIIeHne \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[383,608,880,653]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ {k} ^ {(i)} (0) = \\\\left\\\\{ \\\\begin{array}{l} 0, k \\\\neq i + 1, \\\\\\\\ 1, k = i + 1. \\\\end{array} \\\\right. \\\\tag {8}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[114,674,359,693]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ΦopMyJa JIarpaHka \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,709,880,766]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\Phi \\\\mathsf{y}\\\\mathsf{H}\\\\mathsf{k}\\\\mathsf{I}\\\\mathsf{n}\\\\mathsf{H}\\\\mathsf{o}\\\\mathsf{u} = \\\\mathsf{u}(\\\\mathsf{t}),\\\\mathsf{y}\\\\mathsf{a}\\\\mathsf{O}\\\\mathsf{B}\\\\mathsf{A}\\\\mathsf{e}\\\\mathsf{T}\\\\mathsf{B}\\\\mathsf{o}\\\\mathsf{p}\\\\mathsf{r}\\\\mathsf{H}\\\\mathsf{o}\\\\mathsf{H}\\\\mathsf{Y}\\\\mathsf{U}\\\\mathsf{y}\\\\mathsf{p}\\\\mathsf{a}\\\\mathsf{B}\\\\mathsf{H}\\\\mathsf{E}\\\\mathsf{H}\\\\mathsf{N}\\\\mathsf{I}\\\\mathsf{O}(1)$ AIA BcEx t>0 n TaKyIO, TTO $D_{0t}^{\\\\{\\\\gamma_0,\\\\dots ,\\\\gamma_k\\\\}}u(t)\\\\in AC[0,1],k = 0,m - 1$ , Ha3OBem pezylapnM peueHuem ypaBHeHHa (1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,769,825,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Teopema. $\\\\Pi ycm\\\\text{业}\\\\nu (t)\\\\in L[0,1]$ .To2da cnpaeeeduua afoPMyla AaspanHca \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[205,799,880,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} (L u * v) (t) = \\\\sum_ {k = 0} ^ {m - 1} D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots \\\\gamma_ {k + 1} \\\\}} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {k} \\\\}} u (\\\\xi) \\\\big | _ {0} ^ {t} + \\\\\\\\ + \\\\int_ {0} ^ {t} u (\\\\xi) \\\\left[ D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots , \\\\gamma_ {0} \\\\}} v (t - \\\\xi) - \\\\lambda v (t - \\\\xi) - \\\\mu H (t - \\\\xi - \\\\tau) v (t - \\\\xi) \\\\right] d \\\\xi , \\\\tag {9} \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[114,40,512,57]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aHa KaIII IypaBHeHc Apo6HoI ... \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[737,39,880,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,932,514,946]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"101 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,85,149,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"20e \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[373,99,880,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n(u * v) (t) = \\\\int_ {0} ^ {t} u (\\\\xi) v (t - \\\\xi) d \\\\xi \\\\tag {10}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[114,160,564,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"- cēepmka λanlaça φyнκуu̅u u(t) u v(t) [21]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,183,878,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ioka3aTeJIbCTBO. CBeptKa AnΦΦepeHuaAaBHO r BbIPAxEHNr Lu c ΦyHKnne n (t) paBHa\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[226,219,880,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} (L u * v) (t) = \\\\int_ {0} ^ {t} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\}} u (\\\\xi) d \\\\xi - \\\\lambda \\\\int_ {0} ^ {t} v (t - \\\\xi) u (\\\\xi) d \\\\xi - \\\\\\\\ - \\\\mu \\\\int_ {0} ^ {t} H (\\\\xi - \\\\tau) v (t - \\\\xi) u (\\\\xi - \\\\tau) d \\\\xi . \\\\tag {11} \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,346,880,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IcnoIb3yO nppealeHne IpoOn3BOADHO JxKp6aIIHa - HepceSHa (2) nΦopMyLy Apo6HOrO INHTerPnpOBaHHIO YacTAM [5, c. 15] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[309,395,880,451]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\int_ {a} ^ {b} g (s) D _ {a s} ^ {\\\\alpha} h (s) d s = \\\\int_ {a} ^ {b} h (s) D _ {b s} ^ {\\\\alpha} g (s), \\\\quad \\\\alpha \\\\leq 0, \\\\tag {12}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,464,687,482]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IpoHHTerTpnpyem m pa3 IepBbI INHTerpaB B IIpaBOJ YacTn (11): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,495,897,750]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} \\\\int_ {0} ^ {t} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\right\\\\}} u (\\\\xi) d \\\\xi = \\\\int_ {0} ^ {t} D _ {t \\\\xi} ^ {\\\\gamma_ {m} - 1} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\gamma_ {m} - 1} \\\\dots D _ {0 \\\\xi} ^ {\\\\gamma_ {0}} u (\\\\xi) d \\\\xi = \\\\\\\\ = D _ {t \\\\xi} ^ {\\\\gamma_ {m} - 1} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\gamma_ {m} - 1 - 1} \\\\dots D _ {0 \\\\xi} ^ {\\\\gamma_ {0}} u (\\\\xi) \\\\big | _ {0} ^ {t} + \\\\int_ {0} ^ {t} D _ {t \\\\xi} ^ {\\\\gamma_ {m - 1} - 1} D _ {t \\\\xi} ^ {\\\\gamma_ {m}} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\gamma_ {m - 2}} \\\\dots D _ {0 \\\\xi} ^ {\\\\gamma_ {0}} u (\\\\xi) d \\\\xi = \\\\\\\\ = \\\\dots = \\\\sum_ {k = 0} ^ {m - 1} D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots \\\\gamma_ {m - k} \\\\}} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m - k - 1} \\\\}} u (\\\\xi) \\\\big | _ {0} ^ {t} + \\\\int_ {0} ^ {t} D _ {t \\\\xi} ^ {\\\\gamma_ {1}} \\\\dots D _ {t \\\\xi} ^ {\\\\gamma_ {m}} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\gamma_ {0} - 1} u (\\\\xi) d \\\\xi = \\\\\\\\ = \\\\sum_ {k = 0} ^ {m - 1} D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots \\\\gamma_ {k + 1} \\\\}} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {k} \\\\}} u (\\\\xi) \\\\big | _ {0} ^ {t} + \\\\int_ {0} ^ {t} u (\\\\xi) D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots \\\\gamma_ {0} \\\\}} v (t - \\\\xi) d \\\\xi . \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,758,502,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IIOaCTaBIM IOJyueHHoe BbipaeKeHne B (11): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,790,803,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} \\\\sum_ {k = 0} ^ {m - 1} D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots \\\\gamma_ {k + 1} \\\\}} v (t - \\\\xi) D _ {0 \\\\xi} ^ {\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {k} \\\\}} u (\\\\xi) \\\\big | _ {0} ^ {t} + \\\\int_ {0} ^ {t} u (\\\\xi) D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots \\\\gamma_ {0} \\\\}} v (t - \\\\xi) d \\\\xi - \\\\\\\\ - \\\\lambda \\\\int_ {0} ^ {t} v (t - \\\\xi) u (\\\\xi) d \\\\xi - \\\\mu \\\\int_ {0} ^ {t} v (t - \\\\xi) H (\\\\xi - \\\\tau) u (\\\\xi - \\\\tau) d \\\\xi . \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[115,40,255,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[721,40,878,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MaXrHxOBA M.Γ. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,931,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"102 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,85,642,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aMeHra $\\\\xi -\\\\tau$ Ha $\\\\xi ,B$ IocAeHem HHTeRpaAe IIOyHM, YTO \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[216,116,880,173]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\int_ {0} ^ {t} H (\\\\xi - \\\\tau) u (\\\\xi - \\\\tau) v (t - \\\\xi) d \\\\xi = \\\\int_ {0} ^ {t} H (t - \\\\xi - \\\\tau) u (\\\\xi) v (t - \\\\xi - \\\\tau) d \\\\xi . \\\\tag {13}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,187,596,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ToIa, yuHTbIBa (13), IIpHXoAM K cOpMyl e (11). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,239,448,258]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Фундаментальhoe peшени \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,275,882,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Опразделен.ФундаMeHTaIbHbIMpeIIeHHeM ypaBHeHn（1）Ha3OBemФунКПИu $\\\\nu (t - \\\\xi)$ ，yOвALETBOPRAIOUyO ypaBHeHIO \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,328,880,351]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {t \\\\xi} ^ {\\\\left\\\\{\\\\gamma_ {m}, \\\\dots , \\\\gamma_ {0} \\\\right\\\\}} v (t - \\\\xi) - \\\\lambda v (t - \\\\xi) - \\\\mu H (t - \\\\xi - \\\\tau) v (t - \\\\xi - \\\\tau) = 0 \\\\tag {14}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,370,225,385]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I yCIAOBINM \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,385,880,444]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\left\\\\{\\\\begin{array}{c}\\\\lim _ {\\\\xi \\\\rightarrow t} D _ {t \\\\xi} ^ {\\\\gamma_ {m} - 1} v (t - \\\\xi) = 1,\\\\\\\\\\\\lim _ {\\\\xi \\\\rightarrow t} D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots , \\\\gamma_ {k + 1} \\\\}} v (t - \\\\xi) = 0, \\\\quad k = \\\\overline {{0 , m - 2}}.\\\\end{array}\\\\right. \\\\tag {15}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,456,882,494]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"JIeMa. $\\\\varPhi y_{\\\\mathsf{H}}\\\\kappa u_{\\\\mathsf{A}}$ $W_{\\\\gamma_m}(t - \\\\xi)$ 8aJIaemcra yHdaMeHaMaJIbHbIM peueHeM ypaBHeHu (1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,498,882,552]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Дoka3aTeJIbCTBO. СпраBeДИNBOCTь λeMMы ДOKаЖeМ ИСПОЛБ3уЯ OПрeДeλeHneДрбНо ПрОиЗВОдно ДжрбаIIЯHA - HecceяHA, a ТаКжe сBoйСТВa ФункiiIN W(V(t) (6), (7) II (8). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,555,882,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CHaJaIa IOKaJKeM, YTO yHKnIy v(t-ξ) = Wγm(t-ξ) yOBeTbOpJeT ypaBHeHIO (14): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[134,606,865,756]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} D _ {t \\\\xi} ^ {\\\\gamma_ {0} - 1} \\\\dots D _ {t \\\\xi} ^ {\\\\gamma_ {m}} W _ {\\\\gamma_ {m}} (t - \\\\xi) = D _ {t \\\\xi} ^ {\\\\gamma_ {0} - 1} \\\\dots D _ {t \\\\xi} ^ {\\\\gamma_ {m}} \\\\left(\\\\lambda W _ {\\\\alpha + \\\\gamma_ {m}} (t - \\\\xi) + \\\\mu W _ {\\\\alpha + \\\\gamma_ {m}} (t - \\\\xi - \\\\tau) + \\\\right. \\\\\\\\ \\\\left. + \\\\frac {(t - \\\\xi) ^ {\\\\gamma_ {m} - 1}}{\\\\Gamma (\\\\gamma_ {m})}\\\\right) = D _ {t \\\\xi} ^ {\\\\gamma_ {0} - 1} \\\\dots D _ {t \\\\xi} ^ {\\\\gamma_ {m - 1}} \\\\left(\\\\lambda W _ {\\\\alpha} (t - \\\\xi) + \\\\mu W _ {\\\\alpha} (t - \\\\xi , - \\\\tau)\\\\right) = \\\\\\\\ = \\\\lambda W _ {\\\\alpha - \\\\gamma_ {0} - \\\\dots - \\\\gamma_ {m} + 1 + \\\\gamma_ {m}} (t - \\\\xi) + \\\\mu W _ {\\\\alpha - \\\\gamma_ {0} - \\\\dots - \\\\gamma_ {m} + 1 + \\\\gamma_ {m}} (t - \\\\xi - \\\\tau) = \\\\\\\\ = \\\\lambda W _ {\\\\gamma_ {m}} (t - \\\\xi) + \\\\mu W _ {\\\\gamma_ {m}} (t - \\\\xi - \\\\tau). \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[142,774,692,793]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CπpaBeAλNBOCTb ycλOBn (15) cλeΔyeT n3 φopMyλ (6) n (8): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[268,807,724,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\lim _ {\\\\xi \\\\rightarrow t} D _ {t \\\\xi} ^ {\\\\gamma_ {m} - 1} W _ {\\\\gamma_ {m}} (t - \\\\xi) = \\\\lim _ {\\\\xi \\\\rightarrow t} W _ {1} (t - \\\\xi) = W _ {1} (0) = 1;\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[115,854,878,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\lim _ {\\\\xi \\\\to t} D _ {t \\\\xi} ^ {\\\\{\\\\gamma_ {m}, \\\\dots , \\\\gamma_ {k + 1} \\\\}} W _ {\\\\gamma_ {m}} (t - \\\\xi) = \\\\lim _ {\\\\xi \\\\to t} W _ {\\\\rho_ {k} + 1} (t - \\\\xi) = 0, \\\\quad \\\\rho_ {k} = \\\\gamma_ {0} + \\\\dots + \\\\gamma_ {k}, \\\\quad k = \\\\overline {{0 , m - 2}}.\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[114,896,134,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"□ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,40,512,57]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aHa KaIII IypaBHeHc Apo6HoI ... \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[737,40,880,55]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,932,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"103 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,84,853,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Teopema cyIeCTBOBaHnI eIHHCTBeHHOCTn HaayJIbHOJ 3aJaHn \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,118,774,135]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Haayalbna 3aDaaA ypaBHeHn (1) cTaBntc cJeDyIOHm 6pa3oM. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,137,880,172]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aIaua. Haumu peuehue ypaehnue (1), ydoelmeoprouee hauabhlm ycIOBuaM \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[334,173,880,200]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\lim _ {t \\\\rightarrow 0} D _ {0 t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {i} \\\\right\\\\}} u (t) = u _ {i}, \\\\quad i = \\\\overline {{0 , m - 1}}. \\\\tag {16}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[119,206,356,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CπpaBeaIbBa cλeMyIOIIaIa \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[142,228,653,244]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Teopema. Iycmbfynkuua f(t) npedcmaauma e sude \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,258,880,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nf (t) = D _ {0 t} ^ {\\\\gamma_ {m} - 1} g (t), \\\\quad g (t) \\\\in L (0, 1). \\\\tag {17}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[115,294,828,312]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To2da peuuehe 3a4u (1), (16) cyuecmeyem, euhcmeHno u uMeem bud \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[347,326,880,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nu (t) = \\\\sum_ {i = 0} ^ {m - 1} u _ {i} W _ {\\\\rho_ {i}} (t) + \\\\left(f * W _ {\\\\alpha}\\\\right) (t), \\\\tag {18}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[114,388,253,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nz \\\\partial e \\\\rho_ {i} = \\\\sum_ {k = 0} ^ {i} \\\\gamma_ {k}.\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,429,880,502]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ioka3aTeJIbCTBO. IokaXeM, YTO peIIeHne (18) ydoBLeTbOpReT ypaBHeHIO (1). AIA 3TOrO, yHTbIBaI OIIpeDeIeHne OIIepaTopa Dxp6aIIHa - HecceHa, IIpeCTaBLeHne f(t) (17) nΦopMyIy Apo6HOrO INHTepnPoBaHHI IO YaCTaM (12) BbIHCIM 3HaueHne BbIPAKeHnI: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[163,516,836,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} D _ {0 t} ^ {\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\}} u (t) = D _ {0 t} ^ {\\\\gamma_ {m} - 1} D _ {0 t} ^ {\\\\gamma_ {m} - 1} \\\\dots D _ {0 t} ^ {\\\\gamma_ {0}} \\\\left[ \\\\sum_ {i = 0} ^ {m - 1} u _ {i} W _ {\\\\rho_ {i}} (t) + D _ {0 t} ^ {\\\\gamma_ {m} - 1} g (t) * W _ {\\\\alpha} (t) \\\\right] = \\\\\\\\ = D _ {0 t} ^ {\\\\gamma_ {m - 1}} D _ {0 t} ^ {\\\\gamma_ {m - 1}} \\\\dots D _ {0 t} ^ {\\\\gamma_ {0}} \\\\left[ \\\\sum_ {i = 0} ^ {m - 1} u _ {i} W _ {\\\\rho_ {i}} (t) + g (t) * W _ {\\\\alpha - \\\\gamma_ {m + 1}} (t) \\\\right]. \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,632,616,649]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aaee, HcIOb3yra CBOIcTBo (7) cyHKIIHH W(y(t) HMeem: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[121,665,926,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} D _ {0 t} ^ {\\\\gamma_ {m} - 1} D _ {0 t} ^ {\\\\gamma_ {m} - 1} \\\\dots D _ {0 t} ^ {\\\\gamma_ {0}} \\\\sum_ {i = 0} ^ {m - 1} u _ {i} \\\\left(\\\\lambda W _ {\\\\alpha + \\\\rho_ {i}} (t) + \\\\mu W _ {\\\\alpha + \\\\rho_ {i}} (t - \\\\tau)\\\\right) + \\\\\\\\ + D _ {0 t} ^ {\\\\gamma_ {m} - 1} \\\\frac {d}{d t} D _ {0 t} ^ {\\\\gamma_ {m - 1} - 1} \\\\dots D _ {0 t} ^ {\\\\gamma_ {0}} g (t) * W _ {\\\\alpha - \\\\gamma_ {m} + 1} (t) = \\\\\\\\ = \\\\sum_ {i = 0} ^ {m - 1} u _ {i} \\\\left(\\\\lambda W _ {\\\\rho_ {i}} (t) + \\\\mu W _ {\\\\rho_ {i}} (t - \\\\tau)\\\\right) + D _ {0 t} ^ {\\\\gamma_ {m} - 1} \\\\frac {d}{d t} g (t) * W _ {1} (t) = \\\\\\\\ = \\\\sum_ {i = 0} ^ {m - 1} u _ {i} \\\\left(\\\\lambda W _ {\\\\rho_ {i}} (t) + \\\\mu W _ {\\\\rho_ {i}} (t - \\\\tau)\\\\right) + D _ {0 t} ^ {\\\\gamma_ {m} - 1} g (t) + D _ {0 t} ^ {\\\\gamma_ {m} - 1} g (t) * \\\\frac {d}{d t} [ \\\\lambda W _ {\\\\alpha + 1} (t) + \\\\mu W _ {\\\\alpha + 1} (t - \\\\tau) ] = \\\\\\\\ = \\\\sum_ {i = 0} ^ {m - 1} u _ {i} \\\\left(\\\\lambda W _ {\\\\rho_ {i}} (t) + \\\\mu W _ {\\\\rho_ {i}} (t - \\\\tau)\\\\right) + f (t) + D _ {0 t} ^ {\\\\gamma_ {m} - 1} g (t) * [ \\\\lambda W _ {\\\\alpha} (t) + \\\\mu W _ {\\\\alpha} (t - \\\\tau) ] = \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[115,40,255,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[721,40,878,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MaXrHxOBA M.Γ. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,931,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"104 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[184,84,813,152]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} = \\\\sum_ {i = 0} ^ {m - 1} u _ {i} \\\\left(\\\\lambda W _ {\\\\rho_ {i}} (t) + \\\\mu W _ {\\\\rho_ {i}} (t - \\\\tau)\\\\right) + f (t) + f (t) * \\\\left[ \\\\lambda W _ {\\\\alpha} (t) + \\\\mu W _ {\\\\alpha} (t - \\\\tau) \\\\right] = \\\\\\\\ = f (t) + \\\\lambda u (t) + \\\\mu u (t - \\\\tau). \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,162,880,198]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I3ΦopmybI (8)cLeAyeT, YTO peIIeHne (18) yAOBLeTBOprae T HaHaALbHbIM ycAoBnM (16): \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[164,214,833,302]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{l} \\\\left. D _ {0 t} ^ {\\\\gamma_ {i} - 1} D _ {0 t} ^ {\\\\gamma_ {i} - 1} \\\\dots D _ {0 t} ^ {\\\\gamma_ {0}} u (t) \\\\right| _ {t = 0} = \\\\sum_ {i = 0} ^ {m - 1} u _ {i} D _ {0 t} ^ {\\\\gamma_ {i} - 1} D _ {0 t} ^ {\\\\gamma_ {i} - 1} \\\\dots D _ {0 t} ^ {\\\\gamma_ {0}} W _ {\\\\gamma_ {0} + \\\\gamma_ {1} + \\\\dots + \\\\gamma_ {i}} (t) \\\\Big | _ {t = 0} = \\\\\\\\ = u _ {i} W _ {1} (t) \\\\bigg | _ {t = 0} = u _ {i}. \\\\\\\\ \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[142,307,766,326]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PaccmOTpIM OAnOpOHyIO 3aAauy, COOTBeTcTBYIOIyIO 3aAae (1), (16) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[127,338,880,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {0 t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\right\\\\}} u (t) - \\\\lambda u (t) - \\\\mu H (t - \\\\tau) u (t - \\\\tau) = 0, \\\\quad \\\\lim _ {t \\\\rightarrow 0} D _ {0 t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {i} \\\\right\\\\}} u (t) = 0, \\\\quad i = \\\\overline {{0 , m - 1}}. \\\\tag {19}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,385,880,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IcnoB3yra COOTHOIIeHHe, CBaIBaIOJIee Apo6HyO IpoN3BOADHyO Ajkp6aIIHa - HepcecaHa c IpoN3BOADHO PImaHa -AynBnIa [2] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[149,435,845,480]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {0 t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {m} \\\\right\\\\}} u (t) = D _ {0 t} ^ {\\\\alpha} u (t) - \\\\sum_ {k = 0} ^ {m - 1} \\\\frac {t ^ {\\\\rho_ {k} - \\\\alpha - 1}}{\\\\Gamma \\\\left(\\\\rho_ {k} - \\\\alpha\\\\right)} \\\\left[ D _ {0 t} ^ {\\\\left\\\\{\\\\gamma_ {0}, \\\\dots , \\\\gamma_ {k} \\\\right\\\\}} u (t) \\\\right] _ {t = 0}, \\\\quad m - 1 < \\\\alpha \\\\leq m,\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,495,880,512]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IyHTbBaOHOPOHbIe HaaAlbHbIe ycLOBnI, I3 3aAaN (19) IIpHXoAMK cLaeYIOJIe \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[169,525,825,552]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nD _ {0 t} ^ {\\\\alpha} u (t) - \\\\lambda u (t) - \\\\mu H (t - \\\\tau) u (t - \\\\tau) = 0, \\\\quad \\\\lim _ {t \\\\rightarrow 0} D _ {0 t} ^ {\\\\alpha - i} u (t) = 0, \\\\quad i = \\\\overline {{0 , m - 1}},\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[112,565,880,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"KOTOPaI IMeET ToIbKO TpUbHaIbHoe peIIeHne [5]. 3HaHT, peIIeHne HeoAHOPOAHOJ 3aDaU (1), (16) eAnHCTBeHHO. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,627,267,644]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aKJIIOUeHne \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,663,880,736]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B pa6oTe IIOlyueHo $\\\\phi$ yHdAmeHTaIbHOe peIIeHne dAJI AINHeHOrO o6bIKHOBeHHORO dIΦpeHIIaIbHOrO ypaBHeHnC IIPOIN3BOADHOJ DxKp6aIIHa - HepceSHa C 3aIIa3IbIAIOIM aprYMeHToM. IIOlyueH aHaIor $\\\\phi$ opMyIbI λarpaHxa. Oka3aHa TeOpema CyIeCTBOBaHnI eAHNCTBeHHOCTH peIIeHnHa HaaJIbHOJ 3aDaun. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,739,880,793]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pe3yIbTaTbI, IIOJyUeHHbIe B DaHHO pa6OTe, B DaJIbHeIIIeM 6ydyT IcIOJIb3OBaHbI IIpr INCCJIeIOBaHnI IOKaJIbHbIX N HeLOKaJIbHbIX KpaEBbIX 3aJaY IaI aNΦΦepeHIIaJIbHbIX ypaBHeHn Ipo6HO rOpRAKa C 3aIIa3bIBaIOIIIM aprymeHTOM. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[134,807,381,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cnncok JntepaTpybI \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,834,880,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1.Джрбашян M.M.,HepceснA.B.Dpo6ньe IIpoиЗВОдыи 3aДача KoIII AIAI aIФфеpeHuaIbHbIX ypaBHeHn Ipo6HOrO IopraKa,ИЗe.AkaD.HayKApM.CCP.,1968.T.36,N#1,C.3-29. \\\",\\\"2. Pskhu A. V. The fundamental solution of a diffusion-wave equation of fractional order, Izv. Math., 2009. vol. 73, no. 2, pp. 351-392. \\\",\\\"3. HaxyIeB A. M. Apo6Hoe uCucHeue e 20 npumehue. MockBa: Φn3MaTANT, 2003.272 c. \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[114,40,512,57]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aHa KaIII IypaBHeHc Apo6HoI ... \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[737,39,880,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,932,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"105 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,85,882,626]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"4. Kilbas A. A., Srivastava H. M., Trujillo J. J. Theory and Applications of Factional Differential Equations. Amsterdam: Elsevier, 2006. 523 pp. \\\",\\\"5. Icxy A. B. YpaBHeHra e yacmHbIX npou3eOdbHbIX dpobHo2o nopAka. MockBa: Hayka, 2005.199 c. \\\",\\\"6. Oldham K. B., Spanier J. The fractional calculus. N.-Y. L.: Acad. press., 1974. 234 pp. \\\",\\\"7. Barrett J. H. Differential equation of non-integer order, Canad. J. Math., 1954. vol. 6, no. 4, pp. 529-541. \\\",\\\"8. Pskhu A. V. Initial-value problem for a linear ordinary differential equation of noninteger order, *Sb. Math.*, 2011. vol. 202, no. 4, pp. 571-582. \\\",\\\"9. Fedorov V. E., Plekhanova M. V., Izhberdeeva E. M. Initial value problems of linear equations with the Dzhrbashyan - Nersesyan derivative in Banach spaces, Symmetry., 2021. vol. 13, no. 6, pp. 1058. \\\",\\\"10.BoIkoBaA.P.,Ix6epAeeBaE.M.,ΦeOpOB B.E.HaHaBHeBie3aDaun AλyypaBHeHn c KOMIO3HnHeApO6HbIX IPOIN3BOAdhIX,Yen86.fo3.-MameM. hcyH.,2021.T.6,N3,C.269-277. \\\",\\\"11. BoratbpeBa $\\\\\\\\Phi$ . T.HaalbHa 3aDa aA pyaBHeHn Apo6HOra Iop4Ka c IOCToHHbIMN Ko3ΦΦHnEHTaMn, Becm. KPAVHl. $\\\\\\\\Phi u3$ -MaM. Hayku., 2016. T.16, N4-1, C. 21-26. \\\",\\\"12. Bellman R. E., Cooke K. L. Differential-Difference Equations. New York. London.: Acad. Press., 1963. 462 pp. \\\",\\\"13. Hale J. K, Lunel S. M. V. Introduction to Functional Differential Equations. New York. London.: Springer, 1993. 449 pp. \\\",\\\"14. Θλνκρολις Λ. Ε. Hopкнн C. E. BeedeHue e meopuO duφfepehuaIbHbIX ypaBHeHui c omKLOHOUouMcA apzymeHmOM. MockBa: Hayka, 1971.296 c. \\\",\\\"15. Мьшкс А.Д. Л uehble dupepehuuahbte ypaheu c 3ana3dbiearouum apzymemom. MockBa: Hayka, 1972.351 c. \\\",\\\"16. HopKIN C. E. O peIIeHnIX AInHeHOrO oHOpOaHOrO aHΦΦepeHuaIbHorO ypaBHeHn BToporo IopAka c 3aIa3DbIbAoHmApryMeHTOM, YMH, 1959. T. 14. 1, N85, C. 199-206. \\\",\\\"17. Маринова M. Г.Зада Ковд Дд ДбИКНБЕНОД ДфсpehenlaьHorо уразненя с опетахор PMmaHa-АнвILAЯ c 3aIIa3dIbAIOHm apryMeHTOM, Иseecmua KEHU PAH, 2017. T.75, N#1, C. 24-28. \\\",\\\"18. MaXrHxOBA M. Γ. HauaIbHa I KpaEBa 3aDaun AAn O6bIKHOBeHHORo AnΦΦepeHIIaIbHorO ypaBHeHnA Dpo6HOrO IopraKa C 3aIIa3bIBaIOIIIm apryMeHTOM, YenlaBuHcKu' Fusuko-Mamemamuecku Jyphal, 1968. T. 3, N#1, C. 27-37. \\\",\\\"19. Mazhgikhova M. G. Dirichlet problem for a fractional-order ordinary differential equation with retarded argument, Differential equations, 2018. T.54, N²2, C. 187-194. \\\",\\\"20. Prabhakar T. R. A singular integral equation with a generalized Mittag-Leffler function in the kernel, Yokohama Math. J., 1971. vol. 19, pp. 7-15. \\\",\\\"21. HaimapK M. A. LuneuHbte duufpepeHuuaIbHbte onepamopbl. MockBa: Hayka, 1969.528 c. \\\"]\",\n \"page_idx\": \"8\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[115,673,243,781]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0728/dda61f6e01ef09a890aed28f9b9698a9208ab29b6aba9a13f368e80477d6d952.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[376,656,620,673]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HΦopMaun o6 aBTope \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[252,690,884,764]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MaohcuxoBa MaduHa TymapoeHa - MlaaHn HauHybI coTpydHnK OTaLa Apo6HOrO NcUncLeHn IHCHTyTa IIpHKlaADHO MaTeMaTHKn I aBTOMaTH3aHn KBHII PAH, HaJIbHnK, PocSna, https://orcid.org/0000-0001-7612-8850. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,40,257,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[721,40,880,55]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MaXrIxAoBa M.Γ. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,932,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"106 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,82,243,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,104,880,778]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] Dzhrbashyan M. M., Nersesyan A. B. Fractional derivatives and the Cauchy problem for differential equations of fractional order, Izv. AN Arm. SSR., 1968, 36, 1, 3-29. (In Russian) \\\",\\\"[2] Pskhu A. V. The fundamental solution of a diffusion-wave equation of fractional order, Izv. Math., 2009, 73, 2, 351-392. DOI: 10.4213/im2429 \\\",\\\"[3] Nakhushev A.M. Drobnoe ischislenie i ego primenenie [Fractional calculus and its application]. Fizmatlit, Moskva, 2003, 272 (In Russian) \\\",\\\"[4] Kilbas A.A., Srivastava H.M., Trujillo J.J. Theory and Applications of Factional Differential Equations. Elsevier, Amsterdam, 2006, 523 \\\",\\\"[5] Pskhu A. V. Uravneniya v chastnykh proizvodnykh drobnogo poryadka [Fractional order partial differential equations]. Nauka, Moskva, 2005, 199. (In Russian) \\\",\\\"[6] Oldham K. B., Spanier J. The fractional calculus. N.-Y. L., Acad. press., 1974, 234. \\\",\\\"[7] Barrett J. H. Differential equation of non-integer order, Can. J. Math., 1954, 6, 4, 529-541. \\\",\\\"[8] Pskhu A. V. Initial-value problem for a linear ordinary differential equation of noninteger order, Sb. Math., 2011, 202, 4, 571-582. \\\",\\\"[9] Fedorov V. E., Plekhanova M. V., Izhberdeeva E. M. Initial value problems of linear equations with the Dzhrbashyan - Nersesyan derivative in Banach spaces, Symmetry, 2021, 13, 6, 1058. \\\",\\\"[10] Volkova A. R., IzhberdeevaE. M., Fedorov V. E. Initial value problems for equations with a composition of fractional derivatives, Chel. fiz.-mat. zh., 2021, 6, 3, 269-277. (In Russian) \\\",\\\"[11] Bogatyreva F. T. Initial value problem for fractional order equation with constant coefficients, Vest. KRAUNTs. Fiz.-mat. nauki., 2016, 16, 4-1, 21-6. (In Russian) \\\",\\\"[12] Bellman R. E., Cooke K. L. Differential-Difference Equations, N-Y., Acad. Press, 1963, 462. \\\",\\\"[13] Hale J. K, Lunel S. M. V. Introduction to Functional Differential Equations, N-Y, Springer, 1993. 449. \\\",\\\"[14] El'sgol'ts L. E. Introduction to the theory of differential equations with deviating argument. Nauka, Moskva, 1971, 296. (In Russian) \\\",\\\"[15] Myshkis A.D. Lineynye differentialsial'nye uravneniya s zapazdyvayushchim argumentom [Linear delay differential equations]. Nauka, Moskva, 1972. (In Russian) \\\",\\\"[16] Norkin S. B. On solutions of a linear homogeneous delay differential equation, UMN, 1959, 14, 1:85, 199-206. (In Russian) \\\",\\\"[17] Mazhgikhova M.G. Cauchy problem for ordinary differential equation with Riemann-Liouville operator with delay, Izvestiya KBNTs RAN, 2017, 75, 1, 24-28. (In Russian) \\\",\\\"[18] Mazhgikhova M. G. Initial and boundary value problems for ordinary differential equation of fractional order with delay, Chel. Phys. and Math. Journal, 2018, 3, 1, 27-37. (In Russian) \\\",\\\"[19] Mazhgikhova M. G. Dirichlet problem for a fractional-order ordinary differential equation with retarded argument, Differential equations, 2018, 54, 2, 187-194. (In Russian) \\\",\\\"[20] Prabhakar T. R. A singular integral equation with a generalized Mittag-Leffler function in the kernel, Yokohama Math. J., 1971, 19, 7-15. \\\",\\\"[21] Naymark M. A. Lineynye differentials'nye operatory [Linear differential operators]. Nauka, Moskva, 1969, 528. (In Russian) \\\"]\",\n \"page_idx\": \"9\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[349,782,648,799]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Information about the author \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,799,243,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0270/74c56356ecd384164e3fc52c469722aa544baaa98986d602c105e34eb477f711.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[252,816,884,891]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Mazhgikhova Madina Gumarovna - Junior Researcher, Department of Fractional Calculus, Institute of Applied Mathematics and Automation, KBSC RAS, Nalchik, Russia, https://orcid.org/0000-0001-7612-8850. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,40,515,57]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3aHa KaIII IyapBHeHc Apo6HoI ... \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[737,40,880,55]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN 2079-6641 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[482,931,515,945]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"107 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.26117/2079-6641-2023-42-1-98-107"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"ru"},"sci_category":{"kind":"string","value":"Mathematics and Computational Science"},"sha256":{"kind":"string","value":"a83b7a0e615914456a89a53635722ed4f574aeacce4d676bede2d5c8da90c480"},"title":{"kind":"string","value":"The Cauchy Problem for the Delay Differential Equation with Dzhrbashyan – Nersesyan Fractional Derivative"}}},{"rowIdx":177,"cells":{"abstract":{"kind":"string","value":"The SARS-CoV-2 Pandemic affected the global epidemiology of respiratory infections, including Human Respiratory Syncytial Virus (HRSV), thanks to state governments’ implementation of mitigation strategies, like the promotion of face masks and lockdowns. However, after the Pandemic, the dramatic resurge of these diseases was reported worldwide. Our retrospective study, involving three Spoke Pediatric Departments, includes all the infants under one year of age hospitalized for HRSV bronchiolitis in a period before the Pandemic period (2017–2020), during the SARS-CoV-2 Pandemic (2020–2021), and after the Pandemic (2021–2023). The primary aim was to analyze the temporal trend of HRSV in these three periods. Then, the clinical and epidemiological characteristics were analyzed to highlight the clinical differences in the affected patients, in the severity of the infections, and in the short-term outcomes. Ultimately, we analyzed the HRSV prevalence in the global bronchiolitis hospitalization over the reported periods. Overall, we included 237 patients. Before the Pandemic, the peak was recorded in January and February, while after the Pandemic, the peak was in November and December. A higher prevalence of HRSV was demonstrated after the Pandemic compared to the period before the Pandemic; overall, no difference in severity was reported. In conclusion, an increase in HRSV cases after the Pandemic has been demonstrated with an anticipated peak, while no differences were recorded in severity."},"author":{"kind":"string","value":"Francesca Parola|Giulia Costagliola|Carla Guidi|Virginia Deut|Fabio Timeus|Adalberto Brach del Prever|Neftj Ragusa|Antonella Tuscano|Massimo Berger"},"content_list":{"kind":"list like","value":[{"bbox":"[57,122,105,135]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Article ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,137,919,206]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Impact of SARS-CoV-2 Pandemic and Lockdown on the HRSV Circulation: Experience of Three Spoke Hospitals in Northern Italy ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,219,845,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Francesca Parola $^{1, *}$ , Adalberto Brach del Prever $^{1, *}$ , Virginia Deut $^{2}$ , Giulia Costagliola $^{3}$ , Carla Guidi $^{1}$ , Neftj Ragusa $^{2}$ , Antonella Tuscano $^{3}$ , Fabio Timeus $^{3}$ and Massimo Berger $^{2}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,275,927,340]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1 Pediatric and Neonatology Department, Ciriè Hospital, 10073 Ciriè, TO, Italy \",\"2 Pediatric and Neonatology Department, Ivrea Hospital, 10015 Ivrea, TO, Italy; mberger@aslto4.piemonte.it (M.B.) \",\"3 Pediatric and Neonatology Department, Chivasso Hospital, 10034 Chivasso, TO, Italy \",\"* Correspondence: francesca.parola@aslto4.piemonte.it (F.P.); abrachdelprever@aslto4.piemonte.it (A.B.d.P.) \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[275,357,941,601]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: The SARS-CoV-2 Pandemic affected the global epidemiology of respiratory infections, including Human Respiratory Syncytial Virus (HRSV), thanks to state governments' implementation of mitigation strategies, like the promotion of face masks and lockdowns. However, after the Pandemic, the dramatic resurgence of these diseases was reported worldwide. Our retrospective study, involving three Spoke Pediatric Departments, includes all the infants under one year of age hospitalized for HRSV bronchiolitis in a period before the Pandemic period (2017–2020), during the SARS-CoV-2 Pandemic (2020–2021), and after the Pandemic (2021–2023). The primary aim was to analyze the temporal trend of HRSV in these three periods. Then, the clinical and epidemiological characteristics were analyzed to highlight the clinical differences in the affected patients, in the severity of the infections, and in the short-term outcomes. Ultimately, we analyzed the HRSV prevalence in the global bronchiolitis hospitalization over the reported periods. Overall, we included 237 patients. Before the Pandemic, the peak was recorded in January and February, while after the Pandemic, the peak was in November and December. A higher prevalence of HRSV was demonstrated after the Pandemic compared to the period before the Pandemic; overall, no difference in severity was reported. In conclusion, an increase in HRSV cases after the Pandemic has been demonstrated with an anticipated peak, while no differences were recorded in severity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,526,146,548]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0356/6017fc1b612918b98e5b289e4a5be7bb04110a9122f63df94abbc2a71faa769c.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,552,255,678]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Citation: Parola, F.; Brach del Prever, A.; Deut, V.; Costagliola, G.; Guidi, C.; Ragusa, N.; Tuscano, A.; Timeus, F; Berger, M. Impact of SARS-CoV-2 Pandemic and Lockdown on the HRSV Circulation: Experience of Three Spoke Hospitals in Northern Italy. Viruses 2024, 16, 230. https://doi.org/10.3390/10.3390/v16020230 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,688,216,699]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Academic Editor: Donald Seto ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,709,206,721]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 29 December 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,725,189,734]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Revised: 26 January 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,739,196,749]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted: 30 January 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,753,200,764]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published: 1 February 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,777,154,803]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0636/42b348846c4430cd55b06525a550ea6099c9d8aff2a94684d1987abb42ca86f6.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[57,808,257,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,617,939,646]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: Respiratory Syncytial Virus (HRSV); SARS-CoV-2 Pandemic; epidemiology; seasonality trend; HRSV prevalence ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,692,393,705]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[277,709,941,753]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viral bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children; it represents the most common cause of acute respiratory failure in infants under one year of age in developing countries [1]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,755,941,815]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Many guidelines and consensus have been released to standardize the approach for viral bronchiolitis; the main point of discussion is regarding the definition, diagnosis, and treatment of bronchiolitis. Bronchiolitis has been diagnosed in children under one year of age, but the American guidelines use the diagnosis of bronchiolitis up to two years of age. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,815,941,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The diagnostic criteria of bronchiolitis, defined by an Italian Consensus referred to children under 12 months of age and included the following: an onset with rhinorrhea and/or upper respiratory tract infections; an episode of respiratory distress associated with crackles and/or wheezing, the use of accessory muscles or lower chest wall retractions, low $\\mathrm{O}_2$ saturation levels, high respiratory rate relative to age, skin color changes, nasal flaring, fever, and presentation during epidemic season [2]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,57,115,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[122,66,245,90]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"viruses ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[863,64,939,99]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"MDPI ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[57,965,396,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230. https://doi.org/10.3390/v16020230 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[689,965,939,977]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://www.mdpi.com/journal/viruses ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[275,102,939,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Human Respiratory Syncytial Virus (HRSV) accounts for $60 - 80\\%$ of bronchiolitis presentations. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,131,941,192]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It has been estimated that HRSV infects more than $60\\%$ of all children during the first year of life and that HRSV infects nearly all children by the time they are two years old [3,4]. HRSV is the second cause of death worldwide after malaria and the first cause of death for respiratory illness [5,6]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,192,941,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The clinical presentation of HRSV infections is highly variable. It may be limited to upper respiratory tract symptoms, such as fever, rhinorrhea, and congestion; the severe presentation includes bronchiolitis and pneumonia. Bronchiolitis is generally self-limiting but can lead to hospitalization due to severe respiratory distress, acute respiratory failure, or difficulty in feeding. The main risk factors for severe disease are bronchopulmonary dysplasia, age younger than 12 months, a personal history of prematurity, male sex, immunodeficiency, formula feeding, and congenital heart disease. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,296,941,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The primary preventive measure used is prophylaxis with Palivizumab, a humanized monoclonal antibody against HRSV; Pavilizumab is used to defend against the severe manifestations of respiratory infections due to HRSV in high-risk patients, such as children born preterm or with bronchopulmonary dysplasia [7]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,356,941,401]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HRSV is characterized by a variable epidemiology, depending on geographic area. In Italy, the HRSV circulates from mild November until the end of March. It peaks in January/February; the total circulation duration is about four months [8]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,401,941,461]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Nevertheless, HRSV circulation in the past has been influenced by previous Pandemics; for instance, in 2009, influenza H1N1 delayed the HRSV peak. This variability of seasonality could be explained by the possible viral interference and the impact of preventive measures [9]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,460,941,564]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Concerning viral interference, a virus infection could be influenced by coinfection. Recently, during the Pandemic, the virus-virus interaction has been well defined; this interaction is influenced by the virus type, the infection timing, and the interplay between the response of the host to each virus interplay. A positive interaction is reported when co-infection results in an increased disease severity and pathogenesis, while a negative interaction is reported when an infection reduces or prevents the infection and replication of a second virus (e.g., influenza A virus and HRSV) [10]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,564,941,653]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"During the SARS-CoV-2 Pandemic, various restrictive measures were adopted worldwide, like the imposition of social distancing measures, the closing of schools and commercial activities, strict hygiene behaviors, the use of face masks, and travel limitations. The massive effort to contain the spread of SARS-CoV-2 also affected the circulation of other respiratory pathogens, like influenza and HRSV, with a similar transmission route (contact, droplets, and aerosol transmission) [11]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,653,941,744]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Especially during the 2020-2021 season, a few cases of bronchiolitis were reported worldwide, leading some authors to speak about \"a nearly absent disease\" [12]. In the 2021-2022 season, a dramatic rebound of bronchiolitis was reported in the Northern and Southern hemispheres, due to HRSV infections [12]. This data in Italy was detected by a dedicated Surveillance Network system (RespivirNet), with a weekly report of respiratory viruses' circulation region-by-region [8]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,744,941,788]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The first report of decreased bronchiolitis was in Australia and New Zealand, where the containment of SARS-CoV-2 was excellent and quickly started to relax the SARS-CoV-2 preventive measures. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,788,941,848]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"After, an unexpected unseasonal peak of bronchiolitis compared to that in the pre-Pandemic periods has been registered worldwide [13-15]. These data were confirmed by intercontinental reports; it shows an anticipation of the peak of bronchiolitis, due to HRSV. Also, in Italy, these data have been confirmed [16-19]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,848,941,894]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study aims to provide insights into the impact of the SARS-CoV-2 Pandemic on the epidemiology of HRSV infections in Spoke hospitals of our health district (ASLTO4). The secondary aim was to evaluate the differences in the clinical features of patients affected by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,102,939,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HRSV before and after the SARS-CoV-2 Pandemic and the global increase in bronchiolitis due to HRSV. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,143,473,156]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Materials and Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,161,401,175]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1. Study Design ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[273,178,941,312]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A retrospective study was carried out in Spoke hospitals in the area nearing Turin, Piedmont Region, in the northwest of Italy. Italy is divided into health districts with a hub and spoke model for referral of patients. Our local health district (ASLTO4) includes 174 cities; the overall area is characterized by a great geographical variability, from high Alpine Mountains to urban areas. The total population of this area is 504,467 people, with 3015 inhabitants under one year of age in 2022 [20]. The local healthcare system ASLTO4 is organized into five districts, with great heterogeneity in demography, population density, and infrastructures. The General Emergency Department and Pediatric Unit are present in three Spoke hospitals of Ciriè, Chivasso, and Ivrea. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,313,941,386]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We included patients under one year of age referred to our Pediatric Departments for acute bronchiolitis due to HRSV that required hospitalization over different seasons. The test used to detect the HRSV was a rapid antigen test for the qualitative detection in nasopharyngeal swabs; the test used in our hospitals is the same since 2012 (BinaxNOW HRSV CARD—Abbot). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,387,941,461]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We divided the included patients into two groups: Group A hospitalized before the SARS-CoV-2 Pandemic (from 1 September 2017 to 31 March 2018; from 1 September 2018 to 31 March 2019; and from 1 September 2019 to 31 March 2020) and Group B hospitalized after the period of the Pandemic (from 1 September 2021 to 31 March 2022 and from 1 September 2022 to 31 March 2023) when the restrictive measures were relaxed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,462,941,506]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to estimate the prevalence of HRSV, we reported the total number of cases of bronchiolitis hospitalized during the same periods and the few cases of bronchiolitis in the Pandemic period (from 1 September 2020 to 31 March 2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,507,939,536]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The period of data collection from September to March was established based on the HRSV epidemiology in Italy [8]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,537,941,745]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We collected data about demographic variables (sex, age, months of admission). Clinical and epidemiological data were recorded (age at onset, gestational age and birth weight, weight at admission, feeding, fever) as well as a personal history of chronic illnesses such as cardiopathy, neurological disease, and bronchopulmonary dysplasia. Relevant clinical variables were documented like laboratory (C-reactive protein in a performed blood sample and Pco2 in the Blood Gas Analysis) and microbiology (coinfection by other microbiological agents). C-reactive protein (CRP) was considered normal below $10\\mathrm{mg / dL}$ . The coinfection was investigated based on clinical suspicion: we usually assessed antibodies for Epstein-Barr Virus or Mycoplasma pneumonia in blood samples. In Group B, all patients were tested for SARS-CoV-2 with an antigen rapid test on a nasopharyngeal swab for hospital admission. We reported radiograph results and short-term outcomes (length of hospital stay, complications, Hub hospital transfer). Treatment during hospitalization (low- or high-flow oxygen supplementation, nebulized therapy, steroids, antibiotics, and intravenous hydration) and discharged therapy data were recorded in all patients. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,746,939,775]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Firstly, the temporal trend of HRSV bronchiolitis after the SARS-COV-2 Pandemic (Group B) was compared to that of the previous period (Group A). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,776,939,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Then, the clinical and epidemiological characteristics were compared to assess if there were differences in the patients affected, in the severity of the infections, and the short-term outcomes. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,820,939,848]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, we analyzed the HRSV prevalence in global bronchiolitis hospitalization in the same periods, both over-reported and during the Pandemic. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,850,939,894]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The study was conducted with full conformance to the principles of the Declaration of Helsinki. In accordance with the current legislation, this research is not among the types that requires a formal permission from an ethics committee. This is a secondary use of data ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[272,102,941,134]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"for research purposes for which specific informed consent was requested ab initio from patients who would undertake a treatment process. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,143,443,159]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2. Statistical Analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,162,942,223]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Univariate analysis was performed with the Chi-square or Fisher's test for dichotomous variables, while the Kruskal-Wallis test for nonparametric measures was used for continuous variables [21]. The Kaplan-Meier statistics were used to define the probability of success [22]. The difference between groups was calculated with a log-rank test [23]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,223,941,282]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The univariate analysis was conducted using Vassar Stats (Statistical Computation Web Site), while the Kaplan-Meier statistics were performed using the NCSS software for Windows (https://www.ncss.com/; accessed on 4 December 2023). A $p$ -value below 0.05 was defined as statistically significant. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,294,354,307]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,312,942,386]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Overall, we hospitalized 468 bronchiolitis patients, 272 before the SARS-CoV-2 Pandemic (from 1 September 2017 to 31 March 2018; from 1 September 2018 to 31 March 2019; and from 1 September 2019 to 31 March 2020), 3 during the Pandemic (from 1 September 2020 to 31 March 2021), and 193 after the period of the Pandemic (from 1 September 2021 to 31 March 2022 and from 1 September 2022 to 31 March 2023). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,387,941,447]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In 237 patients, the HRSV was detected on the nasal swab, and for this reason, they were enrolled in the study: 109 in the Group pre-pandemic (named Group A) and 128 in the Group post-pandemic (named Group B). No HRSV bronchiolitis patient was admitted during the SARS-CoV-2 pandemic. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,458,389,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.1. Seasonality ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,476,941,507]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Hospitalization for HRSV bronchiolitis followed a distinct seasonal trend in the two groups, as shown in Figure 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[284,524,905,787]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Seasonal trend of HRSV bronchiolitis. \"]","image_footnote":"[]","img_path":"images/0164/75538af32b07f6b4cbd267a4cf2e2c604dec5730e1cf3323fae7d60e1fc53182.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[272,824,942,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Group A (patients admitted in the period before the SARS-CoV-2 pandemic), the peaks in admissions occurred between November and March, usually lasting 2-4 months. Cases increased significantly in December and peaked in January and February, with only a few cases reported in March. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,102,939,146]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, in Group B (patients admitted after the SARS-CoV-2 pandemic), an anticipated peak was reported. Indeed, bronchiolitis started slowly in October, peaked in November and December, and slowly decreased during February and March. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[312,148,890,162]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The distribution of hospitalization month-by-month is summarized in Table 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,197,939,363]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0288/dca1c3c405a93d00653de01671e08036cd5dc811812176dd7eea3268483fd24c.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td></td><td>Group AN = 109</td><td>Group BN = 128</td><td>p-Value</td></tr><tr><td>September</td><td>0 (0%)</td><td>0 (0%)</td><td></td></tr><tr><td>October</td><td>0 (0%)</td><td>2 (2%)</td><td></td></tr><tr><td>November</td><td>1 (1%)</td><td>36 (28%)</td><td></td></tr><tr><td>December</td><td>10 (9%)</td><td>49 (38%)</td><td><0.0001</td></tr><tr><td>January</td><td>34 (31%)</td><td>31 (24%)</td><td></td></tr><tr><td>February</td><td>53 (49%)</td><td>5 (4%)</td><td></td></tr><tr><td>March</td><td>11 (10%)</td><td>5 (4%)</td><td></td></tr></table>","table_caption":"[\"Table 1. Distribution of the seasonality of infections in the two groups. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[275,379,774,394]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.2. Clinical and Epidemiological Characteristics of Hospitalized Patients ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,398,939,441]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The demography and clinical characteristics of patients hospitalized in all periods that were considered (pre-pandemic, during pandemic, and after pandemic) are provided in Table 2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,475,939,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0017/6ca81f8f9b9b49b48024f7370d6ff3646d54c9b5944a4f844538e904b6d498e3.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group B N = 128</td><td>p-Value</td></tr><tr><td rowspan=\"2\">Gender</td><td>Male</td><td>56 (51%)</td><td>78 (61%)</td><td rowspan=\"2\">0.14</td></tr><tr><td>Female</td><td>53 (49%)</td><td>50 (39%)</td></tr><tr><td>Median Age (months)</td><td></td><td>2 (IQR 1–3)</td><td>2 (IQR 1–4)</td><td>0.85</td></tr><tr><td rowspan=\"3\">Prematurity</td><td>Yes</td><td>12 (11%)</td><td>15 (12%)</td><td rowspan=\"3\">0.36</td></tr><tr><td>No</td><td>95 (87%)</td><td>106 (83%)</td></tr><tr><td>Unknown</td><td>2 (2%)</td><td>7 (5%)</td></tr><tr><td rowspan=\"4\">Months at diagnosis</td><td><1</td><td>37 (34%)</td><td>62 (48%)</td><td rowspan=\"4\">0.0012</td></tr><tr><td>1–3</td><td>52 (48%)</td><td>30 (23%)</td></tr><tr><td>4–6</td><td>14 (13%)</td><td>22 (17%)</td></tr><tr><td>6–12</td><td>6 (5%)</td><td>14 (11%)</td></tr><tr><td rowspan=\"3\">Weight at diagnosis</td><td><4000 g</td><td>21 (19%)</td><td>22 (17%)</td><td rowspan=\"3\">0.21</td></tr><tr><td></td><td>31 (28%)</td><td>34 (26%)</td></tr><tr><td>>5000 g</td><td>57 (52%)</td><td>69 54%)</td></tr><tr><td rowspan=\"3\">Feeding</td><td>Breast-feed</td><td>63 (58%)</td><td>84 (66%)</td><td rowspan=\"3\">0.059</td></tr><tr><td>Artificial</td><td>37 (34%)</td><td>26 (20%)</td></tr><tr><td>Weaned baby</td><td>7 (6%)</td><td>13 (10%)</td></tr><tr><td rowspan=\"2\">Comorbidity</td><td>Yes</td><td>6 (5%)</td><td>10 (8%)</td><td rowspan=\"2\">0.6</td></tr><tr><td>No</td><td>102 (93%)</td><td>118 (92%)</td></tr><tr><td rowspan=\"2\">Coinfection</td><td>Yes</td><td>1 (1%)</td><td>3 (4%)</td><td rowspan=\"2\">0.62</td></tr><tr><td>No</td><td>108 (99%)</td><td>125 (96%)</td></tr></table>","table_caption":"[\"Table 2. Demographic and clinical characteristics of patients. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[57,58,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,123,939,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0735/46112d7627197cdc3b3ed1d9269ec11d556222973c6aef0158cd5439c27caf6a.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group BN = 128</td><td>p-Value</td></tr><tr><td rowspan=\"2\">Fever</td><td>Yes</td><td>45 (41%)</td><td>31 (24%)</td><td rowspan=\"2\">0.0054</td></tr><tr><td>No</td><td>64 (59%)</td><td>97 (76%)</td></tr><tr><td>Profilaxed with Palivizumab</td><td></td><td>0 (0%)</td><td>1 (0,78%)</td><td>1</td></tr></table>","table_caption":"[\"Table 2. Cont. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[273,231,939,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Group A, males were more represented than females (51% vs. 49%); gestational age was reported in 98% of patients. Preterm infants accounted for about 11%; half of the patients had a gestational age between 30 and 34 weeks, and the remaining patients had a gestational age between 35 and 36 weeks. In this group (patients admitted before SARS-SARS-CoV-2 pandemic), no patient had a gestational age under 30 weeks. Two patients had bronchopulmonary dysplasia, two infants had chronic heart conditions, one had a neurological disease like epilepsy, and no infant with immunodeficiency was recorded. At the time of diagnosis, most patients (48%) had an age between one and three months while 34% of them were under one month of age; furthermore, 13% had an age between four and six months and 5% of them were over six months of age. Breastfeeding was reported in 58% of all patients, while formula feeding was reported in 34% of patients of the Group A. Furthermore, 6% of infants had already been weaned. In one patient, during the hospitalization, a coinfection of Epstein-Barr Virus (EBV) was detected. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,426,941,454]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As specified before, no HRSV bronchiolitis was found during the SARS-CoV-2 pandemic in our hospitals. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,456,939,693]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In Group B (patients admitted after the SARS-CoV-2 pandemic), more males than females $(61\\%$ vs. $39\\%)$ were represented, and the gestational age was reported in $95\\%$ of patients. Among the patients for whom the gestational age was available, preterm infants were calculated to be $12\\%$ of all patients; most of these patients $(67\\%)$ had a gestational age between 35 and 36 weeks, while $27\\%$ of them had a gestational age between 30 and 34 weeks, and only one infant had a gestational age of 25 weeks. Two patients had bronchopulmonary dysplasia, and one infant had a neurological disease with hypotonia. No infants affected by immunodeficiency or chronic heart conditions were recorded. When hospitalized, most patients $(48\\%)$ were newborns under one month of age, while $23\\%$ had an age between one and three months, and $17\\%$ were between four and six months. Overall, $11\\%$ of infants were over six months old of age. Breastfeeding was reported in $66\\%$ of all patients, while formula feeding was reported as feeding modality in $20\\%$ of all patients. Furthermore, $10\\%$ of infants had already been weaned. Concerning the coinfections, we reported three cases in whom another pathogen was found. In one case, we also found an EBV first infection; in the second patient, a Mycoplasma pneumoniae co-infection occurred, and in the last patient, the nasal swab tested positive for both HRSV and SARS-CoV-2. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,695,941,753]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the description of the demographic features of patients involved in the study, we found a remarkable difference in the age of the infants; in Group B (post-pandemic), there were more newborns. No statistical differences in sex, gestational age, feeding, and comorbidity were recorded. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,755,939,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Concerning the prophylaxis with Palivizumab, only one patient in Group B was hospitalized for bronchiolitis due to HRSV; he was born at 31 weeks of gestational age and needed Continuous Positive Airway Pressure (CPAP) at birth. He also presented pneumothorax in the hours after birth. During the hospitalization for bronchiolitis, he did not need oxygen supplementation and was admitted to the hospital for three days. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,829,939,856]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Laboratory, X-ray findings, and treatment during hospitalization are provided in Table 3. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,58,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,123,939,542]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0773/97c0a4c1f233debc439a50b99abd549541013f1773dd9f78ab8660fe2b0225e1.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group B N = 128</td><td>p-Value</td></tr><tr><td></td><td></td><td>1.98 (0–63.5)</td><td>1.19 (0–60.3)</td><td>0.039</td></tr><tr><td rowspan=\"2\">Chest X-rays (number)</td><td>Yes</td><td>23 (21%)</td><td>19 (15%)</td><td rowspan=\"2\">0.23</td></tr><tr><td>No</td><td>86 (79%)</td><td>109 (85%)</td></tr><tr><td>Chest X-rays (pathologic results)</td><td></td><td>13 (12%)</td><td>10 (8%)</td><td>0.27</td></tr><tr><td>Higher level of pCO2 (mmHg)</td><td></td><td>46 (28.2–64.1)</td><td>48 (31.7–74)</td><td>1</td></tr><tr><td rowspan=\"2\">Low-flow Oxygen</td><td>Yes</td><td>64 (59%)</td><td>79 (62%)</td><td rowspan=\"2\">0.69</td></tr><tr><td>No</td><td>45 (41%)</td><td>49 (38%)</td></tr><tr><td>Low-flow Oxygen days</td><td></td><td>3 (0–8)</td><td>3 (0–9)</td><td>0.76</td></tr><tr><td rowspan=\"2\">High-flow Oxygen</td><td>Yes</td><td>29 (27%)</td><td>33 (26%)</td><td rowspan=\"2\">1</td></tr><tr><td>No</td><td>80 (73%)</td><td>94 (73%)</td></tr><tr><td>High-flow Oxygen days</td><td></td><td>4 (1–8)</td><td>5 (1–11)</td><td>0.38</td></tr><tr><td>Fraction of inspired Oxygen %</td><td></td><td>35 (21–50)</td><td>34 (25–65)</td><td>0.56</td></tr><tr><td rowspan=\"2\">Aerosolized drugs</td><td>Yes</td><td>96 (88%)</td><td>122 (95%)</td><td rowspan=\"2\">0.054</td></tr><tr><td>No</td><td>13 (12%)</td><td>6 (5%)</td></tr><tr><td rowspan=\"2\">Antibiotics</td><td>Yes</td><td>42 (38%)</td><td>24 (19%)</td><td rowspan=\"2\">0.00082</td></tr><tr><td>No</td><td>67 (61%)</td><td>104 (81%)</td></tr><tr><td rowspan=\"2\">Steroids</td><td>Yes</td><td>13 (12%)</td><td>17 (13%)</td><td rowspan=\"2\">0.84</td></tr><tr><td>No</td><td>96 (88%)</td><td>111 (87%)</td></tr><tr><td rowspan=\"2\">Hydration IV</td><td>Yes</td><td>32 (29%)</td><td>23 (18%)</td><td rowspan=\"2\">0.045</td></tr><tr><td>No</td><td>77 (71%)</td><td>105 (82%)</td></tr></table>","table_caption":"[\"Table 3. Laboratory, X-ray findings, and treatment during hospitalization. \"]","table_footnote":"[\"Notes: CRP: C-reactive protein; $\\\\mathsf{pCO}_2$ : partial pressure of carbon dioxide; and IV: intravenous. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[275,574,939,602]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There were no significant differences between the two groups in X-ray findings, while there was a remarkable difference in CRP values. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,604,939,662]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Concerning the treatment, some differences were remarkable. Antibiotics and IV Hydration were less used in Group B; in Group A, $38\\%$ received an antibiotic therapy compared to the $19\\%$ of patients in Group B. Similarly, in Group B, only $18\\%$ of patients were treated with IV hydration (vs. $29\\%$ in Group A). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,664,939,693]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"There were no statistically significant differences in the type of respiratory support and the length of respiratory support in days. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,694,939,766]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, concerning the short-term outcome, the complications, the length of hospital stay, and the need to transfer to a Hub hospital were similar in the two groups. These data are provided in Table 4. Figure 2 reports the probability of treatment success (discharge to home without transfer to a Hub hospital with PICU or NICU): $96\\%$ of patients in Group A and $94\\%$ in Group B. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,58,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[275,123,941,253]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0032/2d969a743a687ca3e45227aa5f13e7dc8ffb6c9e6803370df69d6ade6f7412f3.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group B N = 128</td><td>p-Value</td></tr><tr><td rowspan=\"2\">Complications</td><td>Yes</td><td>12 (11%)</td><td>12 (9%)</td><td rowspan=\"2\">0.82</td></tr><tr><td>No</td><td>97 (89%)</td><td>116 (91%)</td></tr><tr><td>Hospitalization (days)</td><td></td><td>6 (2–33)</td><td>5 (1–13)</td><td>0.051</td></tr><tr><td rowspan=\"2\">Transfer to a Hub hospital</td><td>Yes</td><td>4 (4%)</td><td>7 (5%)</td><td rowspan=\"2\">0.55</td></tr><tr><td>No</td><td>105 (96%)</td><td>121 (94%)</td></tr></table>","table_caption":"[\"Table 4. Short-term outcome. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[282,275,643,513]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. Probability of treatment success (discharge to home). Notes: gray line: Group A and light blue line: Group B. \"]","image_footnote":"[]","img_path":"images/0011/c8f777ddacff35f66e6b368f67a8f39003ab819a18c44f8cec72a4de6845febd.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[273,563,433,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3.3. HRSV Prevalence ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[272,582,939,655]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the period before the SARS-CoV-2 Pandemic (from 1 September 2017 to 31 March 2018; from 1 September 2018 to 31 March 2019; and from 1 September 2019 to 31 March 2020) in the three ASLTO4 Pediatric Departments, 272 patients were hospitalized with the diagnosis of bronchiolitis, and in 109 $(40\\%)$ of them, HRSV (Group A) was detected on the nasal swab. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,657,941,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"During the SARS-CoV-2 Pandemic (from 1 September 2020 to 31 March 2021), when restrictive measures were adopted, 3 patients were hospitalized for bronchiolitis, and HRSV was not detected. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,701,941,745]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"After the SARS-CoV-2 pandemic (from 1 September 2021 to 31 March 2022 and from 1 September 2022 to 31 March 2023), the total number of hospitalizations for bronchiolitis were 193. In 128 cases $(66\\%)$ , the detected agent was HRSV (Group B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[272,746,941,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Therefore, we can demonstrate a significant increase in the prevalence of HRSV after the SARS-CoV-2 Pandemic; moreover, we noticed a significant drop in the cases of bronchiolitis, but, above all, we found the complete absence of HRSV infection in the Pandemic period. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[309,806,769,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All these data are summarized in Table 5 and Figures 3 and 4. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,854,939,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0771/66dfb6009d3a14c322d30b1074cd89c8be6269e65173bb0a2e07c76d315197b2.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td></td><td>2017–2020</td><td>2021–2023</td><td>p-Value</td></tr><tr><td>HRSV positive</td><td>109 (40%)</td><td>128 (66%)</td><td rowspan=\"2\"><0.0001</td></tr><tr><td>HRSV negative</td><td>163 (60%)</td><td>65 (34%)</td></tr></table>","table_caption":"[\"Table 5. Cases of HRSV infections in patients hospitalized for bronchiolitis. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[55,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[282,103,855,350]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Hospitalization for bronchiolitis before, during, and after SARS-CoV-2 Pandemic. \"]","image_footnote":"[]","img_path":"images/0543/5ef20952dec04c152c846ac71965a24ec3fda5a76b4d6f621ef0bc4561d7b974.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[284,394,855,633]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Prevalence of HRSV detected in bronchiolitis hospitalized before, during, and after the SARS-CoV-2 Pandemic. \"]","image_footnote":"[]","img_path":"images/0943/13a9976bebac7040922abfa7c3d382bd291537a730696cb2cbfe6c9b9559f29a.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[275,684,381,697]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[275,703,941,807]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Pandemic shows the importance of respiratory viruses' circulation surveillance. Respiratory infections are very common in infants and their severity varies based on the host features (for instance, the presence of prematurity or cardio-pulmonary broncho dysplasia). Above all causes of respiratory infection, viral bronchiolitis is the most frequent lower respiratory tract infection and the leading cause of hospitalization in children less than twelve months of age. HRSV is the virus most involved in severe bronchiolitis, and its prevalence shows territorial differences. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,808,941,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study analyzes the characteristics of infants hospitalized for acute HRSV bronchiolitis in the three Pediatric Departments of ASLTO4 before, during, and after the SARS-CoV-2 Pandemic. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[275,852,941,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our data highlight that after the SARS-CoV-2 Pandemic, the HRSV epidemic started earlier than usual. We showed a peak in November–December in Group B (post-pandemic), while in Group A (pre-pandemic), the peak was reached in January–February. This confirms new epidemiological trends of HRSV infection as reported worldwide [18,24–27]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,58,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[897,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,102,939,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The surveillance of the seasonality of HRSV is very important for the improvement and adaptation of the prevention measures. The logistics and timing are very important to optimize its prevention results; if the prophylaxis begins months before the HRSV season, the protection could wane before the end of the epidemic, leaving infants susceptible to HRSV. Similarly, if the HRSV season starts earlier than the prophylaxis, high-risk infants remain vulnerable. Considering the new epidemiological trends, in Piedmont, prophylaxis with Palivizumab in high-risk patients begins in October, starting from 2022, providing the first dose before the onset of the circulation of HRSV. This highlights the importance of improving and updating the system of local surveillance that started in Italy in 2019-2020 as the Influenza Surveillance Network (Respirvirnet) system. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,252,939,356]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In accordance with the current literature, no differences in the severity of HRSV infection have been demonstrated in our study; other authors have reported no differences in X-ray findings, short-term outcomes (like complications, the length of hospitalization, the type of respiratory support, the length of oxygen supplementation, and the need of transfer to a Hub hospital) [28-30]. The only remarkable difference in our study is in the results of the CRP dosage; in Group A (pre-pandemic), its average value was higher than that in Group B (post-pandemic). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,356,939,460]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Other studies, similar to this one, were conducted in Italy. It is very interesting to note that studies conducted in Sicily, a region in the South of Italy, have a similar trend of HRSV infection. The authors did not similarly report a variation in the disease severity [31,32]. Piedmont (in the northwest of Italy) and Sicily (an island in the south of Italy) have very different climate and air characteristics. The similar results in HRSV trends suggest that even in parts of Italy where there is different weather due to the different latitudes, the HRSV epidemiological trend, the severity of the disease, and its prevalence are similar. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,460,939,579]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Interestingly, we showed remarkable differences in treatment; fewer antibiotics were used in Group B. This suggests better adherence to the guidelines, making an important effort to reduce the development of antibiotic resistance. On the other hand, a higher CRP value was found in Group A; this finding may explain the higher use of antibiotics in this group of patients: clinicians had more suspicion of bacterial complications, so they prescribed antibiotics. Lastly, by reducing the rate of IV hydration over the years, the patients were encouraged to maintain oral feeding with a higher number of fractionated meals, as suggested by the national guidelines [4]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,580,939,713]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Looking at the HRSV prevalence, during the SARS-CoV-2 pandemic, we observed a drop in bronchiolitis hospitalizations. We reported three patients that were hospitalized for bronchiolitis, but no case of HRSV infection was found. These data are in agreement with other studies and the epidemiological surveillance of viruses that show a global reduction in respiratory infections that share the transmission path with SARS-CoV-2, like influenza and HRSV [26,33]. Given that the transmission of HRSV occurs through droplets, the containment measures of the SARS-CoV-2 Pandemic (like the use of face masks, social distancing, smart working, and the closure of schools) have led to the reduction in HRSV transmission [11,34,35]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,714,939,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Moreover, there is a strong correlation between environmental conditions, for example, weather and air pollution, and the incidence of HRSV. A study shows a correlation between HRSV transmission, benzene levels, and humidity, while there is an inverse correlation with temperature [36]. Given that a significant reduction in air pollutants such as benzene was recorded during the Pandemic, it can be hypothesized that the pollution reduction helped to decrease the circulation of HRSV. It is very hard to quantify the contribution, but we can suggest that it is not comparable with restrictive measures. We aim to explore such hypotheses in future studies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,833,939,892]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The prevalence of HRSV in our study group increased significantly after the SARS-CoV-2 Pandemic, confirming previously published data; we reported an HRSV surge when the prevention measures were relaxed, and the social interactions increased. This finding confirms the main role of social distance measures in the containment of HRSV circulation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[278,102,939,191]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Furthermore, the \"immunity debt\" played a role in the increased circulation of HRSV: during the Pandemic period, the cohort of HRSV-naive patients expanded. It happened for two reasons: (1) due to the presence of children who have never had HRSV infections and (2) due to the reduction in immunity duration, which decreased during the time and without re-exposure to HRSV. This is confirmed by studies that show an increased number of older infants affected by HRSV [36]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,192,939,281]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In our study, there is a remarkable difference in newborns hospitalized for HRSV bronchiolitis comparing pre- and post-pandemic, with $48\\%$ of newborns in Group B vs. $34\\%$ of newborns in Group A. This result is due to the reduced exposure to respiratory viruses not only in children but also in pregnant women; above all, it is known that the infection in the third trimester of pregnancy could protect newborns against HRSV infections through antibodies contained in breast milk and those transferred transplacentally [37-39]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,282,939,414]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our study has some limitations. Our analysis is conducted in Hub hospitals with a small sample size, due to the characteristics of our health district as detailed below: First of all, a small percentage of children aged less than one year live in our district. Furthermore, the study is based on a retrospective data collection of hospital records; as a consequence, this study may be subject to information bias due to the lack of data or incomplete hospital records. In addition, we only reported data about hospitalized patients with bronchiolitis, while patients who visited the Emergency Department and were discharged or treated by general pediatric practitioners were not included. Consequently, the global prevalence and the incidence of HRSV may be underestimated. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,414,939,519]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The main strength of our study is that it was performed in three Spoke hospitals that are a part of the same health district (ASL); therefore, clinicians had the same devices for the treatment of respiratory failure and the same tests to detect HRSV. The test used was an antigen test that was less sensitive and specific than molecular methods, but the same test was used in the three hospitals and in the different analyzed periods. Furthermore, clinicians used the same protocols of treatment and had the same criteria of transfer to Hub Hospital because of the lack of Pediatric Intensive Care Unit in our health district. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,532,391,545]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5. Conclusions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[278,550,939,653]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The SARS-CoV-2 Pandemic has changed the epidemiological trend of HRSV infections in our territory. In detail, the bronchiolitis season started earlier than usual after the Pandemic; this is reported in our study in accordance with the data records from other countries. The unusual resurgence of HRSV infection was not associated with an increased severity of the illness in our study group. In addition, we reported an increase in the prevalence of HRSV bronchiolitis hospitalized after the Pandemic, with a high proportion of newborns possibly due to the \"immunity debt\" and the lower exposure in pregnant women. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,655,939,803]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The surveillance of the circulation of the respiratory virus is necessary to adapt the preventive measures and the hospital activity organization to the seasonal changes; indeed, the analysis of changes in seasonality allows high-risk patients to receive the optimal level of prevention with the correct prophylaxis while hospitals reorganize their activities. It may also imply transferring patients from the Hub to the Spoke hospitals, leading to a remarkable reduction in costs. Lastly, a lesson learned during the Pandemic period was that the simple preventive measures should not be forgotten, because they can markedly reduce HRSV circulation; this finding underlines the importance of the strict hygiene behaviors and the utilization of face masks by healthcare workers, who predominantly deal with high-risk patients. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,816,939,873]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author Contributions: F.P., A.B.d.P., V.D., G.C., C.G., N.R., A.T., F.T. and M.B. contributed equally to all sections of the paper, including contribution to data curation, to the analysis of the results and to the writing of the manuscript. F.P. and M.B. contributed to the draft. All authors have read and agreed to the published version of the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[278,881,631,894]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding: This research received no external funding. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,58,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,60,939,70]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[272,103,941,146]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki. In accordance with the current legislation, this research is not among the types that requires a formal permission from an ethics committee. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,152,589,166]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Informed Consent Statement: Not applicable. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,173,907,187]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data Availability Statement: The collected data are available from the corresponding authors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[273,193,709,208]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflicts of Interest: The authors declare no conflicts of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,219,144,234]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[55,237,942,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Meissner, H.C. Viral Bronchiolitis in Children. N. Engl. J. Med. 2016, 374, 62-72. [CrossRef] \",\"2. Baraldi, E.; Lanari, M.; Manzoni, P.; Rossi, G.A.; Vandini, S.; Rimini, A.; Romagnoli, C.; Colonna, P.; Biondi, A.; Biban, P.; et al. Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants. Ital. J. Pediatr. 2014, 40, 65. [CrossRef] [PubMed] \",\"3. Perez, A.; Lively, J.Y.; Curns, A.; Weinberg, G.A.; Halasa, N.B.; Staat, M.A.; Szilagyi, P.G.; Stewart, L.S.; McNeal, M.M.; Clopper, B.; et al. Respiratory Virus Surveillance Among Children with Acute Respiratory Illnesses—New Vaccine Surveillance Network, United States, 2016-2021. MMWR Morb. Mortal. Wkly. Rep. 2022, 71, 1253-1259. [CrossRef] \",\"4. Manti, S.; Staiano, A.; Orfeo, L.; Midulla, F.; Marseglia, G.L.; Ghizzi, C.; Zampogna, S.; Carnielli, V.P.; Favilli, S.; Ruggieri, M.; et al. UPDATE—2022 Italian guidelines on the management of bronchiolitis in infants. Ital. J. Pediatr. 2023, 49, 19. [CrossRef] \",\"5. Cutrera, R.; Wolfler, A.; Picone, S.; Rossi, G.A.; Gualberti, G.; Merolla, R.; Del Vecchio, A.; Villani, A.; Midulla, F.; Dotta, A. Impact of the 2014 American Academy of Pediatrics recommendation and of the resulting limited financial coverage by the Italian Medicines Agency for palivizumab prophylaxis on the RSV-associated hospitalizations in preterm infants during the 2016-2017 epidemic season: A systematic review of seven Italian reports. Ital. J. Pediatr. 2019, 45, 139. [CrossRef] \",\"6. Mazur, N.I.; Martinón-Torres, F.; Baraldi, E.; Fauroux, B.; Greenough, A.; Heikkinen, T.; Manzoni, P.; Mejias, A.; Nair, H.; Papadopoulos, N.G.; et al. Lower respiratory tract infection caused by respiratory syncytial virus: Current management and new therapeutics. Lancet Respir. Med. 2015, 3, 888-900. [CrossRef] [PubMed] \",\"7. Viguria, N.; Navascués, A.; Juanbeltz, R.; Echeverria, A.; Ezpeleta, C.; Castilla, J. Effectiveness of palivizumab in preventing respiratory syncytial virus infection in high-risk children. Hum. Vaccines Immunother. 2021, 17, 1867-1872. [CrossRef] [PubMed] \",\"8. Azzari, C.; Baraldi, E.; Bonanni, P.; Bozzola, E.; Coscia, A.; Lanari, M.; Manzoni, P.; Mazzone, T.; Sandri, F.; Lisi, G.C.; et al. Epidemiology and prevention of respiratory syncytial virus infections in children in Italy. Ital. J. Pediatr. 2021, 47, 198. [CrossRef] \",\"9. Li, Y.; Wang, X.; Msosa, T.; de Wit, F.; Murdock, J.; Nair, H. The impact of the 2009 influenza pandemic on the seasonality of human respiratory syncytial virus: A systematic analysis. Influenza Other Respir. Viruses 2021, 15, 804-812. [CrossRef] \",\"10. Piret, J.; Boivin, G. Viral Interference between Respiratory Viruses. Emerg. Infect. Dis. 2022, 28, 273-281. [CrossRef] \",\"11. Nascimento, M.S.; Baggio, D.M.; Fascina, L.P.; Prado, C.D. Impact of social isolation due to COVID-19 on the seasonality of pediatric respiratory diseases. PLoS ONE 2020, 15, e0243694. [CrossRef] \",\"12. Van Brusselen, D.; De Troeyer, K.; Ter Haar, E.; Vander Auwera, A.; Poschet, K.; Van Nuijs, S.; Bael, A.; Stobbelaar, K.; Verhulst, S.; Van Herendael, B.; et al. Bronchiolitis in COVID-19 times: A nearly absent disease? Eur. J. Pediatr. 2021, 180, 1969-1973. [CrossRef] \",\"13. Foley, D.A.; Yeoh, D.K.; Minney-Smith, C.A.; Martin, A.C.; Mace, A.O.; Sikazwe, C.T.; Le, H.; Levy, A.; Moore, H.C.; Blyth, C.C. The Interseasonal Resurgence of Respiratory Syncytial Virus in Australian Children Following the Reduction of Coronavirus Disease 2019-Related Public Health Measures. Clin. Infect. Dis. 2021, 73, e2829-e2830. [CrossRef] \",\"14. Saravanos, G.L.; Hu, N.; Homaira, N.; Muscatello, D.J.; Jaffe, A.; Bartlett, A.W.; Wood, N.J.; Rawlinson, W.; Kesson, A.; Lingam, R.; et al. RSV Epidemiology in Australia Before and During COVID-19. Pediatrics 2022, 149, e2021053537. [CrossRef] \",\"15. Public Health Surveillance Information for New Zealands Public Health Action. Laboratory-Based Virology Weekly Report, 2004-2019. 2021. Available online: https://surv.esr.cri.nz/virology/virology_annually_report.php (accessed on 28 December 2023). \",\"16. Camporesi, A.; Morello, R.; Ferro, V.; Pierantoni, L.; Rocca, A.; Lanari, M.; Trobia, G.L.; Sciacca, T.; Bellinvia, A.G.; De Ferrari, A.; et al. Epidemiology, Microbiology and Severity of Bronchiolitis in the First Post-Lockdown Cold Season in Three Different Geographical Areas in Italy: A Prospective, Observational Study. Children 2022, 9, 491. [CrossRef] [PubMed] \",\"17. Tulyapronchote, R.; Selhorst, J.B.; Malkoff, M.D.; Gomez, C.R. Delayed sequelae of vertebral artery dissection and occult cervical fractures. Neurology 1994, 44, 1397. [CrossRef] [PubMed] \",\"18. Agha, R.; Avner, J.R. Delayed Seasonal RSV Surge Observed During the COVID-19 Pandemic. Pediatrics 2021, 148, e2021052089. [CrossRef] \",\"19. Guitart, C.; Bobillo-Perez, S.; Alejandre, C.; Armero, G.; Launes, C.; Cambra, F.J.; Balaguer, M.; Jordan, I.; Pagarolas, A.A.; Vila, J.; et al. Bronchiolitis, epidemiological changes during the SARS-CoV-2 pandemic. BMC Infect. Dis. 2022, 22, 84. [CrossRef] [PubMed] \",\"20. Available online: http://www.ruparpiemonte.it/infostat/risultati.jsp (accessed on 28 December 2023). \",\"21. Kaplan, E.L.; Meier, P. Nonparametric Estimation from Incomplete Observations. J. Am. Stat. Assoc. 1958, 53, 457-481. [CrossRef] \",\"22. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 1966, 50, 163-170. \"]","page_idx":"11","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[55,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 of 13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[53,102,941,678]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"23. Kruskal, W.H.; Wallis, W.A. Use of Ranks in One-Criterion Variance Analysis. J. Am. Stat. Assoc. 1952, 47, 583-621. [CrossRef] \",\"24. Curatola, A.; Graglia, B.; Ferretti, S.; Covino, M.; Pansini, V.; Eftimiadi, G.; Chiaretti, A.; Gatto, A. The acute bronchiolitis rebound in children after COVID-19 restrictions: A retrospective, observational analysis. Acta Bio Med. Atenei Parm. 2023, 94, e2023031. [CrossRef] \",\"25. Pruccoli, G.; Castagno, E.; Raffaldi, I.; Denina, M.; Barisone, E.; Baroero, L.; Timeus, F.; Rabbone, I.; Monzani, A.; Terragni, G.M.; et al. The Importance of RSV Epidemiological Surveillance: A Multicenter Observational Study of RSV Infection during the COVID-19 Pandemic. Viruses 2023, 15, 280. [CrossRef] \",\"26. Olsen, S.J.; Winn, A.K.; Budd, A.P.; Prill, M.M.; Steel, J.; Midgley, C.M.; Kniss, K.; Rowe, T.; Foust, A.; et al. Changes in Influenza and Other Respiratory Virus Activity During the COVID-19 Pandemic—United States, 2020–2021. MMWR Morb. Mortal. Wkly. Rep. 2021, 70, 1013–1019. [CrossRef] \",\"27. Opek, M.W.; Yeshayahu, Y.; Glatman-Freedman, A.; Kaufman, Z.; Sorek, N.; Brosh-Nissimov, T. Delayed respiratory syncytial virus epidemic in children after relaxation of COVID-19 physical distancing measures, Ashdod, Israel, 2021. *Eurosurveillance* 2021, 26, 2100706. [CrossRef] \",\"28. Barrezuela, L.B.; Zamorano, M.G.; López-Casillas, P.; Brezmes-Raposo, M.; Fernández, I.S.; Vázquez, M.d.l.A.P. Influenca de la pandemia COVID-19 sobre la epidemiología de la bronquiolitis aguda. Enferm. Infect. Microbiol. Clin. 2023, 41, 348–351. [CrossRef] \",\"29. Shanahan, K.H.; Monuteaux, M.C.; Bachur, R.G. Severity of Illness in Bronchiolitis Amid Unusual Seasonal Pattern During the COVID-19 Pandemic. Hosp. Pediatr. 2022, 12, e119-e123. [CrossRef] [PubMed] \",\"30. Correction to: Outbreak of Respiratory Syncytial Virus Bronchiolitis in Italy. Clin. Infect. Dis. 2023, 76, 777-779. [CrossRef] [PubMed] \",\"31. Manti, S.; Giallongo, A.; Parisi, G.F.; Papale, M.; Presti, S.; Bianco, M.L.; Spicuzza, L.; Leonardi, S. Impact of COVID-19 Pandemic and Lockdown on the Epidemiology of RSV-Mediated Bronchiolitis: Experience from Our Centre. Children 2022, 9, 1723. [CrossRef] \",\"32. Presti, S.; Manti, S.; Gambilonghi, F.; Parisi, G.F.; Papale, M.; Leonardi, S. Comparative Analysis of Pediatric Hospitalizations during Two Consecutive Influenza and Respiratory Virus Seasons Post-Pandemic. Viruses 2023, 15, 1825. [CrossRef] [PubMed] \",\"33. Nenna, R.; Matera, L.; Pierangeli, A.; Oliveto, G.; Viscido, A.; Petrarca, L.; La Regina, D.P.; Mancino, E.; Di Mattia, G.; Villani, A.; et al. First COVID-19 lockdown resulted in most respiratory viruses disappearing among hospitalised children, with the exception of rhinoviruses. Acta Paediatr. 2022, 111, 1399-1403. [CrossRef] \",\"34. Ferrero, F.; Ossorio, M.F. Is there a place for bronchiolitis in the COVID-19 era? Lack of hospitalizations due to common respiratory viruses during the 2020 winter. Pediatr. Pulmonol. 2021, 56, 2372-2373. [CrossRef] \",\"35. Wilder, J.L.; Parsons, C.R.; Growdon, A.S.; Toomey, S.L.; Mansbach, J.M. Pediatric Hospitalizations During the COVID-19 Pandemic. Pediatrics 2020, 146, e2020005983. [CrossRef] \",\"36. Lumley, S.F.; Richens, N.; Lees, E.; Cregan, J.; Kalimeris, E.; Oakley, S.; Morgan, M.; Segal, S.; Dawson, M.; Walker, A.S.; et al. Changes in paediatric respiratory infections at a UK teaching hospital 2016-2021; impact of the SARS-CoV-2 pandemic. J. Infect. 2022, 84, 40-47. [CrossRef] \",\"37. Koivisto, K.; Nieminen, T.; Mejias, A.; Gonzalez, C.C.; Ye, F.; Mertz, S.; Peebles, M.; Ramilo, O.; Saxén, H. Respiratory Syncytial Virus (RSV)-Specific Antibodies in Pregnant Women and Subsequent Risk of RSV Hospitalization in Young Infants. J. Infect. Dis. 2022, 225, 1189-1196. [CrossRef] \",\"38. Manti, S.; Leonardi, S.; Rezaee, F.; Harford, T.J.; Perez, M.K.; Piedimonte, G. Effects of Vertical Transmission of Respiratory Viruses to the Offspring. Front. Immunol. 2022, 13, 853009. [CrossRef] \",\"39. Hatter, L.; Eathorne, A.; Hills, T.; Bruce, P.; Beasley, R. Respiratory syncytial virus: Paying the immunity debt with interest. Lancet Child Adolesc. Health 2021, 5, e44-e45. [CrossRef] \"]","page_idx":"12","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[53,694,941,738]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[55,57,176,68]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Viruses 2024, 16, 230 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[890,59,939,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 of 13 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[57,122,105,135]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,137,919,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Impact of SARS-CoV-2 Pandemic and Lockdown on the HRSV Circulation: Experience of Three Spoke Hospitals in Northern Italy \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,219,845,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Francesca Parola $^{1, *}$ , Adalberto Brach del Prever $^{1, *}$ , Virginia Deut $^{2}$ , Giulia Costagliola $^{3}$ , Carla Guidi $^{1}$ , Neftj Ragusa $^{2}$ , Antonella Tuscano $^{3}$ , Fabio Timeus $^{3}$ and Massimo Berger $^{2}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,275,927,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1 Pediatric and Neonatology Department, Ciriè Hospital, 10073 Ciriè, TO, Italy \\\",\\\"2 Pediatric and Neonatology Department, Ivrea Hospital, 10015 Ivrea, TO, Italy; mberger@aslto4.piemonte.it (M.B.) \\\",\\\"3 Pediatric and Neonatology Department, Chivasso Hospital, 10034 Chivasso, TO, Italy \\\",\\\"* Correspondence: francesca.parola@aslto4.piemonte.it (F.P.); abrachdelprever@aslto4.piemonte.it (A.B.d.P.) \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[275,357,941,601]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: The SARS-CoV-2 Pandemic affected the global epidemiology of respiratory infections, including Human Respiratory Syncytial Virus (HRSV), thanks to state governments' implementation of mitigation strategies, like the promotion of face masks and lockdowns. However, after the Pandemic, the dramatic resurgence of these diseases was reported worldwide. Our retrospective study, involving three Spoke Pediatric Departments, includes all the infants under one year of age hospitalized for HRSV bronchiolitis in a period before the Pandemic period (2017–2020), during the SARS-CoV-2 Pandemic (2020–2021), and after the Pandemic (2021–2023). The primary aim was to analyze the temporal trend of HRSV in these three periods. Then, the clinical and epidemiological characteristics were analyzed to highlight the clinical differences in the affected patients, in the severity of the infections, and in the short-term outcomes. Ultimately, we analyzed the HRSV prevalence in the global bronchiolitis hospitalization over the reported periods. Overall, we included 237 patients. Before the Pandemic, the peak was recorded in January and February, while after the Pandemic, the peak was in November and December. A higher prevalence of HRSV was demonstrated after the Pandemic compared to the period before the Pandemic; overall, no difference in severity was reported. In conclusion, an increase in HRSV cases after the Pandemic has been demonstrated with an anticipated peak, while no differences were recorded in severity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,526,146,548]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0356/6017fc1b612918b98e5b289e4a5be7bb04110a9122f63df94abbc2a71faa769c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,552,255,678]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Citation: Parola, F.; Brach del Prever, A.; Deut, V.; Costagliola, G.; Guidi, C.; Ragusa, N.; Tuscano, A.; Timeus, F; Berger, M. Impact of SARS-CoV-2 Pandemic and Lockdown on the HRSV Circulation: Experience of Three Spoke Hospitals in Northern Italy. Viruses 2024, 16, 230. https://doi.org/10.3390/10.3390/v16020230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,688,216,699]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Academic Editor: Donald Seto \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,709,206,721]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 29 December 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,725,189,734]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Revised: 26 January 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,739,196,749]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Accepted: 30 January 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,753,200,764]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published: 1 February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,777,154,803]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0636/42b348846c4430cd55b06525a550ea6099c9d8aff2a94684d1987abb42ca86f6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[57,808,257,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,617,939,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: Respiratory Syncytial Virus (HRSV); SARS-CoV-2 Pandemic; epidemiology; seasonality trend; HRSV prevalence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,692,393,705]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,709,941,753]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viral bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children; it represents the most common cause of acute respiratory failure in infants under one year of age in developing countries [1]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,755,941,815]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Many guidelines and consensus have been released to standardize the approach for viral bronchiolitis; the main point of discussion is regarding the definition, diagnosis, and treatment of bronchiolitis. Bronchiolitis has been diagnosed in children under one year of age, but the American guidelines use the diagnosis of bronchiolitis up to two years of age. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,815,941,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The diagnostic criteria of bronchiolitis, defined by an Italian Consensus referred to children under 12 months of age and included the following: an onset with rhinorrhea and/or upper respiratory tract infections; an episode of respiratory distress associated with crackles and/or wheezing, the use of accessory muscles or lower chest wall retractions, low $\\\\mathrm{O}_2$ saturation levels, high respiratory rate relative to age, skin color changes, nasal flaring, fever, and presentation during epidemic season [2]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,57,115,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[122,66,245,90]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"viruses \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[863,64,939,99]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"MDPI \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[57,965,396,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230. https://doi.org/10.3390/v16020230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[689,965,939,977]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://www.mdpi.com/journal/viruses \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[275,102,939,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Human Respiratory Syncytial Virus (HRSV) accounts for $60 - 80\\\\%$ of bronchiolitis presentations. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,131,941,192]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It has been estimated that HRSV infects more than $60\\\\%$ of all children during the first year of life and that HRSV infects nearly all children by the time they are two years old [3,4]. HRSV is the second cause of death worldwide after malaria and the first cause of death for respiratory illness [5,6]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,192,941,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The clinical presentation of HRSV infections is highly variable. It may be limited to upper respiratory tract symptoms, such as fever, rhinorrhea, and congestion; the severe presentation includes bronchiolitis and pneumonia. Bronchiolitis is generally self-limiting but can lead to hospitalization due to severe respiratory distress, acute respiratory failure, or difficulty in feeding. The main risk factors for severe disease are bronchopulmonary dysplasia, age younger than 12 months, a personal history of prematurity, male sex, immunodeficiency, formula feeding, and congenital heart disease. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,296,941,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The primary preventive measure used is prophylaxis with Palivizumab, a humanized monoclonal antibody against HRSV; Pavilizumab is used to defend against the severe manifestations of respiratory infections due to HRSV in high-risk patients, such as children born preterm or with bronchopulmonary dysplasia [7]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,356,941,401]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HRSV is characterized by a variable epidemiology, depending on geographic area. In Italy, the HRSV circulates from mild November until the end of March. It peaks in January/February; the total circulation duration is about four months [8]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,401,941,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Nevertheless, HRSV circulation in the past has been influenced by previous Pandemics; for instance, in 2009, influenza H1N1 delayed the HRSV peak. This variability of seasonality could be explained by the possible viral interference and the impact of preventive measures [9]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,460,941,564]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Concerning viral interference, a virus infection could be influenced by coinfection. Recently, during the Pandemic, the virus-virus interaction has been well defined; this interaction is influenced by the virus type, the infection timing, and the interplay between the response of the host to each virus interplay. A positive interaction is reported when co-infection results in an increased disease severity and pathogenesis, while a negative interaction is reported when an infection reduces or prevents the infection and replication of a second virus (e.g., influenza A virus and HRSV) [10]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,564,941,653]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"During the SARS-CoV-2 Pandemic, various restrictive measures were adopted worldwide, like the imposition of social distancing measures, the closing of schools and commercial activities, strict hygiene behaviors, the use of face masks, and travel limitations. The massive effort to contain the spread of SARS-CoV-2 also affected the circulation of other respiratory pathogens, like influenza and HRSV, with a similar transmission route (contact, droplets, and aerosol transmission) [11]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,653,941,744]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Especially during the 2020-2021 season, a few cases of bronchiolitis were reported worldwide, leading some authors to speak about \\\"a nearly absent disease\\\" [12]. In the 2021-2022 season, a dramatic rebound of bronchiolitis was reported in the Northern and Southern hemispheres, due to HRSV infections [12]. This data in Italy was detected by a dedicated Surveillance Network system (RespivirNet), with a weekly report of respiratory viruses' circulation region-by-region [8]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,744,941,788]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The first report of decreased bronchiolitis was in Australia and New Zealand, where the containment of SARS-CoV-2 was excellent and quickly started to relax the SARS-CoV-2 preventive measures. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,788,941,848]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"After, an unexpected unseasonal peak of bronchiolitis compared to that in the pre-Pandemic periods has been registered worldwide [13-15]. These data were confirmed by intercontinental reports; it shows an anticipation of the peak of bronchiolitis, due to HRSV. Also, in Italy, these data have been confirmed [16-19]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,848,941,894]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study aims to provide insights into the impact of the SARS-CoV-2 Pandemic on the epidemiology of HRSV infections in Spoke hospitals of our health district (ASLTO4). The secondary aim was to evaluate the differences in the clinical features of patients affected by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,102,939,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HRSV before and after the SARS-CoV-2 Pandemic and the global increase in bronchiolitis due to HRSV. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,143,473,156]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Materials and Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,161,401,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1. Study Design \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,178,941,312]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A retrospective study was carried out in Spoke hospitals in the area nearing Turin, Piedmont Region, in the northwest of Italy. Italy is divided into health districts with a hub and spoke model for referral of patients. Our local health district (ASLTO4) includes 174 cities; the overall area is characterized by a great geographical variability, from high Alpine Mountains to urban areas. The total population of this area is 504,467 people, with 3015 inhabitants under one year of age in 2022 [20]. The local healthcare system ASLTO4 is organized into five districts, with great heterogeneity in demography, population density, and infrastructures. The General Emergency Department and Pediatric Unit are present in three Spoke hospitals of Ciriè, Chivasso, and Ivrea. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,313,941,386]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We included patients under one year of age referred to our Pediatric Departments for acute bronchiolitis due to HRSV that required hospitalization over different seasons. The test used to detect the HRSV was a rapid antigen test for the qualitative detection in nasopharyngeal swabs; the test used in our hospitals is the same since 2012 (BinaxNOW HRSV CARD—Abbot). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,387,941,461]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We divided the included patients into two groups: Group A hospitalized before the SARS-CoV-2 Pandemic (from 1 September 2017 to 31 March 2018; from 1 September 2018 to 31 March 2019; and from 1 September 2019 to 31 March 2020) and Group B hospitalized after the period of the Pandemic (from 1 September 2021 to 31 March 2022 and from 1 September 2022 to 31 March 2023) when the restrictive measures were relaxed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,462,941,506]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to estimate the prevalence of HRSV, we reported the total number of cases of bronchiolitis hospitalized during the same periods and the few cases of bronchiolitis in the Pandemic period (from 1 September 2020 to 31 March 2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,507,939,536]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The period of data collection from September to March was established based on the HRSV epidemiology in Italy [8]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,537,941,745]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We collected data about demographic variables (sex, age, months of admission). Clinical and epidemiological data were recorded (age at onset, gestational age and birth weight, weight at admission, feeding, fever) as well as a personal history of chronic illnesses such as cardiopathy, neurological disease, and bronchopulmonary dysplasia. Relevant clinical variables were documented like laboratory (C-reactive protein in a performed blood sample and Pco2 in the Blood Gas Analysis) and microbiology (coinfection by other microbiological agents). C-reactive protein (CRP) was considered normal below $10\\\\mathrm{mg / dL}$ . The coinfection was investigated based on clinical suspicion: we usually assessed antibodies for Epstein-Barr Virus or Mycoplasma pneumonia in blood samples. In Group B, all patients were tested for SARS-CoV-2 with an antigen rapid test on a nasopharyngeal swab for hospital admission. We reported radiograph results and short-term outcomes (length of hospital stay, complications, Hub hospital transfer). Treatment during hospitalization (low- or high-flow oxygen supplementation, nebulized therapy, steroids, antibiotics, and intravenous hydration) and discharged therapy data were recorded in all patients. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,746,939,775]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Firstly, the temporal trend of HRSV bronchiolitis after the SARS-COV-2 Pandemic (Group B) was compared to that of the previous period (Group A). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,776,939,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Then, the clinical and epidemiological characteristics were compared to assess if there were differences in the patients affected, in the severity of the infections, and the short-term outcomes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,820,939,848]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, we analyzed the HRSV prevalence in global bronchiolitis hospitalization in the same periods, both over-reported and during the Pandemic. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,850,939,894]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The study was conducted with full conformance to the principles of the Declaration of Helsinki. In accordance with the current legislation, this research is not among the types that requires a formal permission from an ethics committee. This is a secondary use of data \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[272,102,941,134]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"for research purposes for which specific informed consent was requested ab initio from patients who would undertake a treatment process. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,143,443,159]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2. Statistical Analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,162,942,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Univariate analysis was performed with the Chi-square or Fisher's test for dichotomous variables, while the Kruskal-Wallis test for nonparametric measures was used for continuous variables [21]. The Kaplan-Meier statistics were used to define the probability of success [22]. The difference between groups was calculated with a log-rank test [23]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,223,941,282]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The univariate analysis was conducted using Vassar Stats (Statistical Computation Web Site), while the Kaplan-Meier statistics were performed using the NCSS software for Windows (https://www.ncss.com/; accessed on 4 December 2023). A $p$ -value below 0.05 was defined as statistically significant. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,294,354,307]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,312,942,386]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Overall, we hospitalized 468 bronchiolitis patients, 272 before the SARS-CoV-2 Pandemic (from 1 September 2017 to 31 March 2018; from 1 September 2018 to 31 March 2019; and from 1 September 2019 to 31 March 2020), 3 during the Pandemic (from 1 September 2020 to 31 March 2021), and 193 after the period of the Pandemic (from 1 September 2021 to 31 March 2022 and from 1 September 2022 to 31 March 2023). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,387,941,447]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In 237 patients, the HRSV was detected on the nasal swab, and for this reason, they were enrolled in the study: 109 in the Group pre-pandemic (named Group A) and 128 in the Group post-pandemic (named Group B). No HRSV bronchiolitis patient was admitted during the SARS-CoV-2 pandemic. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,458,389,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.1. Seasonality \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,476,941,507]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Hospitalization for HRSV bronchiolitis followed a distinct seasonal trend in the two groups, as shown in Figure 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[284,524,905,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Seasonal trend of HRSV bronchiolitis. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0164/75538af32b07f6b4cbd267a4cf2e2c604dec5730e1cf3323fae7d60e1fc53182.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[272,824,942,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Group A (patients admitted in the period before the SARS-CoV-2 pandemic), the peaks in admissions occurred between November and March, usually lasting 2-4 months. Cases increased significantly in December and peaked in January and February, with only a few cases reported in March. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,102,939,146]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, in Group B (patients admitted after the SARS-CoV-2 pandemic), an anticipated peak was reported. Indeed, bronchiolitis started slowly in October, peaked in November and December, and slowly decreased during February and March. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[312,148,890,162]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The distribution of hospitalization month-by-month is summarized in Table 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,197,939,363]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0288/dca1c3c405a93d00653de01671e08036cd5dc811812176dd7eea3268483fd24c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td>Group AN = 109</td><td>Group BN = 128</td><td>p-Value</td></tr><tr><td>September</td><td>0 (0%)</td><td>0 (0%)</td><td></td></tr><tr><td>October</td><td>0 (0%)</td><td>2 (2%)</td><td></td></tr><tr><td>November</td><td>1 (1%)</td><td>36 (28%)</td><td></td></tr><tr><td>December</td><td>10 (9%)</td><td>49 (38%)</td><td><0.0001</td></tr><tr><td>January</td><td>34 (31%)</td><td>31 (24%)</td><td></td></tr><tr><td>February</td><td>53 (49%)</td><td>5 (4%)</td><td></td></tr><tr><td>March</td><td>11 (10%)</td><td>5 (4%)</td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Distribution of the seasonality of infections in the two groups. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[275,379,774,394]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.2. Clinical and Epidemiological Characteristics of Hospitalized Patients \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,398,939,441]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The demography and clinical characteristics of patients hospitalized in all periods that were considered (pre-pandemic, during pandemic, and after pandemic) are provided in Table 2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,475,939,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0017/6ca81f8f9b9b49b48024f7370d6ff3646d54c9b5944a4f844538e904b6d498e3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group B N = 128</td><td>p-Value</td></tr><tr><td rowspan=\\\"2\\\">Gender</td><td>Male</td><td>56 (51%)</td><td>78 (61%)</td><td rowspan=\\\"2\\\">0.14</td></tr><tr><td>Female</td><td>53 (49%)</td><td>50 (39%)</td></tr><tr><td>Median Age (months)</td><td></td><td>2 (IQR 1–3)</td><td>2 (IQR 1–4)</td><td>0.85</td></tr><tr><td rowspan=\\\"3\\\">Prematurity</td><td>Yes</td><td>12 (11%)</td><td>15 (12%)</td><td rowspan=\\\"3\\\">0.36</td></tr><tr><td>No</td><td>95 (87%)</td><td>106 (83%)</td></tr><tr><td>Unknown</td><td>2 (2%)</td><td>7 (5%)</td></tr><tr><td rowspan=\\\"4\\\">Months at diagnosis</td><td><1</td><td>37 (34%)</td><td>62 (48%)</td><td rowspan=\\\"4\\\">0.0012</td></tr><tr><td>1–3</td><td>52 (48%)</td><td>30 (23%)</td></tr><tr><td>4–6</td><td>14 (13%)</td><td>22 (17%)</td></tr><tr><td>6–12</td><td>6 (5%)</td><td>14 (11%)</td></tr><tr><td rowspan=\\\"3\\\">Weight at diagnosis</td><td><4000 g</td><td>21 (19%)</td><td>22 (17%)</td><td rowspan=\\\"3\\\">0.21</td></tr><tr><td></td><td>31 (28%)</td><td>34 (26%)</td></tr><tr><td>>5000 g</td><td>57 (52%)</td><td>69 54%)</td></tr><tr><td rowspan=\\\"3\\\">Feeding</td><td>Breast-feed</td><td>63 (58%)</td><td>84 (66%)</td><td rowspan=\\\"3\\\">0.059</td></tr><tr><td>Artificial</td><td>37 (34%)</td><td>26 (20%)</td></tr><tr><td>Weaned baby</td><td>7 (6%)</td><td>13 (10%)</td></tr><tr><td rowspan=\\\"2\\\">Comorbidity</td><td>Yes</td><td>6 (5%)</td><td>10 (8%)</td><td rowspan=\\\"2\\\">0.6</td></tr><tr><td>No</td><td>102 (93%)</td><td>118 (92%)</td></tr><tr><td rowspan=\\\"2\\\">Coinfection</td><td>Yes</td><td>1 (1%)</td><td>3 (4%)</td><td rowspan=\\\"2\\\">0.62</td></tr><tr><td>No</td><td>108 (99%)</td><td>125 (96%)</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Demographic and clinical characteristics of patients. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[57,58,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,123,939,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0735/46112d7627197cdc3b3ed1d9269ec11d556222973c6aef0158cd5439c27caf6a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group BN = 128</td><td>p-Value</td></tr><tr><td rowspan=\\\"2\\\">Fever</td><td>Yes</td><td>45 (41%)</td><td>31 (24%)</td><td rowspan=\\\"2\\\">0.0054</td></tr><tr><td>No</td><td>64 (59%)</td><td>97 (76%)</td></tr><tr><td>Profilaxed with Palivizumab</td><td></td><td>0 (0%)</td><td>1 (0,78%)</td><td>1</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Cont. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[273,231,939,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Group A, males were more represented than females (51% vs. 49%); gestational age was reported in 98% of patients. Preterm infants accounted for about 11%; half of the patients had a gestational age between 30 and 34 weeks, and the remaining patients had a gestational age between 35 and 36 weeks. In this group (patients admitted before SARS-SARS-CoV-2 pandemic), no patient had a gestational age under 30 weeks. Two patients had bronchopulmonary dysplasia, two infants had chronic heart conditions, one had a neurological disease like epilepsy, and no infant with immunodeficiency was recorded. At the time of diagnosis, most patients (48%) had an age between one and three months while 34% of them were under one month of age; furthermore, 13% had an age between four and six months and 5% of them were over six months of age. Breastfeeding was reported in 58% of all patients, while formula feeding was reported in 34% of patients of the Group A. Furthermore, 6% of infants had already been weaned. In one patient, during the hospitalization, a coinfection of Epstein-Barr Virus (EBV) was detected. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,426,941,454]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As specified before, no HRSV bronchiolitis was found during the SARS-CoV-2 pandemic in our hospitals. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,456,939,693]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In Group B (patients admitted after the SARS-CoV-2 pandemic), more males than females $(61\\\\%$ vs. $39\\\\%)$ were represented, and the gestational age was reported in $95\\\\%$ of patients. Among the patients for whom the gestational age was available, preterm infants were calculated to be $12\\\\%$ of all patients; most of these patients $(67\\\\%)$ had a gestational age between 35 and 36 weeks, while $27\\\\%$ of them had a gestational age between 30 and 34 weeks, and only one infant had a gestational age of 25 weeks. Two patients had bronchopulmonary dysplasia, and one infant had a neurological disease with hypotonia. No infants affected by immunodeficiency or chronic heart conditions were recorded. When hospitalized, most patients $(48\\\\%)$ were newborns under one month of age, while $23\\\\%$ had an age between one and three months, and $17\\\\%$ were between four and six months. Overall, $11\\\\%$ of infants were over six months old of age. Breastfeeding was reported in $66\\\\%$ of all patients, while formula feeding was reported as feeding modality in $20\\\\%$ of all patients. Furthermore, $10\\\\%$ of infants had already been weaned. Concerning the coinfections, we reported three cases in whom another pathogen was found. In one case, we also found an EBV first infection; in the second patient, a Mycoplasma pneumoniae co-infection occurred, and in the last patient, the nasal swab tested positive for both HRSV and SARS-CoV-2. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,695,941,753]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the description of the demographic features of patients involved in the study, we found a remarkable difference in the age of the infants; in Group B (post-pandemic), there were more newborns. No statistical differences in sex, gestational age, feeding, and comorbidity were recorded. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,755,939,828]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Concerning the prophylaxis with Palivizumab, only one patient in Group B was hospitalized for bronchiolitis due to HRSV; he was born at 31 weeks of gestational age and needed Continuous Positive Airway Pressure (CPAP) at birth. He also presented pneumothorax in the hours after birth. During the hospitalization for bronchiolitis, he did not need oxygen supplementation and was admitted to the hospital for three days. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,829,939,856]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Laboratory, X-ray findings, and treatment during hospitalization are provided in Table 3. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,58,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,123,939,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0773/97c0a4c1f233debc439a50b99abd549541013f1773dd9f78ab8660fe2b0225e1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group B N = 128</td><td>p-Value</td></tr><tr><td></td><td></td><td>1.98 (0–63.5)</td><td>1.19 (0–60.3)</td><td>0.039</td></tr><tr><td rowspan=\\\"2\\\">Chest X-rays (number)</td><td>Yes</td><td>23 (21%)</td><td>19 (15%)</td><td rowspan=\\\"2\\\">0.23</td></tr><tr><td>No</td><td>86 (79%)</td><td>109 (85%)</td></tr><tr><td>Chest X-rays (pathologic results)</td><td></td><td>13 (12%)</td><td>10 (8%)</td><td>0.27</td></tr><tr><td>Higher level of pCO2 (mmHg)</td><td></td><td>46 (28.2–64.1)</td><td>48 (31.7–74)</td><td>1</td></tr><tr><td rowspan=\\\"2\\\">Low-flow Oxygen</td><td>Yes</td><td>64 (59%)</td><td>79 (62%)</td><td rowspan=\\\"2\\\">0.69</td></tr><tr><td>No</td><td>45 (41%)</td><td>49 (38%)</td></tr><tr><td>Low-flow Oxygen days</td><td></td><td>3 (0–8)</td><td>3 (0–9)</td><td>0.76</td></tr><tr><td rowspan=\\\"2\\\">High-flow Oxygen</td><td>Yes</td><td>29 (27%)</td><td>33 (26%)</td><td rowspan=\\\"2\\\">1</td></tr><tr><td>No</td><td>80 (73%)</td><td>94 (73%)</td></tr><tr><td>High-flow Oxygen days</td><td></td><td>4 (1–8)</td><td>5 (1–11)</td><td>0.38</td></tr><tr><td>Fraction of inspired Oxygen %</td><td></td><td>35 (21–50)</td><td>34 (25–65)</td><td>0.56</td></tr><tr><td rowspan=\\\"2\\\">Aerosolized drugs</td><td>Yes</td><td>96 (88%)</td><td>122 (95%)</td><td rowspan=\\\"2\\\">0.054</td></tr><tr><td>No</td><td>13 (12%)</td><td>6 (5%)</td></tr><tr><td rowspan=\\\"2\\\">Antibiotics</td><td>Yes</td><td>42 (38%)</td><td>24 (19%)</td><td rowspan=\\\"2\\\">0.00082</td></tr><tr><td>No</td><td>67 (61%)</td><td>104 (81%)</td></tr><tr><td rowspan=\\\"2\\\">Steroids</td><td>Yes</td><td>13 (12%)</td><td>17 (13%)</td><td rowspan=\\\"2\\\">0.84</td></tr><tr><td>No</td><td>96 (88%)</td><td>111 (87%)</td></tr><tr><td rowspan=\\\"2\\\">Hydration IV</td><td>Yes</td><td>32 (29%)</td><td>23 (18%)</td><td rowspan=\\\"2\\\">0.045</td></tr><tr><td>No</td><td>77 (71%)</td><td>105 (82%)</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3. Laboratory, X-ray findings, and treatment during hospitalization. \\\"]\",\n \"table_footnote\": \"[\\\"Notes: CRP: C-reactive protein; $\\\\\\\\mathsf{pCO}_2$ : partial pressure of carbon dioxide; and IV: intravenous. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[275,574,939,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There were no significant differences between the two groups in X-ray findings, while there was a remarkable difference in CRP values. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,604,939,662]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Concerning the treatment, some differences were remarkable. Antibiotics and IV Hydration were less used in Group B; in Group A, $38\\\\%$ received an antibiotic therapy compared to the $19\\\\%$ of patients in Group B. Similarly, in Group B, only $18\\\\%$ of patients were treated with IV hydration (vs. $29\\\\%$ in Group A). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,664,939,693]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"There were no statistically significant differences in the type of respiratory support and the length of respiratory support in days. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,694,939,766]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, concerning the short-term outcome, the complications, the length of hospital stay, and the need to transfer to a Hub hospital were similar in the two groups. These data are provided in Table 4. Figure 2 reports the probability of treatment success (discharge to home without transfer to a Hub hospital with PICU or NICU): $96\\\\%$ of patients in Group A and $94\\\\%$ in Group B. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,58,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[275,123,941,253]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0032/2d969a743a687ca3e45227aa5f13e7dc8ffb6c9e6803370df69d6ade6f7412f3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td>Group AN = 109</td><td>Group B N = 128</td><td>p-Value</td></tr><tr><td rowspan=\\\"2\\\">Complications</td><td>Yes</td><td>12 (11%)</td><td>12 (9%)</td><td rowspan=\\\"2\\\">0.82</td></tr><tr><td>No</td><td>97 (89%)</td><td>116 (91%)</td></tr><tr><td>Hospitalization (days)</td><td></td><td>6 (2–33)</td><td>5 (1–13)</td><td>0.051</td></tr><tr><td rowspan=\\\"2\\\">Transfer to a Hub hospital</td><td>Yes</td><td>4 (4%)</td><td>7 (5%)</td><td rowspan=\\\"2\\\">0.55</td></tr><tr><td>No</td><td>105 (96%)</td><td>121 (94%)</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 4. Short-term outcome. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[282,275,643,513]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. Probability of treatment success (discharge to home). Notes: gray line: Group A and light blue line: Group B. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0011/c8f777ddacff35f66e6b368f67a8f39003ab819a18c44f8cec72a4de6845febd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[273,563,433,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3.3. HRSV Prevalence \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,582,939,655]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the period before the SARS-CoV-2 Pandemic (from 1 September 2017 to 31 March 2018; from 1 September 2018 to 31 March 2019; and from 1 September 2019 to 31 March 2020) in the three ASLTO4 Pediatric Departments, 272 patients were hospitalized with the diagnosis of bronchiolitis, and in 109 $(40\\\\%)$ of them, HRSV (Group A) was detected on the nasal swab. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,657,941,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"During the SARS-CoV-2 Pandemic (from 1 September 2020 to 31 March 2021), when restrictive measures were adopted, 3 patients were hospitalized for bronchiolitis, and HRSV was not detected. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,701,941,745]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"After the SARS-CoV-2 pandemic (from 1 September 2021 to 31 March 2022 and from 1 September 2022 to 31 March 2023), the total number of hospitalizations for bronchiolitis were 193. In 128 cases $(66\\\\%)$ , the detected agent was HRSV (Group B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[272,746,941,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Therefore, we can demonstrate a significant increase in the prevalence of HRSV after the SARS-CoV-2 Pandemic; moreover, we noticed a significant drop in the cases of bronchiolitis, but, above all, we found the complete absence of HRSV infection in the Pandemic period. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[309,806,769,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All these data are summarized in Table 5 and Figures 3 and 4. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,854,939,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0771/66dfb6009d3a14c322d30b1074cd89c8be6269e65173bb0a2e07c76d315197b2.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td>2017–2020</td><td>2021–2023</td><td>p-Value</td></tr><tr><td>HRSV positive</td><td>109 (40%)</td><td>128 (66%)</td><td rowspan=\\\"2\\\"><0.0001</td></tr><tr><td>HRSV negative</td><td>163 (60%)</td><td>65 (34%)</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 5. Cases of HRSV infections in patients hospitalized for bronchiolitis. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[55,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[282,103,855,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Hospitalization for bronchiolitis before, during, and after SARS-CoV-2 Pandemic. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0543/5ef20952dec04c152c846ac71965a24ec3fda5a76b4d6f621ef0bc4561d7b974.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[284,394,855,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Prevalence of HRSV detected in bronchiolitis hospitalized before, during, and after the SARS-CoV-2 Pandemic. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0943/13a9976bebac7040922abfa7c3d382bd291537a730696cb2cbfe6c9b9559f29a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[275,684,381,697]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,703,941,807]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Pandemic shows the importance of respiratory viruses' circulation surveillance. Respiratory infections are very common in infants and their severity varies based on the host features (for instance, the presence of prematurity or cardio-pulmonary broncho dysplasia). Above all causes of respiratory infection, viral bronchiolitis is the most frequent lower respiratory tract infection and the leading cause of hospitalization in children less than twelve months of age. HRSV is the virus most involved in severe bronchiolitis, and its prevalence shows territorial differences. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,808,941,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study analyzes the characteristics of infants hospitalized for acute HRSV bronchiolitis in the three Pediatric Departments of ASLTO4 before, during, and after the SARS-CoV-2 Pandemic. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[275,852,941,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our data highlight that after the SARS-CoV-2 Pandemic, the HRSV epidemic started earlier than usual. We showed a peak in November–December in Group B (post-pandemic), while in Group A (pre-pandemic), the peak was reached in January–February. This confirms new epidemiological trends of HRSV infection as reported worldwide [18,24–27]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,58,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[897,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,102,939,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The surveillance of the seasonality of HRSV is very important for the improvement and adaptation of the prevention measures. The logistics and timing are very important to optimize its prevention results; if the prophylaxis begins months before the HRSV season, the protection could wane before the end of the epidemic, leaving infants susceptible to HRSV. Similarly, if the HRSV season starts earlier than the prophylaxis, high-risk infants remain vulnerable. Considering the new epidemiological trends, in Piedmont, prophylaxis with Palivizumab in high-risk patients begins in October, starting from 2022, providing the first dose before the onset of the circulation of HRSV. This highlights the importance of improving and updating the system of local surveillance that started in Italy in 2019-2020 as the Influenza Surveillance Network (Respirvirnet) system. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,252,939,356]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In accordance with the current literature, no differences in the severity of HRSV infection have been demonstrated in our study; other authors have reported no differences in X-ray findings, short-term outcomes (like complications, the length of hospitalization, the type of respiratory support, the length of oxygen supplementation, and the need of transfer to a Hub hospital) [28-30]. The only remarkable difference in our study is in the results of the CRP dosage; in Group A (pre-pandemic), its average value was higher than that in Group B (post-pandemic). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,356,939,460]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Other studies, similar to this one, were conducted in Italy. It is very interesting to note that studies conducted in Sicily, a region in the South of Italy, have a similar trend of HRSV infection. The authors did not similarly report a variation in the disease severity [31,32]. Piedmont (in the northwest of Italy) and Sicily (an island in the south of Italy) have very different climate and air characteristics. The similar results in HRSV trends suggest that even in parts of Italy where there is different weather due to the different latitudes, the HRSV epidemiological trend, the severity of the disease, and its prevalence are similar. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,460,939,579]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Interestingly, we showed remarkable differences in treatment; fewer antibiotics were used in Group B. This suggests better adherence to the guidelines, making an important effort to reduce the development of antibiotic resistance. On the other hand, a higher CRP value was found in Group A; this finding may explain the higher use of antibiotics in this group of patients: clinicians had more suspicion of bacterial complications, so they prescribed antibiotics. Lastly, by reducing the rate of IV hydration over the years, the patients were encouraged to maintain oral feeding with a higher number of fractionated meals, as suggested by the national guidelines [4]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,580,939,713]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Looking at the HRSV prevalence, during the SARS-CoV-2 pandemic, we observed a drop in bronchiolitis hospitalizations. We reported three patients that were hospitalized for bronchiolitis, but no case of HRSV infection was found. These data are in agreement with other studies and the epidemiological surveillance of viruses that show a global reduction in respiratory infections that share the transmission path with SARS-CoV-2, like influenza and HRSV [26,33]. Given that the transmission of HRSV occurs through droplets, the containment measures of the SARS-CoV-2 Pandemic (like the use of face masks, social distancing, smart working, and the closure of schools) have led to the reduction in HRSV transmission [11,34,35]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,714,939,832]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Moreover, there is a strong correlation between environmental conditions, for example, weather and air pollution, and the incidence of HRSV. A study shows a correlation between HRSV transmission, benzene levels, and humidity, while there is an inverse correlation with temperature [36]. Given that a significant reduction in air pollutants such as benzene was recorded during the Pandemic, it can be hypothesized that the pollution reduction helped to decrease the circulation of HRSV. It is very hard to quantify the contribution, but we can suggest that it is not comparable with restrictive measures. We aim to explore such hypotheses in future studies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,833,939,892]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The prevalence of HRSV in our study group increased significantly after the SARS-CoV-2 Pandemic, confirming previously published data; we reported an HRSV surge when the prevention measures were relaxed, and the social interactions increased. This finding confirms the main role of social distance measures in the containment of HRSV circulation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[278,102,939,191]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Furthermore, the \\\"immunity debt\\\" played a role in the increased circulation of HRSV: during the Pandemic period, the cohort of HRSV-naive patients expanded. It happened for two reasons: (1) due to the presence of children who have never had HRSV infections and (2) due to the reduction in immunity duration, which decreased during the time and without re-exposure to HRSV. This is confirmed by studies that show an increased number of older infants affected by HRSV [36]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,192,939,281]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In our study, there is a remarkable difference in newborns hospitalized for HRSV bronchiolitis comparing pre- and post-pandemic, with $48\\\\%$ of newborns in Group B vs. $34\\\\%$ of newborns in Group A. This result is due to the reduced exposure to respiratory viruses not only in children but also in pregnant women; above all, it is known that the infection in the third trimester of pregnancy could protect newborns against HRSV infections through antibodies contained in breast milk and those transferred transplacentally [37-39]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,282,939,414]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our study has some limitations. Our analysis is conducted in Hub hospitals with a small sample size, due to the characteristics of our health district as detailed below: First of all, a small percentage of children aged less than one year live in our district. Furthermore, the study is based on a retrospective data collection of hospital records; as a consequence, this study may be subject to information bias due to the lack of data or incomplete hospital records. In addition, we only reported data about hospitalized patients with bronchiolitis, while patients who visited the Emergency Department and were discharged or treated by general pediatric practitioners were not included. Consequently, the global prevalence and the incidence of HRSV may be underestimated. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,414,939,519]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The main strength of our study is that it was performed in three Spoke hospitals that are a part of the same health district (ASL); therefore, clinicians had the same devices for the treatment of respiratory failure and the same tests to detect HRSV. The test used was an antigen test that was less sensitive and specific than molecular methods, but the same test was used in the three hospitals and in the different analyzed periods. Furthermore, clinicians used the same protocols of treatment and had the same criteria of transfer to Hub Hospital because of the lack of Pediatric Intensive Care Unit in our health district. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,532,391,545]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5. Conclusions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,550,939,653]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The SARS-CoV-2 Pandemic has changed the epidemiological trend of HRSV infections in our territory. In detail, the bronchiolitis season started earlier than usual after the Pandemic; this is reported in our study in accordance with the data records from other countries. The unusual resurgence of HRSV infection was not associated with an increased severity of the illness in our study group. In addition, we reported an increase in the prevalence of HRSV bronchiolitis hospitalized after the Pandemic, with a high proportion of newborns possibly due to the \\\"immunity debt\\\" and the lower exposure in pregnant women. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,655,939,803]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The surveillance of the circulation of the respiratory virus is necessary to adapt the preventive measures and the hospital activity organization to the seasonal changes; indeed, the analysis of changes in seasonality allows high-risk patients to receive the optimal level of prevention with the correct prophylaxis while hospitals reorganize their activities. It may also imply transferring patients from the Hub to the Spoke hospitals, leading to a remarkable reduction in costs. Lastly, a lesson learned during the Pandemic period was that the simple preventive measures should not be forgotten, because they can markedly reduce HRSV circulation; this finding underlines the importance of the strict hygiene behaviors and the utilization of face masks by healthcare workers, who predominantly deal with high-risk patients. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,816,939,873]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author Contributions: F.P., A.B.d.P., V.D., G.C., C.G., N.R., A.T., F.T. and M.B. contributed equally to all sections of the paper, including contribution to data curation, to the analysis of the results and to the writing of the manuscript. F.P. and M.B. contributed to the draft. All authors have read and agreed to the published version of the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[278,881,631,894]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Funding: This research received no external funding. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,58,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,60,939,70]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[272,103,941,146]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki. In accordance with the current legislation, this research is not among the types that requires a formal permission from an ethics committee. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,152,589,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Informed Consent Statement: Not applicable. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,173,907,187]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data Availability Statement: The collected data are available from the corresponding authors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[273,193,709,208]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflicts of Interest: The authors declare no conflicts of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,219,144,234]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,237,942,908]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Effectiveness of palivizumab in preventing respiratory syncytial virus infection in high-risk children. Hum. Vaccines Immunother. 2021, 17, 1867-1872. [CrossRef] [PubMed] \\\",\\\"8. Azzari, C.; Baraldi, E.; Bonanni, P.; Bozzola, E.; Coscia, A.; Lanari, M.; Manzoni, P.; Mazzone, T.; Sandri, F.; Lisi, G.C.; et al. Epidemiology and prevention of respiratory syncytial virus infections in children in Italy. Ital. J. Pediatr. 2021, 47, 198. [CrossRef] \\\",\\\"9. Li, Y.; Wang, X.; Msosa, T.; de Wit, F.; Murdock, J.; Nair, H. The impact of the 2009 influenza pandemic on the seasonality of human respiratory syncytial virus: A systematic analysis. Influenza Other Respir. Viruses 2021, 15, 804-812. [CrossRef] \\\",\\\"10. Piret, J.; Boivin, G. Viral Interference between Respiratory Viruses. Emerg. Infect. Dis. 2022, 28, 273-281. [CrossRef] \\\",\\\"11. Nascimento, M.S.; Baggio, D.M.; Fascina, L.P.; Prado, C.D. Impact of social isolation due to COVID-19 on the seasonality of pediatric respiratory diseases. PLoS ONE 2020, 15, e0243694. [CrossRef] \\\",\\\"12. Van Brusselen, D.; De Troeyer, K.; Ter Haar, E.; Vander Auwera, A.; Poschet, K.; Van Nuijs, S.; Bael, A.; Stobbelaar, K.; Verhulst, S.; Van Herendael, B.; et al. Bronchiolitis in COVID-19 times: A nearly absent disease? Eur. J. Pediatr. 2021, 180, 1969-1973. [CrossRef] \\\",\\\"13. Foley, D.A.; Yeoh, D.K.; Minney-Smith, C.A.; Martin, A.C.; Mace, A.O.; Sikazwe, C.T.; Le, H.; Levy, A.; Moore, H.C.; Blyth, C.C. The Interseasonal Resurgence of Respiratory Syncytial Virus in Australian Children Following the Reduction of Coronavirus Disease 2019-Related Public Health Measures. Clin. Infect. Dis. 2021, 73, e2829-e2830. [CrossRef] \\\",\\\"14. Saravanos, G.L.; Hu, N.; Homaira, N.; Muscatello, D.J.; Jaffe, A.; Bartlett, A.W.; Wood, N.J.; Rawlinson, W.; Kesson, A.; Lingam, R.; et al. RSV Epidemiology in Australia Before and During COVID-19. 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Pediatrics 2021, 148, e2021052089. [CrossRef] \\\",\\\"19. Guitart, C.; Bobillo-Perez, S.; Alejandre, C.; Armero, G.; Launes, C.; Cambra, F.J.; Balaguer, M.; Jordan, I.; Pagarolas, A.A.; Vila, J.; et al. Bronchiolitis, epidemiological changes during the SARS-CoV-2 pandemic. BMC Infect. Dis. 2022, 22, 84. [CrossRef] [PubMed] \\\",\\\"20. Available online: http://www.ruparpiemonte.it/infostat/risultati.jsp (accessed on 28 December 2023). \\\",\\\"21. Kaplan, E.L.; Meier, P. Nonparametric Estimation from Incomplete Observations. J. Am. Stat. Assoc. 1958, 53, 457-481. [CrossRef] \\\",\\\"22. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 1966, 50, 163-170. \\\"]\",\n \"page_idx\": \"11\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[55,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[53,102,941,678]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"23. Kruskal, W.H.; Wallis, W.A. Use of Ranks in One-Criterion Variance Analysis. J. Am. Stat. Assoc. 1952, 47, 583-621. [CrossRef] \\\",\\\"24. Curatola, A.; Graglia, B.; Ferretti, S.; Covino, M.; Pansini, V.; Eftimiadi, G.; Chiaretti, A.; Gatto, A. The acute bronchiolitis rebound in children after COVID-19 restrictions: A retrospective, observational analysis. Acta Bio Med. Atenei Parm. 2023, 94, e2023031. [CrossRef] \\\",\\\"25. Pruccoli, G.; Castagno, E.; Raffaldi, I.; Denina, M.; Barisone, E.; Baroero, L.; Timeus, F.; Rabbone, I.; Monzani, A.; Terragni, G.M.; et al. The Importance of RSV Epidemiological Surveillance: A Multicenter Observational Study of RSV Infection during the COVID-19 Pandemic. Viruses 2023, 15, 280. [CrossRef] \\\",\\\"26. Olsen, S.J.; Winn, A.K.; Budd, A.P.; Prill, M.M.; Steel, J.; Midgley, C.M.; Kniss, K.; Rowe, T.; Foust, A.; et al. Changes in Influenza and Other Respiratory Virus Activity During the COVID-19 Pandemic—United States, 2020–2021. MMWR Morb. Mortal. Wkly. Rep. 2021, 70, 1013–1019. [CrossRef] \\\",\\\"27. Opek, M.W.; Yeshayahu, Y.; Glatman-Freedman, A.; Kaufman, Z.; Sorek, N.; Brosh-Nissimov, T. Delayed respiratory syncytial virus epidemic in children after relaxation of COVID-19 physical distancing measures, Ashdod, Israel, 2021. *Eurosurveillance* 2021, 26, 2100706. [CrossRef] \\\",\\\"28. Barrezuela, L.B.; Zamorano, M.G.; López-Casillas, P.; Brezmes-Raposo, M.; Fernández, I.S.; Vázquez, M.d.l.A.P. Influenca de la pandemia COVID-19 sobre la epidemiología de la bronquiolitis aguda. Enferm. Infect. Microbiol. Clin. 2023, 41, 348–351. [CrossRef] \\\",\\\"29. Shanahan, K.H.; Monuteaux, M.C.; Bachur, R.G. Severity of Illness in Bronchiolitis Amid Unusual Seasonal Pattern During the COVID-19 Pandemic. Hosp. Pediatr. 2022, 12, e119-e123. [CrossRef] [PubMed] \\\",\\\"30. Correction to: Outbreak of Respiratory Syncytial Virus Bronchiolitis in Italy. Clin. Infect. Dis. 2023, 76, 777-779. [CrossRef] [PubMed] \\\",\\\"31. Manti, S.; Giallongo, A.; Parisi, G.F.; Papale, M.; Presti, S.; Bianco, M.L.; Spicuzza, L.; Leonardi, S. Impact of COVID-19 Pandemic and Lockdown on the Epidemiology of RSV-Mediated Bronchiolitis: Experience from Our Centre. Children 2022, 9, 1723. [CrossRef] \\\",\\\"32. Presti, S.; Manti, S.; Gambilonghi, F.; Parisi, G.F.; Papale, M.; Leonardi, S. Comparative Analysis of Pediatric Hospitalizations during Two Consecutive Influenza and Respiratory Virus Seasons Post-Pandemic. Viruses 2023, 15, 1825. [CrossRef] [PubMed] \\\",\\\"33. Nenna, R.; Matera, L.; Pierangeli, A.; Oliveto, G.; Viscido, A.; Petrarca, L.; La Regina, D.P.; Mancino, E.; Di Mattia, G.; Villani, A.; et al. First COVID-19 lockdown resulted in most respiratory viruses disappearing among hospitalised children, with the exception of rhinoviruses. Acta Paediatr. 2022, 111, 1399-1403. [CrossRef] \\\",\\\"34. Ferrero, F.; Ossorio, M.F. Is there a place for bronchiolitis in the COVID-19 era? Lack of hospitalizations due to common respiratory viruses during the 2020 winter. Pediatr. Pulmonol. 2021, 56, 2372-2373. [CrossRef] \\\",\\\"35. Wilder, J.L.; Parsons, C.R.; Growdon, A.S.; Toomey, S.L.; Mansbach, J.M. Pediatric Hospitalizations During the COVID-19 Pandemic. Pediatrics 2020, 146, e2020005983. [CrossRef] \\\",\\\"36. Lumley, S.F.; Richens, N.; Lees, E.; Cregan, J.; Kalimeris, E.; Oakley, S.; Morgan, M.; Segal, S.; Dawson, M.; Walker, A.S.; et al. Changes in paediatric respiratory infections at a UK teaching hospital 2016-2021; impact of the SARS-CoV-2 pandemic. J. Infect. 2022, 84, 40-47. [CrossRef] \\\",\\\"37. Koivisto, K.; Nieminen, T.; Mejias, A.; Gonzalez, C.C.; Ye, F.; Mertz, S.; Peebles, M.; Ramilo, O.; Saxén, H. Respiratory Syncytial Virus (RSV)-Specific Antibodies in Pregnant Women and Subsequent Risk of RSV Hospitalization in Young Infants. J. Infect. Dis. 2022, 225, 1189-1196. [CrossRef] \\\",\\\"38. Manti, S.; Leonardi, S.; Rezaee, F.; Harford, T.J.; Perez, M.K.; Piedimonte, G. Effects of Vertical Transmission of Respiratory Viruses to the Offspring. Front. Immunol. 2022, 13, 853009. [CrossRef] \\\",\\\"39. Hatter, L.; Eathorne, A.; Hills, T.; Bruce, P.; Beasley, R. Respiratory syncytial virus: Paying the immunity debt with interest. Lancet Child Adolesc. Health 2021, 5, e44-e45. [CrossRef] \\\"]\",\n \"page_idx\": \"12\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[53,694,941,738]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[55,57,176,68]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Viruses 2024, 16, 230 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[890,59,939,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 of 13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.3390/v16020230"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"150b271e08b019f5cb8aa4415444a39172b352545f21df8c76e4caeb56d1855f"},"title":{"kind":"string","value":"Impact of SARS-CoV-2 Pandemic and Lockdown on the HRSV Circulation: Experience of Three Spoke Hospitals in Northern Italy"}}},{"rowIdx":178,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"A S Gogolevskii|V A Sokolova|S V Alekseeva|S A Trepkova|S A Voinash|D A Iljushenko|N V Melamed"},"content_list":{"kind":"list like","value":[{"bbox":"[62,157,833,180]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Production chains configuration based on a systematic approach ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[62,195,524,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To cite this article: N V Melamed et al 2020 J. Phys.: Conf. Ser. 1679 042074 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[62,251,388,263]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View the article online for updates and enhancements. 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[386,881,798,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Start exploring the collection-download the first chapter of every title for free. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,42,406,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[257,942,747,956]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This content was downloaded from IP address 49.146.39.25 on 17/12/2020 at 13:15 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[62,131,242,146]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PAPER • OPEN ACCESS ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[117,230,783,275]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Production chains configuration based on a systematic approach ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[235,307,857,340]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"N V Melamed1, V A Sokolova1, D A Iljushenko1, S A Voinash2, S V Alekseeva1, A S Gogolevskii3 and S A Trepkova3 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[236,346,882,435]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 Saint Petersburg State Forest Technical University, 5, Institutskiy Per., St. \nPetersburg 194021, Russian Federation \n2 Novosibirsk State Agrarian University, 160 Dobrolyubova str., Novosibirsk, 630039, Russian Federation \n3 A.F. Mozhaisky military space Academy, 13 Zhdanovskaya str., St. Petersburg 197198, Russian Federation ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[236,466,830,495]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"E-mail: natali@melamed.su, sokolova_vika@inbox.ru, dilium@ya.ru, sergey_voi $@$ mail.ru, pum222@mail.ru, gogolevski $@$ bk.ru, romanprio@mail.ru ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[236,510,882,714]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract. The formalization of production tasks has been carried out, including the tasks of selecting individual links in the production chain (suppliers, carriers, warehouses) and choosing production chains based on the principles of a systematic approach. Hierarchical structures are constructed (basic criteria and alternatives are defined) for two classes of production problems of choice - the choice of a link in a production system and the choice of a configuration option for a production chain (network).As calculation methods, it is proposed to use methods for processing inaccurate pairwise comparisons to solve multi-criteria decision-making problems. An extension of the DS/AHP method is proposed in the paper. A new method for analyzing hierarchies to solve the problem of multi-criteria decision making using the Dempster-Scheifer theory differs from existing methods in that pairwise comparisons of elements, both at the level of alternatives and at the level of criteria, are replaced by the choice of the most preferred groups of elements. It takes into account the fact that the multi-criteria decision problem might have several levels of criteria. Moreover, it is assumed that expert judgments concerning the criteria are imprecise and incomplete. A numerical example explains in detail and illustrates the proposed approach. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,743,238,756]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[117,757,882,892]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At present, the development of the international market for the production of goods follows the path of specialization and simultaneous integration, when industrial enterprises concentrate on the direction of their work, which they consider to be the main one, and give secondary functions (transport, warehouse, sales) to logistics intermediaries (suppliers, transport carriers, freight forwarders, etc.). An integrative approach requires the integration of various functional areas and their participants into a single logistics system or chain. The enterprises united in the supply chain receive undeniable advantages over the others: their independent risks are combined, costs are reduced, and the quality of the functioning of the entire logistics system is improved. And in modern economic conditions, it is not individual enterprises that compete with each other, but the logistics chains of which these enterprises are part [1-2]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[458,82,882,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[112,914,880,952]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CC $\\textcircled{6}$ Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. Published under licence by IOP Publishing Ltd 1 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[117,134,882,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Today, only in some functional areas of logistics there is an advanced analytical apparatus that allows solving particular problems of optimization of transport, storage and distribution processes in industrial, transport and trade enterprises. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,179,882,315]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Currently, supply chains are built on the basis of one key indicator, for example, total logistics costs, quality of service, productivity, etc. If possible, the desire to take into account most of the key factors leads to the necessity of applying the multi-criteria optimization methodology. However, the application of a multicriteria approach to the problems under consideration is constrained by a number of factors such as: 1) the criteria are multidirectional; 2) their heterogeneous nature (quantitative and qualitative criteria, the latter tend to dominate); 3) inaccuracy, incompleteness and subjectivity of information about the parameters of the designed system; 4) with a large number of logistics intermediaries (links in the logistics chain) performing the corresponding operations, there is a large number of alternative configuration options for the logistics chains formed of various links [3]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,316,882,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thus, the need for a systematic analysis of supply chains based on the development of new multicriteria decision-making methods that take into account the fact that the assessments of experts or decision makers are usually inaccurate is obvious. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,374,334,388]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Methods and Algorithms ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,404,522,418]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.1. Choosing a logistics network configuration option ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[122,419,877,449]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Configuration of a logistics network is defined as the composition of the links of the logistics system, their capacity and placement in space in accordance with the adopted logistics strategy. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,449,882,538]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In general, the supplier and consumer of the material flow are two micro-logistics systems connected by a logistics channel (distribution channel). A logistics channel is a partially ordered set of various intermediaries carrying the flow of material from a specific producer to its consumers. The set is partially ordered until specific participants in the process of moving the material flow from supplier to consumer have been chosen. After that, the logistics channel is transformed into a logistics chain. The set of supply chains forms the logistics network of the enterprise. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,539,882,599]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"When deciding on the type of a distribution channel, a choice is made between the types of distribution of goods - transit or storage, and when deciding on the type of a logistics chain - the choice of a specific carrier, insurer, freight forwarder, distributor, banker, etc. The choice of the optimal configuration of a logistics network has to be made from a large number of predefined alternatives. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,600,880,658]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The classical approach to designing means a transition from particular to general (induction). This approach to designing the supply chain structure does not take into account the integrative qualities of the logistics system. Integrative qualities cannot be applied to any of the individual elements, but can be characterized by the definition “the effect of the sum exceeds the sum of the effects”. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,659,882,780]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The functional approach is based on the sequential evaluation of the chain links according to the functional criterion, when the output stream of each previous link of the logistics chain is the input for the next. The resulting material flow is the output stream of the last link in the supply chain. The strengths of this approach is the ability to evaluate alternatives that belong to the same functional area in relation to the parameters of the previous one. However, this does not take into account the fact that there is a number of criteria that, while not decisive at the current functional stage, affect the effectiveness of subsequent stages. A systematic approach involves a gradual transition from a general to a particular, when it is based on the common goal for which the system is created. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,781,878,814]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Consider the options for building logistics networks for a manufacturing enterprise in the production process $A _ { i }$ consisting of various components $A _ { i j }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[776,66,880,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,203,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[458,82,882,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[499,941,507,950]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[210,139,789,275]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Logistic network of the enterprise: $=$ Logistic Channel; Z - purchase, Т - transport, С - warehouse, $\\\\mathrm { P r }$ - production, Р – distribution. \"]","image_footnote":"[]","img_path":"images/0053/8846c9bc83e0e9285e34dfcd664205c3a1339e31d3a5e72a69eccd46112310d1.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[115,337,885,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The starting point of the material flow is the supplier’s warehouse $A _ { i j }$ , and the end is the consumer’s warehouse $A _ { i }$ . We denote $P = ( P _ { 1 } , P _ { 2 } , . . . , P _ { p } )$ - many suppliers providing their services $P ( A _ { i j } ) =$ ${ \\big ( } P _ { 1 } ( A _ { i j } ) , P _ { 2 } ( A _ { i j } ) , \\dots , P _ { n } ( A _ { i j } ) { \\big ) } .$ - many product manufacturers of $A _ { i j }$ (suppliers); ???????? $( A _ { i j } )$ - consumer of the product $A _ { i j }$ ; and???????? $( A _ { i } )$ - consumer of the product $A _ { i }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,430,884,612]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative $I$ : The producer is the initiator of the supply chain $A _ { i }$ , which is connected with the suppliers of the initial products for its activity and with the consumers of its products through a direct supply channel, when there are no intermediaries between the supplier and the consumer and all operations related to transportation, storage and distribution of materials and finished products is performed by the manufacturer $A _ { i }$ . The logistics channel in this case has the following structure: $P _ { p } \\left( A _ { i j } \\right) - P r \\left( A _ { i j } \\right) - C o n s \\left( A _ { i j } \\right)$ . The logistics system (LS, figure 1) is a combination of four logistics chains, each of which is composed of three links: supplierof $A _ { i j }$ , manufacturer of $A _ { i }$ and consumer of the product $A _ { i }$ . Each of the links of the LS is a micro-logical system composed of subsystems: supply $( Z , \\mathrm { T } , \\mathrm { C } )$ , production (P), sales (С, Т). Some industrial or commercial enterprises may act as suppliers of components $A _ { i j }$ and consumers of products $A _ { i }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,615,884,667]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 2: A form of a transit movement with the possibility of attracting forwarding companies (logistics intermediaries). The logistics channel has the following structure: $P _ { p } \\big ( A _ { i j } \\big ) - T \\big ( A _ { i j } \\big ) -$ $P r \\big ( A _ { i j } \\big ) - T \\big ( A _ { i j } \\big ) - C o n s ( A _ { i j } )$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,668,882,697]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this case, it is necessary to make a decision whether the function of transporting materials and / or finished products is outsourced. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,699,884,900]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Figure 1 shows the case of a single-link production of a product $A _ { i }$ when components $A _ { i j }$ are required for its production, i.e. $A _ { i } = \\sum _ { j = 1 } ^ { n } A _ { i j }$ , where $n$ is the number of product components $A _ { i }$ . Each of the components $A _ { i j }$ can be either a material or a semi-finished product, $A _ { i j } = \\sum _ { k = 1 } ^ { m } A _ { i j k }$ , where $m$ is the number of components of the product $A _ { i j }$ , and so on. In modern industrial enterprises, the number of components can be in the hundreds and thousands of units. The solution to the issue of whether to produce of to buy is in some cases key to maintaining the image and competitiveness of the enterprise, as it is strategic in nature and affects the structure of the supply chain. Traditionally, such a decision has been made on the basis of comparing the costs of outsourcing and insourcing, and more often the decision has been made in favour of the insourcing, which meant expanding the production base. In recent years, due to increasing demands for the flexibility and competitiveness of enterprises, the decision to “produce or buy” is increasingly being made in favor of finding an external supplier. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[457,82,882,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[497,941,507,951]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[117,134,884,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,179,457,195]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2.2. Evaluation criteria for logistics networks ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,191,882,239]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The key criteria when comparing different options for supply chains are: general costs;the duration of order execution; maximization of competitive advantages; quality of logistics service; uncertainty and risk. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,242,884,328]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Consider in more detail selected key criteria. In most cases, the criteria $C _ { 1 }$ and $C _ { 2 }$ are quantitative, and $C _ { 3 }$ , $C _ { 4 }$ , and $C _ { 5 }$ are qualitative. However, often at the time of decision-making there is no information that allows an objective assessment of quantitative criteria. But since a decision must be made, the information gap must be filled in. This can only be done with the participation of people on the basis of their experience and intuition, that is, with the involvement of experts. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,328,880,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In the proposed algorithm (figure 2) as calculation methods, it has been proposed to use methods for processing inaccurate pairwise comparisons to solve multi-criteria decision-making problems [4-10]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[132,378,863,831]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. The algorithm for the selection of logistics intermediaries. \"]","image_footnote":"[]","img_path":"images/0864/2fa51cb30eddc23af2dde46973e4434ff582105399357d0dc7070546c10f6f07.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[776,66,880,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[457,82,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[497,941,507,950]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[117,134,304,149]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3. Calculation Example ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,149,882,240]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As an example, we consider possible configuration options for production chains for a timber company LLC Akvilon engaged in the manufacture of edged softwood boards and doors for country houses. In connection with the decision to expand the range of products at LLC Akvilon, the task arose to revise its production chain. To synthesize possible options for constructing the production chain, we consider the production and technological scheme of the forest industry complex, of which this enterprise is a part (figure 3). The dashed arrows in figure 3 indicate possible material flows of LLC Akvilon. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[171,267,805,542]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3. Production and technological chain of the forest industry complex. \"]","image_footnote":"[]","img_path":"images/0423/8ec844080bdcd2a4577f06b5eeccc6d02cc6ec655948a1b52a468eb92d3caf7f.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[117,586,882,751]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Based on the analysis of figure 3, we can draw the following conclusions about possible options for building the production chain: 1) The raw material for production is roundwood, which is currently being purchased from a number of logging enterprises and dealers. An alternative to this option of organizing the material flow may be a forest industry chain, which starts not from a logging company, but from a forestry enterprise, when the timber processing enterprise takes over the logging function. 2) During the processing of wood, waste is generated, which is currently burned in the boiler room. With small production volumes this is quite acceptable, but with an increase in production volume it makes sense to consider the option when the wood waste is transformed into wood chips, which are then delivered to pulp and paper mills, fuel pellet plants, etc. 3) Finished products are delivered to the final consumer with the involvement of private carriers. A variant of organizing production with its own transport division is possible. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,752,882,812]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 1: Only the logging enterprises are included in the production chain (LLC Les, PiM LLC, LODBALTLES LLP, Timberg Holding OJSC, Domozhirovsky Lespromkhoz OJSC, Georgievsky Lesokombinat, Aurora OAZT), i.e. the enterprise does not carry out logging, and carries out transportation by itself. Window blocks are added to the product range of the enterprise. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,813,878,841]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 2: The difference from the previous alternative is that the transportation function is transferred to private carriers. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,843,880,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 3: The production chain includes the logging enterprises (the same as in alternative 1), a pulp and paper mill (or a plant for the production of fuel pellets), and a set of private carriers. Window blocks and technological chips are added to the product range of the enterprise; the enterprise performs the transportation function independently. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[458,82,882,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[499,941,507,951]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,134,882,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 4: Forestry enterprises (State Forestry Enterprise, Forestry Enterprise Lodeinopolsky, Oyatsky Forestry), i.e. the enterprise performs logging and transportation on its own. Window blocks are added to the product range of the enterprise. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,180,880,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 5: The difference from the previous alternative is that the transportation function is transferred to private carriers. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,210,882,254]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Alternative 6: Forestry enterprises (State Forestry Enterprise, Forestry Enterprise Lodeynopolsky, Oyatsky Forestry), Pulp and Paper Mill (or a plant for the production of fuel pellets), and a set of private carriers. Window blocks are added to the product range of the enterprise. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,255,882,315]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The expert group included: 1 - the general director of the enterprise; 2 - technical director; 3 - commercial director; 4 - chief economist; 5 - chief engineer; 6 - chief mechanic; 7 - head of sawmill production; 8 - the head of the carpentry unit; 9 - power engineer; 10 - head of the department of logistics and external cooperation; 11, 12, 13, 14 - process engineers of the sawmill. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[136,316,645,330]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Imagine the problem in the form of a two-level hierarchy (figure 4). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[206,354,791,550]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Hierarchical structure of the task of choosing a forest industry chain. \"]","image_footnote":"[]","img_path":"images/0879/2f6472be85b68752686845e21cd14a527e41c0645ad97877bb024e2716a235b8.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[139,596,361,611]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Let us introduce the notation: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,612,885,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathbf { A } = \\{ A _ { 1 } , A _ { 2 } , \\dots , A _ { n } \\}$ - - many alternatives consisting of $n$ elements; $P _ { 0 } ( A )$ - a set of cardinalities of alternatives, the elements of which are all possible combinations of alternatives of a universal set of alternatives??; $P _ { 0 } ( A ) = \\{ B _ { 1 } , B _ { 2 } , \\dots , B _ { l } \\}$ , $l = 2 ^ { n } - 1$ (the empty set is excluded from consideration); $\\complement =$ $\\{ C _ { 1 } , C _ { 2 } , \\ldots , C _ { r } \\}$ - set of criteria consisting of $r$ elements; $P _ { 0 } ( \\mathbb { C } )$ - set of criteria cardinality, elements of which are all possible combinations of criteria for the universal set ∁, $P _ { 0 } ( \\mathsf { C } ) = \\big \\{ C ^ { ( 1 ) } , C ^ { ( 2 ) } , \\ldots C ^ { ( k ) } \\big \\} , k =$ $\\overline { { 1 , r } } , C ^ { ( k ) } = \\Big \\{ \\mathbb { C } _ { 1 } ^ { ( k ) } , \\mathbb { C } _ { i } ^ { ( k ) } , \\dots , \\mathbb { C } _ { s } ^ { ( k ) } \\Big \\} .$ -is the set of all subsets of criteria of length $k$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[110,713,882,744]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Each of the experts selects the subset of criteria that, in his opinion, is the most preferable in comparison with the entire set of criteria ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[231,749,761,795]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0933/07923f91d80c859800db19511d3dd37cc7705448d2f0b36f19f1c214d157c1b0.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array}{c} \\begin{array} { r l r } { \\left\\{ \\mathbf { c } _ { n i } ^ { ( k ) } = 1 , \\quad \\right.} & { i f t h e n e x p e r t s e l e c t s a s u b s e t \\mathbb { C } _ { i } ^ { ( k ) } , i . e . \\mathbb { C } _ { i } ^ { ( k ) } \\succ \\mathsf { C } } & \\\\ { \\mathbf { c } _ { n i } ^ { ( k ) } = 0 , \\quad } & { o t h e r w i s e } & \\end{array} \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[122,800,880,831]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For example, an expert's choice of a pair of $\\mathrm { C } _ { 3 } \\mathrm { C } _ { 4 }$ criteria means that this expert cannot determine the most preferable criterion from ${ \\mathsf { C } } _ { 3 }$ and $\\mathsf { C } _ { 4 }$ - both criteria are the most important. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[132,831,820,846]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"After polling all $N _ { c }$ experts, the number of occurrences of the selected subsets is calculated ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[440,850,559,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0162/0e350e52a4715ea53267ccee4b5b4c3f4daeb29969390ebf0e9a44dedcfcf9a0.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nc _ { i } ^ { ( k ) } = \\sum _ { n = 1 } ^ { N _ { c } } c _ { n i } ^ { ( k ) }\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[457,82,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[497,941,507,951]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,82,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[114,134,884,166]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At the second stage, the expert, in accordance with the given criterion $C _ { i } , i = 1 , \\ldots , r$ selects a certain subset $B _ { j } \\in P _ { 0 } ( A )$ as the most preferable among the whole set of alternatives ??. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[386,171,611,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"0986/9c202f6ef4f5f57f8904cfca1fad6ca6f8d58f6b07622e1b07a27c571d3eddee.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n\\begin{array} { r } { \\left\\{ \\begin{array} { l } { c _ { n j i } = 1 , \\quad \\quad i f t h e B _ { j } \\succ A } \\\\ { c _ { n j i } = 0 , \\quad \\quad o t h e r w i s e } \\end{array} \\right. } \\end{array}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[115,217,878,254]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\begin{array} { r } { c _ { i j } = \\sum _ { n = 1 } ^ { N _ { A } ^ { ( i ) } } c _ { n j i } } \\end{array}$ ??, ????(??)- t he total number of assessments of alternatives (groups of alternatives) by criterion i. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,255,882,285]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"During the survey, the experts provided inaccurate pairwise comparisons of the criteria (table 1) and alternatives in accordance with a given criterion (tables 2 – 5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,312,850,529]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0779/4c8a0c3c95c2e061a0123072bfb20e7c66ea7deaaf10ac8a76de58f331157f34.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>C C C C4 C; CC4 C4C; CCC5</td><td>C3C4C5</td><td>C2C4C5</td><td>C</td></tr><tr><td>C</td><td></td><td>4</td><td></td><td>2</td><td>1</td><td></td><td></td><td>1</td><td>1</td><td></td><td>4</td></tr><tr><td>C</td><td></td><td></td><td></td><td>=</td><td>-</td><td></td><td></td><td></td><td>1</td><td></td><td>6</td></tr><tr><td>C</td><td></td><td></td><td></td><td></td><td>2</td><td>=</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>C4</td><td></td><td></td><td></td><td></td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CC2</td><td></td><td></td><td></td><td></td><td></td><td>2</td><td></td><td></td><td></td><td></td><td>3</td></tr><tr><td>CC3</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td><td></td><td></td><td></td><td></td></tr><tr><td>CC4</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>CC2C3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>C.C2C3C4</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr></table>","table_caption":"[\"Table 1. Expanded matrix of pairwise comparisons of subsets of criteria. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[292,594,704,789]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0635/e17026ce4e116abebe100dcbd665be814786a40be80ae7b9385fc27d7c1a317b.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAAAAAAAA</td><td></td><td></td></tr><tr><td></td><td></td><td>=</td><td></td><td></td><td></td><td>2</td><td>-</td></tr><tr><td>AAA</td><td>5</td><td></td><td></td><td></td><td>3</td><td></td><td>2</td></tr><tr><td></td><td>1</td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>A</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>AA</td><td></td><td></td><td>1</td><td></td><td></td><td></td><td>3</td></tr><tr><td>AA4</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr><tr><td>AA6</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>AAA</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr></table>","table_caption":"[\"Table 2. Expanded matrix of pairwise comparisons of forest industry chains according to the criterion of total costs. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[295,854,699,900]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0207/b6700ca53d71714b79fabda232b2fec823c6ed6c699997a8ab94ac71aadbd000.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAAAAAAA</td><td></td><td>A</td></tr><tr><td>A</td><td>=</td><td>1</td><td>=</td><td>1</td><td>4</td><td>=</td><td>=</td></tr><tr><td>A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>4</td></tr><tr><td>AA</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr><tr><td>A4AA6</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>AAA</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr></table>","table_caption":"[\"Table 3. Expanded matrix of paired comparisons of forest industry chains according to the criterion of reliability. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,65,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[457,82,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,82,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[499,941,507,951]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[297,131,702,241]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[292,306,704,417]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0405/5e512ba19b93331aa8dcc7b9ce45ba4122ef6b906161379f174b6a9244e91bd1.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAAAAAAAA</td><td></td><td></td></tr><tr><td>AA</td><td>2</td><td>1</td><td></td><td>-</td><td></td><td></td><td>3</td></tr><tr><td>AA6</td><td></td><td>、</td><td></td><td>1</td><td></td><td></td><td>2</td></tr><tr><td>A4A</td><td>1</td><td>1</td><td></td><td></td><td></td><td></td><td>2</td></tr><tr><td>A4AA6</td><td></td><td></td><td></td><td></td><td></td><td></td><td>8</td></tr></table>","table_caption":"[\"Table 4. Expanded matrix of pairwise comparisons of forest industry chains in accordance with the criterion of service quality. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[292,481,705,593]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0672/ad7d5c88db64767a005899f47de12ab69837070613a5f6e520aa4c678f196f0f.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAA4AAAAA</td><td></td><td>A</td></tr><tr><td>A</td><td>1</td><td>1</td><td>2</td><td>=</td><td>1</td><td></td><td>-</td></tr><tr><td>AA</td><td></td><td>2</td><td>1</td><td>-</td><td>1</td><td></td><td>1</td></tr><tr><td>A4A</td><td>=</td><td>1</td><td>1</td><td>2</td><td></td><td></td><td>-</td></tr><tr><td>A4AA6</td><td></td><td></td><td></td><td></td><td></td><td></td><td>5</td></tr></table>","table_caption":"[\"Table 5. Expanded matrix of pairwise comparisons of subsets of criteria according to the criterion duration of order execution. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,621,885,677]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"According to the criterion of uncertainty and risk, ten experts were not able to identify subsets of alternatives, i.e. provided an assessment $\\mathbf { A { \\underline { { \\succ } } } A }$ , two experts - $A _ { 1 } A _ { 2 } A _ { 3 } { \\underline { { \\succ } } } \\mathbf { A }$ , one expert - $A _ { 1 } A _ { 2 } { \\succeq } A _ { 4 } A _ { 5 }$ , and one expert - $A _ { 2 } A _ { 5 } { \\simeq } \\mathbf { A }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[107,680,882,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In table 6, the results of calculations performed in accordance with the general method of pairwise comparisons are given. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[277,752,722,821]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0003/b9126f9a7c4f91de4fec2bd9e3013bdfc64ced36072c84d0067be582983ee5f0.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td></td><td>A</td><td>A</td><td>A</td><td>A4</td><td>A</td><td>A6</td></tr><tr><td>Bel(B)</td><td>0.06</td><td>0.14</td><td>0.05</td><td>0.07</td><td>0.18</td><td>0.10</td></tr><tr><td>Pl(B)</td><td>0.80</td><td>0.85</td><td>0.43</td><td>0.82</td><td>0.78</td><td>0.76</td></tr></table>","table_caption":"[\"Table 6. Lower and upper boundaries of the probabilities of forest industry chains. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[457,82,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[497,941,507,951]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[127,131,606,375]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5. Rating dependence $Y = \\\\gamma \\\\cdot B e l ( B _ { l } ) + ( 1 - \\\\gamma ) \\\\cdot P l ( B _ { l } )$ from the attitude of the LPR to the risk. \"]","image_footnote":"[]","img_path":"images/0217/d8cd1fe1a9a12bb4a5f04df00315d4e6a618cb781548c31c23b9c70af1699af8.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[115,393,882,447]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In figure 5, rating dependence $Y = \\gamma \\cdot B e l ( B _ { l } ) + ( 1 - \\gamma ) \\cdot P l ( B _ { l } )$ from the attitude of the LPR to the risk is presented. The general director of LLC Akvilon acted as an LPR, who assessed his attitude to risk by a value $\\gamma = 0 . 4$ . When $\\gamma = 0 . 4$ , alternatives are ranked as follows: $A _ { 2 } { \\succeq } A _ { 5 } { \\succeq } A _ { 4 } { \\succeq } A _ { 1 } { \\succeq } A _ { 6 } { \\succeq } A _ { 3 }$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,466,208,479]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[117,480,872,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The formalization of production tasks has been carried out, including the tasks of selecting individual links in the production chain (suppliers, carriers, warehouses) and choosing production chains based on the principles of a systematic approach. As calculation methods, it is proposed to use methods for processing inaccurate pairwise comparisons to solve multi-criteria decision-making problems. An extension of the DS/AHP method is proposed in the paper. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,569,206,583]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,585,885,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"[1] Saati T and Vachnadze R G 1993 Decision Making. Hierarchy Analysis Method (Moscow: Radio and Communications) \n[2] Simanova N V 2005 Logistics information system for managing a forestry enterprise Bulletin of St. Petersburg Forest Technical Academy:Proc. Annual Conf. of Young Scientists(St. Petersburg:State Forest Technical Academy) pp 62-5 \n[3] Melamed N V and Sokolova V A 2018 Developing the model of an automated rotary-cut veneer sorting system IOP Conference Series: Materials Science and Engineering 450(4) 042007 \n[4] Simanova N V 2007 A generalized method of pairwise comparisons to solve multi-criteria problems Proc. XX Int.Conf.on Mathematical Methods and Information Technologies in Economics, Sociology and Education (Penza: Volga House of Knowledge) pp 259-62 \n[5] Simanova N V 2007 New methods of multi-criteria decision-making in logistics Proc. II All-Russian Conf.on Actual Problems of Anaging Technical, Information, Socio-Economic and Transport Systems (St. Petersburg: Publishing House of SZTU) 2 pp 122-6 \n[6] Simanova N V2008 New methods for making multi-criteria decisions in the design of logistic chains of the timber industry complex Proc.Int.Conf. of Young Scientists November 13-14, 2007, St. Petersburg State Forest Technical Academy:Modern Problems and Prospects of Rational Forest Management in the Market (St. Petersburg: Publishing House of the Polytechnic University) pp 221-7 \n[7] Simanova N V and Utkin L V 2008 Soft measurements Proc. XI Int. Conf. on Soft Computing and Measurements: Inaccurate Preferences for Soft Ranking of Objects in Conditions of Incomplete Information(St. Petersburg: Publishing House of SPb SETU) 1 pp 205-9 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[776,66,882,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[457,82,882,95]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[497,941,507,950]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,134,882,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"[8] Utkin L V and Simanova N V 2007 Using the Dirichlet model and evidence theory to modify the method of analysis of hierarchies Proc. XI Int. Conf.on System Analysis in Design in Management(St. Petersburg: Publishing House of the Polytechnic University) 1 pp 116-7 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,180,882,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"[9] Utkin L V and Simanova N V 2007A method for analyzing hierarchies with incomplete information about criteria and alternatives Fuzzy Systems and Soft Computing 2 31-40 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,210,884,269]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"[10] Utkin L V and Simanova N V 2007A generalization of the hierarchy analysis method for decision making with inaccurate comparisons using the Dempster-Scheifer theory Izvestia OrelGTU: Fundamental and applied problems of engineering and technology: information systems and technologies 4 223-9 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[776,66,880,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[457,82,882,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,66,205,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"APITECH II ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[495,941,510,951]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"discarded"},{"bbox":"[115,83,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"discarded"}],"string":"[\n {\n \"bbox\": \"[62,157,833,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Production chains configuration based on a systematic approach \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[62,195,524,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To cite this article: N V Melamed et al 2020 J. Phys.: Conf. Ser. 1679 042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[62,251,388,263]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View the article online for updates and enhancements. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,771,373,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0234/c14a4db280c92f93ad7c73cf864a9987444c2378d893f8883cc93bce9168ab56.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n 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null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Production chains configuration based on a systematic approach \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[235,307,857,340]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"N V Melamed1, V A Sokolova1, D A Iljushenko1, S A Voinash2, S V Alekseeva1, A S Gogolevskii3 and S A Trepkova3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[236,346,882,435]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 Saint Petersburg State Forest Technical University, 5, Institutskiy Per., St. \\nPetersburg 194021, Russian Federation \\n2 Novosibirsk State Agrarian University, 160 Dobrolyubova str., Novosibirsk, 630039, Russian Federation \\n3 A.F. Mozhaisky military space Academy, 13 Zhdanovskaya str., St. Petersburg 197198, Russian Federation \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[236,466,830,495]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"E-mail: natali@melamed.su, sokolova_vika@inbox.ru, dilium@ya.ru, sergey_voi $@$ mail.ru, pum222@mail.ru, gogolevski $@$ bk.ru, romanprio@mail.ru \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[236,510,882,714]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract. The formalization of production tasks has been carried out, including the tasks of selecting individual links in the production chain (suppliers, carriers, warehouses) and choosing production chains based on the principles of a systematic approach. Hierarchical structures are constructed (basic criteria and alternatives are defined) for two classes of production problems of choice - the choice of a link in a production system and the choice of a configuration option for a production chain (network).As calculation methods, it is proposed to use methods for processing inaccurate pairwise comparisons to solve multi-criteria decision-making problems. An extension of the DS/AHP method is proposed in the paper. A new method for analyzing hierarchies to solve the problem of multi-criteria decision making using the Dempster-Scheifer theory differs from existing methods in that pairwise comparisons of elements, both at the level of alternatives and at the level of criteria, are replaced by the choice of the most preferred groups of elements. It takes into account the fact that the multi-criteria decision problem might have several levels of criteria. Moreover, it is assumed that expert judgments concerning the criteria are imprecise and incomplete. A numerical example explains in detail and illustrates the proposed approach. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,743,238,756]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,757,882,892]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At present, the development of the international market for the production of goods follows the path of specialization and simultaneous integration, when industrial enterprises concentrate on the direction of their work, which they consider to be the main one, and give secondary functions (transport, warehouse, sales) to logistics intermediaries (suppliers, transport carriers, freight forwarders, etc.). An integrative approach requires the integration of various functional areas and their participants into a single logistics system or chain. The enterprises united in the supply chain receive undeniable advantages over the others: their independent risks are combined, costs are reduced, and the quality of the functioning of the entire logistics system is improved. And in modern economic conditions, it is not individual enterprises that compete with each other, but the logistics chains of which these enterprises are part [1-2]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[458,82,882,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[112,914,880,952]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CC $\\\\textcircled{6}$ Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. Published under licence by IOP Publishing Ltd 1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[117,134,882,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Today, only in some functional areas of logistics there is an advanced analytical apparatus that allows solving particular problems of optimization of transport, storage and distribution processes in industrial, transport and trade enterprises. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,179,882,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Currently, supply chains are built on the basis of one key indicator, for example, total logistics costs, quality of service, productivity, etc. If possible, the desire to take into account most of the key factors leads to the necessity of applying the multi-criteria optimization methodology. However, the application of a multicriteria approach to the problems under consideration is constrained by a number of factors such as: 1) the criteria are multidirectional; 2) their heterogeneous nature (quantitative and qualitative criteria, the latter tend to dominate); 3) inaccuracy, incompleteness and subjectivity of information about the parameters of the designed system; 4) with a large number of logistics intermediaries (links in the logistics chain) performing the corresponding operations, there is a large number of alternative configuration options for the logistics chains formed of various links [3]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,316,882,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thus, the need for a systematic analysis of supply chains based on the development of new multicriteria decision-making methods that take into account the fact that the assessments of experts or decision makers are usually inaccurate is obvious. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,374,334,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Methods and Algorithms \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,404,522,418]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.1. Choosing a logistics network configuration option \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[122,419,877,449]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Configuration of a logistics network is defined as the composition of the links of the logistics system, their capacity and placement in space in accordance with the adopted logistics strategy. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,449,882,538]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In general, the supplier and consumer of the material flow are two micro-logistics systems connected by a logistics channel (distribution channel). A logistics channel is a partially ordered set of various intermediaries carrying the flow of material from a specific producer to its consumers. The set is partially ordered until specific participants in the process of moving the material flow from supplier to consumer have been chosen. After that, the logistics channel is transformed into a logistics chain. The set of supply chains forms the logistics network of the enterprise. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,539,882,599]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"When deciding on the type of a distribution channel, a choice is made between the types of distribution of goods - transit or storage, and when deciding on the type of a logistics chain - the choice of a specific carrier, insurer, freight forwarder, distributor, banker, etc. The choice of the optimal configuration of a logistics network has to be made from a large number of predefined alternatives. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,600,880,658]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The classical approach to designing means a transition from particular to general (induction). This approach to designing the supply chain structure does not take into account the integrative qualities of the logistics system. Integrative qualities cannot be applied to any of the individual elements, but can be characterized by the definition “the effect of the sum exceeds the sum of the effects”. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,659,882,780]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The functional approach is based on the sequential evaluation of the chain links according to the functional criterion, when the output stream of each previous link of the logistics chain is the input for the next. The resulting material flow is the output stream of the last link in the supply chain. The strengths of this approach is the ability to evaluate alternatives that belong to the same functional area in relation to the parameters of the previous one. However, this does not take into account the fact that there is a number of criteria that, while not decisive at the current functional stage, affect the effectiveness of subsequent stages. A systematic approach involves a gradual transition from a general to a particular, when it is based on the common goal for which the system is created. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,781,878,814]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Consider the options for building logistics networks for a manufacturing enterprise in the production process $A _ { i }$ consisting of various components $A _ { i j }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[776,66,880,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,203,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[458,82,882,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[499,941,507,950]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[210,139,789,275]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Logistic network of the enterprise: $=$ Logistic Channel; Z - purchase, Т - transport, С - warehouse, $\\\\\\\\mathrm { P r }$ - production, Р – distribution. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0053/8846c9bc83e0e9285e34dfcd664205c3a1339e31d3a5e72a69eccd46112310d1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[115,337,885,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The starting point of the material flow is the supplier’s warehouse $A _ { i j }$ , and the end is the consumer’s warehouse $A _ { i }$ . We denote $P = ( P _ { 1 } , P _ { 2 } , . . . , P _ { p } )$ - many suppliers providing their services $P ( A _ { i j } ) =$ ${ \\\\big ( } P _ { 1 } ( A _ { i j } ) , P _ { 2 } ( A _ { i j } ) , \\\\dots , P _ { n } ( A _ { i j } ) { \\\\big ) } .$ - many product manufacturers of $A _ { i j }$ (suppliers); ???????? $( A _ { i j } )$ - consumer of the product $A _ { i j }$ ; and???????? $( A _ { i } )$ - consumer of the product $A _ { i }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,430,884,612]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative $I$ : The producer is the initiator of the supply chain $A _ { i }$ , which is connected with the suppliers of the initial products for its activity and with the consumers of its products through a direct supply channel, when there are no intermediaries between the supplier and the consumer and all operations related to transportation, storage and distribution of materials and finished products is performed by the manufacturer $A _ { i }$ . The logistics channel in this case has the following structure: $P _ { p } \\\\left( A _ { i j } \\\\right) - P r \\\\left( A _ { i j } \\\\right) - C o n s \\\\left( A _ { i j } \\\\right)$ . The logistics system (LS, figure 1) is a combination of four logistics chains, each of which is composed of three links: supplierof $A _ { i j }$ , manufacturer of $A _ { i }$ and consumer of the product $A _ { i }$ . Each of the links of the LS is a micro-logical system composed of subsystems: supply $( Z , \\\\mathrm { T } , \\\\mathrm { C } )$ , production (P), sales (С, Т). Some industrial or commercial enterprises may act as suppliers of components $A _ { i j }$ and consumers of products $A _ { i }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,615,884,667]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 2: A form of a transit movement with the possibility of attracting forwarding companies (logistics intermediaries). The logistics channel has the following structure: $P _ { p } \\\\big ( A _ { i j } \\\\big ) - T \\\\big ( A _ { i j } \\\\big ) -$ $P r \\\\big ( A _ { i j } \\\\big ) - T \\\\big ( A _ { i j } \\\\big ) - C o n s ( A _ { i j } )$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,668,882,697]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this case, it is necessary to make a decision whether the function of transporting materials and / or finished products is outsourced. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,699,884,900]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Figure 1 shows the case of a single-link production of a product $A _ { i }$ when components $A _ { i j }$ are required for its production, i.e. $A _ { i } = \\\\sum _ { j = 1 } ^ { n } A _ { i j }$ , where $n$ is the number of product components $A _ { i }$ . Each of the components $A _ { i j }$ can be either a material or a semi-finished product, $A _ { i j } = \\\\sum _ { k = 1 } ^ { m } A _ { i j k }$ , where $m$ is the number of components of the product $A _ { i j }$ , and so on. In modern industrial enterprises, the number of components can be in the hundreds and thousands of units. The solution to the issue of whether to produce of to buy is in some cases key to maintaining the image and competitiveness of the enterprise, as it is strategic in nature and affects the structure of the supply chain. Traditionally, such a decision has been made on the basis of comparing the costs of outsourcing and insourcing, and more often the decision has been made in favour of the insourcing, which meant expanding the production base. In recent years, due to increasing demands for the flexibility and competitiveness of enterprises, the decision to “produce or buy” is increasingly being made in favor of finding an external supplier. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[457,82,882,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[497,941,507,951]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[117,134,884,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[119,179,457,195]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2.2. Evaluation criteria for logistics networks \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,191,882,239]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The key criteria when comparing different options for supply chains are: general costs;the duration of order execution; maximization of competitive advantages; quality of logistics service; uncertainty and risk. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,242,884,328]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Consider in more detail selected key criteria. In most cases, the criteria $C _ { 1 }$ and $C _ { 2 }$ are quantitative, and $C _ { 3 }$ , $C _ { 4 }$ , and $C _ { 5 }$ are qualitative. However, often at the time of decision-making there is no information that allows an objective assessment of quantitative criteria. But since a decision must be made, the information gap must be filled in. This can only be done with the participation of people on the basis of their experience and intuition, that is, with the involvement of experts. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,328,880,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In the proposed algorithm (figure 2) as calculation methods, it has been proposed to use methods for processing inaccurate pairwise comparisons to solve multi-criteria decision-making problems [4-10]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[132,378,863,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. The algorithm for the selection of logistics intermediaries. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0864/2fa51cb30eddc23af2dde46973e4434ff582105399357d0dc7070546c10f6f07.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[776,66,880,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[457,82,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[497,941,507,950]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[117,134,304,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3. Calculation Example \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,149,882,240]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As an example, we consider possible configuration options for production chains for a timber company LLC Akvilon engaged in the manufacture of edged softwood boards and doors for country houses. In connection with the decision to expand the range of products at LLC Akvilon, the task arose to revise its production chain. To synthesize possible options for constructing the production chain, we consider the production and technological scheme of the forest industry complex, of which this enterprise is a part (figure 3). The dashed arrows in figure 3 indicate possible material flows of LLC Akvilon. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[171,267,805,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3. Production and technological chain of the forest industry complex. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0423/8ec844080bdcd2a4577f06b5eeccc6d02cc6ec655948a1b52a468eb92d3caf7f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[117,586,882,751]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Based on the analysis of figure 3, we can draw the following conclusions about possible options for building the production chain: 1) The raw material for production is roundwood, which is currently being purchased from a number of logging enterprises and dealers. An alternative to this option of organizing the material flow may be a forest industry chain, which starts not from a logging company, but from a forestry enterprise, when the timber processing enterprise takes over the logging function. 2) During the processing of wood, waste is generated, which is currently burned in the boiler room. With small production volumes this is quite acceptable, but with an increase in production volume it makes sense to consider the option when the wood waste is transformed into wood chips, which are then delivered to pulp and paper mills, fuel pellet plants, etc. 3) Finished products are delivered to the final consumer with the involvement of private carriers. A variant of organizing production with its own transport division is possible. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,752,882,812]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 1: Only the logging enterprises are included in the production chain (LLC Les, PiM LLC, LODBALTLES LLP, Timberg Holding OJSC, Domozhirovsky Lespromkhoz OJSC, Georgievsky Lesokombinat, Aurora OAZT), i.e. the enterprise does not carry out logging, and carries out transportation by itself. Window blocks are added to the product range of the enterprise. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,813,878,841]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 2: The difference from the previous alternative is that the transportation function is transferred to private carriers. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,843,880,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 3: The production chain includes the logging enterprises (the same as in alternative 1), a pulp and paper mill (or a plant for the production of fuel pellets), and a set of private carriers. Window blocks and technological chips are added to the product range of the enterprise; the enterprise performs the transportation function independently. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[458,82,882,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[499,941,507,951]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,134,882,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 4: Forestry enterprises (State Forestry Enterprise, Forestry Enterprise Lodeinopolsky, Oyatsky Forestry), i.e. the enterprise performs logging and transportation on its own. Window blocks are added to the product range of the enterprise. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,180,880,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 5: The difference from the previous alternative is that the transportation function is transferred to private carriers. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,210,882,254]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Alternative 6: Forestry enterprises (State Forestry Enterprise, Forestry Enterprise Lodeynopolsky, Oyatsky Forestry), Pulp and Paper Mill (or a plant for the production of fuel pellets), and a set of private carriers. Window blocks are added to the product range of the enterprise. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,255,882,315]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The expert group included: 1 - the general director of the enterprise; 2 - technical director; 3 - commercial director; 4 - chief economist; 5 - chief engineer; 6 - chief mechanic; 7 - head of sawmill production; 8 - the head of the carpentry unit; 9 - power engineer; 10 - head of the department of logistics and external cooperation; 11, 12, 13, 14 - process engineers of the sawmill. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[136,316,645,330]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Imagine the problem in the form of a two-level hierarchy (figure 4). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[206,354,791,550]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Hierarchical structure of the task of choosing a forest industry chain. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0879/2f6472be85b68752686845e21cd14a527e41c0645ad97877bb024e2716a235b8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[139,596,361,611]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Let us introduce the notation: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,612,885,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathbf { A } = \\\\{ A _ { 1 } , A _ { 2 } , \\\\dots , A _ { n } \\\\}$ - - many alternatives consisting of $n$ elements; $P _ { 0 } ( A )$ - a set of cardinalities of alternatives, the elements of which are all possible combinations of alternatives of a universal set of alternatives??; $P _ { 0 } ( A ) = \\\\{ B _ { 1 } , B _ { 2 } , \\\\dots , B _ { l } \\\\}$ , $l = 2 ^ { n } - 1$ (the empty set is excluded from consideration); $\\\\complement =$ $\\\\{ C _ { 1 } , C _ { 2 } , \\\\ldots , C _ { r } \\\\}$ - set of criteria consisting of $r$ elements; $P _ { 0 } ( \\\\mathbb { C } )$ - set of criteria cardinality, elements of which are all possible combinations of criteria for the universal set ∁, $P _ { 0 } ( \\\\mathsf { C } ) = \\\\big \\\\{ C ^ { ( 1 ) } , C ^ { ( 2 ) } , \\\\ldots C ^ { ( k ) } \\\\big \\\\} , k =$ $\\\\overline { { 1 , r } } , C ^ { ( k ) } = \\\\Big \\\\{ \\\\mathbb { C } _ { 1 } ^ { ( k ) } , \\\\mathbb { C } _ { i } ^ { ( k ) } , \\\\dots , \\\\mathbb { C } _ { s } ^ { ( k ) } \\\\Big \\\\} .$ -is the set of all subsets of criteria of length $k$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[110,713,882,744]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Each of the experts selects the subset of criteria that, in his opinion, is the most preferable in comparison with the entire set of criteria \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[231,749,761,795]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0933/07923f91d80c859800db19511d3dd37cc7705448d2f0b36f19f1c214d157c1b0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array}{c} \\\\begin{array} { r l r } { \\\\left\\\\{ \\\\mathbf { c } _ { n i } ^ { ( k ) } = 1 , \\\\quad \\\\right.} & { i f t h e n e x p e r t s e l e c t s a s u b s e t \\\\mathbb { C } _ { i } ^ { ( k ) } , i . e . \\\\mathbb { C } _ { i } ^ { ( k ) } \\\\succ \\\\mathsf { C } } & \\\\\\\\ { \\\\mathbf { c } _ { n i } ^ { ( k ) } = 0 , \\\\quad } & { o t h e r w i s e } & \\\\end{array} \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[122,800,880,831]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For example, an expert's choice of a pair of $\\\\mathrm { C } _ { 3 } \\\\mathrm { C } _ { 4 }$ criteria means that this expert cannot determine the most preferable criterion from ${ \\\\mathsf { C } } _ { 3 }$ and $\\\\mathsf { C } _ { 4 }$ - both criteria are the most important. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[132,831,820,846]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"After polling all $N _ { c }$ experts, the number of occurrences of the selected subsets is calculated \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[440,850,559,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0162/0e350e52a4715ea53267ccee4b5b4c3f4daeb29969390ebf0e9a44dedcfcf9a0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nc _ { i } ^ { ( k ) } = \\\\sum _ { n = 1 } ^ { N _ { c } } c _ { n i } ^ { ( k ) }\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[457,82,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[497,941,507,951]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,82,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[114,134,884,166]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At the second stage, the expert, in accordance with the given criterion $C _ { i } , i = 1 , \\\\ldots , r$ selects a certain subset $B _ { j } \\\\in P _ { 0 } ( A )$ as the most preferable among the whole set of alternatives ??. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[386,171,611,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"0986/9c202f6ef4f5f57f8904cfca1fad6ca6f8d58f6b07622e1b07a27c571d3eddee.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n\\\\begin{array} { r } { \\\\left\\\\{ \\\\begin{array} { l } { c _ { n j i } = 1 , \\\\quad \\\\quad i f t h e B _ { j } \\\\succ A } \\\\\\\\ { c _ { n j i } = 0 , \\\\quad \\\\quad o t h e r w i s e } \\\\end{array} \\\\right. } \\\\end{array}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[115,217,878,254]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\begin{array} { r } { c _ { i j } = \\\\sum _ { n = 1 } ^ { N _ { A } ^ { ( i ) } } c _ { n j i } } \\\\end{array}$ ??, ????(??)- t he total number of assessments of alternatives (groups of alternatives) by criterion i. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,255,882,285]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"During the survey, the experts provided inaccurate pairwise comparisons of the criteria (table 1) and alternatives in accordance with a given criterion (tables 2 – 5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,312,850,529]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0779/4c8a0c3c95c2e061a0123072bfb20e7c66ea7deaaf10ac8a76de58f331157f34.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>C C C C4 C; CC4 C4C; CCC5</td><td>C3C4C5</td><td>C2C4C5</td><td>C</td></tr><tr><td>C</td><td></td><td>4</td><td></td><td>2</td><td>1</td><td></td><td></td><td>1</td><td>1</td><td></td><td>4</td></tr><tr><td>C</td><td></td><td></td><td></td><td>=</td><td>-</td><td></td><td></td><td></td><td>1</td><td></td><td>6</td></tr><tr><td>C</td><td></td><td></td><td></td><td></td><td>2</td><td>=</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>C4</td><td></td><td></td><td></td><td></td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CC2</td><td></td><td></td><td></td><td></td><td></td><td>2</td><td></td><td></td><td></td><td></td><td>3</td></tr><tr><td>CC3</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td><td></td><td></td><td></td><td></td></tr><tr><td>CC4</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>CC2C3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>C.C2C3C4</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Expanded matrix of pairwise comparisons of subsets of criteria. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[292,594,704,789]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0635/e17026ce4e116abebe100dcbd665be814786a40be80ae7b9385fc27d7c1a317b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAAAAAAAA</td><td></td><td></td></tr><tr><td></td><td></td><td>=</td><td></td><td></td><td></td><td>2</td><td>-</td></tr><tr><td>AAA</td><td>5</td><td></td><td></td><td></td><td>3</td><td></td><td>2</td></tr><tr><td></td><td>1</td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>A</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>AA</td><td></td><td></td><td>1</td><td></td><td></td><td></td><td>3</td></tr><tr><td>AA4</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr><tr><td>AA6</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>AAA</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2. Expanded matrix of pairwise comparisons of forest industry chains according to the criterion of total costs. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[295,854,699,900]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0207/b6700ca53d71714b79fabda232b2fec823c6ed6c699997a8ab94ac71aadbd000.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAAAAAAA</td><td></td><td>A</td></tr><tr><td>A</td><td>=</td><td>1</td><td>=</td><td>1</td><td>4</td><td>=</td><td>=</td></tr><tr><td>A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>4</td></tr><tr><td>AA</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr><tr><td>A4AA6</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td>1</td></tr><tr><td>AAA</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3. Expanded matrix of paired comparisons of forest industry chains according to the criterion of reliability. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,65,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[457,82,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,82,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[499,941,507,951]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[297,131,702,241]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[292,306,704,417]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0405/5e512ba19b93331aa8dcc7b9ce45ba4122ef6b906161379f174b6a9244e91bd1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAAAAAAAA</td><td></td><td></td></tr><tr><td>AA</td><td>2</td><td>1</td><td></td><td>-</td><td></td><td></td><td>3</td></tr><tr><td>AA6</td><td></td><td>、</td><td></td><td>1</td><td></td><td></td><td>2</td></tr><tr><td>A4A</td><td>1</td><td>1</td><td></td><td></td><td></td><td></td><td>2</td></tr><tr><td>A4AA6</td><td></td><td></td><td></td><td></td><td></td><td></td><td>8</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 4. Expanded matrix of pairwise comparisons of forest industry chains in accordance with the criterion of service quality. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[292,481,705,593]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0672/ad7d5c88db64767a005899f47de12ab69837070613a5f6e520aa4c678f196f0f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td></td><td></td><td></td><td></td><td>AAA4AAAAA</td><td></td><td>A</td></tr><tr><td>A</td><td>1</td><td>1</td><td>2</td><td>=</td><td>1</td><td></td><td>-</td></tr><tr><td>AA</td><td></td><td>2</td><td>1</td><td>-</td><td>1</td><td></td><td>1</td></tr><tr><td>A4A</td><td>=</td><td>1</td><td>1</td><td>2</td><td></td><td></td><td>-</td></tr><tr><td>A4AA6</td><td></td><td></td><td></td><td></td><td></td><td></td><td>5</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 5. Expanded matrix of pairwise comparisons of subsets of criteria according to the criterion duration of order execution. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,621,885,677]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"According to the criterion of uncertainty and risk, ten experts were not able to identify subsets of alternatives, i.e. provided an assessment $\\\\mathbf { A { \\\\underline { { \\\\succ } } } A }$ , two experts - $A _ { 1 } A _ { 2 } A _ { 3 } { \\\\underline { { \\\\succ } } } \\\\mathbf { A }$ , one expert - $A _ { 1 } A _ { 2 } { \\\\succeq } A _ { 4 } A _ { 5 }$ , and one expert - $A _ { 2 } A _ { 5 } { \\\\simeq } \\\\mathbf { A }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[107,680,882,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In table 6, the results of calculations performed in accordance with the general method of pairwise comparisons are given. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[277,752,722,821]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0003/b9126f9a7c4f91de4fec2bd9e3013bdfc64ced36072c84d0067be582983ee5f0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td></td><td>A</td><td>A</td><td>A</td><td>A4</td><td>A</td><td>A6</td></tr><tr><td>Bel(B)</td><td>0.06</td><td>0.14</td><td>0.05</td><td>0.07</td><td>0.18</td><td>0.10</td></tr><tr><td>Pl(B)</td><td>0.80</td><td>0.85</td><td>0.43</td><td>0.82</td><td>0.78</td><td>0.76</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 6. Lower and upper boundaries of the probabilities of forest industry chains. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[457,82,882,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[497,941,507,951]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[127,131,606,375]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5. Rating dependence $Y = \\\\\\\\gamma \\\\\\\\cdot B e l ( B _ { l } ) + ( 1 - \\\\\\\\gamma ) \\\\\\\\cdot P l ( B _ { l } )$ from the attitude of the LPR to the risk. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0217/d8cd1fe1a9a12bb4a5f04df00315d4e6a618cb781548c31c23b9c70af1699af8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[115,393,882,447]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In figure 5, rating dependence $Y = \\\\gamma \\\\cdot B e l ( B _ { l } ) + ( 1 - \\\\gamma ) \\\\cdot P l ( B _ { l } )$ from the attitude of the LPR to the risk is presented. The general director of LLC Akvilon acted as an LPR, who assessed his attitude to risk by a value $\\\\gamma = 0 . 4$ . When $\\\\gamma = 0 . 4$ , alternatives are ranked as follows: $A _ { 2 } { \\\\succeq } A _ { 5 } { \\\\succeq } A _ { 4 } { \\\\succeq } A _ { 1 } { \\\\succeq } A _ { 6 } { \\\\succeq } A _ { 3 }$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,466,208,479]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,480,872,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The formalization of production tasks has been carried out, including the tasks of selecting individual links in the production chain (suppliers, carriers, warehouses) and choosing production chains based on the principles of a systematic approach. As calculation methods, it is proposed to use methods for processing inaccurate pairwise comparisons to solve multi-criteria decision-making problems. An extension of the DS/AHP method is proposed in the paper. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,569,206,583]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,585,885,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"[1] Saati T and Vachnadze R G 1993 Decision Making. Hierarchy Analysis Method (Moscow: Radio and Communications) \\n[2] Simanova N V 2005 Logistics information system for managing a forestry enterprise Bulletin of St. Petersburg Forest Technical Academy:Proc. Annual Conf. of Young Scientists(St. Petersburg:State Forest Technical Academy) pp 62-5 \\n[3] Melamed N V and Sokolova V A 2018 Developing the model of an automated rotary-cut veneer sorting system IOP Conference Series: Materials Science and Engineering 450(4) 042007 \\n[4] Simanova N V 2007 A generalized method of pairwise comparisons to solve multi-criteria problems Proc. XX Int.Conf.on Mathematical Methods and Information Technologies in Economics, Sociology and Education (Penza: Volga House of Knowledge) pp 259-62 \\n[5] Simanova N V 2007 New methods of multi-criteria decision-making in logistics Proc. II All-Russian Conf.on Actual Problems of Anaging Technical, Information, Socio-Economic and Transport Systems (St. Petersburg: Publishing House of SZTU) 2 pp 122-6 \\n[6] Simanova N V2008 New methods for making multi-criteria decisions in the design of logistic chains of the timber industry complex Proc.Int.Conf. of Young Scientists November 13-14, 2007, St. Petersburg State Forest Technical Academy:Modern Problems and Prospects of Rational Forest Management in the Market (St. Petersburg: Publishing House of the Polytechnic University) pp 221-7 \\n[7] Simanova N V and Utkin L V 2008 Soft measurements Proc. XI Int. Conf. on Soft Computing and Measurements: Inaccurate Preferences for Soft Ranking of Objects in Conditions of Incomplete Information(St. Petersburg: Publishing House of SPb SETU) 1 pp 205-9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[776,66,882,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[457,82,882,95]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1679 (2020) 042074 doi:10.1088/1742-6596/1679/4/042074 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,66,205,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"APITECH II \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[497,941,507,950]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,134,882,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"[8] Utkin L V and Simanova N V 2007 Using the Dirichlet model and evidence theory to modify the method of analysis of hierarchies Proc. XI Int. Conf.on System Analysis in Design in Management(St. Petersburg: Publishing House of the Polytechnic University) 1 pp 116-7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,180,882,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"[9] Utkin L V and Simanova N V 2007A method for analyzing hierarchies with incomplete information about criteria and alternatives Fuzzy Systems and Soft Computing 2 31-40 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,210,884,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n 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\"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n },\n {\n \"bbox\": \"[115,83,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"discarded\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1088/1742-6596/1679/4/042074"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Mathematics and Computational Science"},"sha256":{"kind":"string","value":"237c776024dce13ba0df8d14edb40a191097ba6591b26592c425c0a447839006"},"title":{"kind":"string","value":"Production chains configuration based on a systematic approach"}}},{"rowIdx":179,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Justin Ting|Arijit Raychowdhury|Yan Fang|Ashwin Sanjay Lele"},"content_list":{"kind":"list like","value":[{"bbox":"[127,112,868,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Learning to Walk: Spike Based Reinforcement Learning for Hexapod Robot Central Pattern Generation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[309,180,705,205]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ashwin Sanjay Lele, Yan Fang, Justin Ting, Arijit Raychowdhury \nSchool of Electrical and Computer Engineering ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[352,206,663,217]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Georgia Institute of Technology, Atlanta, GA, USA ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[280,217,739,229]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"{alele9, jting31, yan.fang}@gatech.edu, arijit.raychowdhury@ece.gatech.edu ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,250,489,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Learning to walk - i.e., learning locomotion under performance and energy constraints continues to be a challenge in legged robotics. Methods such as stochastic gradient, deep reinforcement learning (RL) have been explored for bipeds, quadrupeds and hexapods. These techniques are computationally intensive and often prohibitive for edge applications. These methods rely on complex sensors and pre-processing of data, which further increases energy and latency. Recent advances in spiking neural networks (SNNs) promise significant reduction in computing owing to the sparse firing of neuros and has been shown to integrate reinforcement learning mechanisms with biologically observed spike time dependent plasticity (STDP). However, training a legged robot to walk by learning the synchronization patterns of central pattern generators (CPG) in an SNN framework has not been shown. This can marry the efficiency of SNNs with synchronized locomotion of CPG based systems - providing breakthrough end-to-end learning in mobile robotics. In this paper, we propose a reinforcement based stochastic weight update technique for training a spiking CPG. The whole system is implemented on a lightweight raspberry pi platform with integrated sensors, thus opening up exciting new possibilities. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,502,489,538]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Index Terms—Central pattern generator, spiking neural Networks, Spike time dependent plasticity, Stochastic Reinforcement based STDP, robotic locomotion ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[216,565,344,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"I. INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,581,489,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Locomotion of animals emerge from the biomechanical interaction between the environment and the body controlled by the nervous systems [1]. Locomotion of invertebrate and vertebrates with limbs is generated by Central pattern generators (CPGs), which are biological neural circuits that produce rhythmic outputs [2][3]. CPG-inspired control systems have been widely applied to the locomotion of legged robots and exoskeletal prosthetic systems [4-6]. Compared to a traditional centralized control that calculates the activity of each leg independently, a distributed CPG-based de-centralized approach can locally control each joint through a combination of local and global network dynamics. Thus, it decreases the dimensionality of the control signal and reduce the time delays in motor control loop. Researchers also discovered that CPG not only gives rise to complex rhythmic patterns for locomotion and seamless gait transition but also receives modulation from higher regions in the brain. Inspired by these findings in neurosciences, we develop an end-to-end autonomous system where sensory inputs can directly interface with CPG to not only provide a means of adaptive locomotion and gait; but also enable the agent to walk or run without any prior knowledge or model-based experience replay. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,252,927,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Besides enabling functional end-to-end learning, we also consider the energy consumption of such autonomous systems. This is particularly important for micro-robots for real-world tasks in energy-constrained environments. Recent advances in spiking neural networks (SNN) and neuromorphic computing hardware has tremendously improved the energy-efficiency of cognitive tasks thus bridging the gap between hardware and wetware [7][8]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,382,912,578]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0301/b34caa41101722820e2412580e4382424e76a986b046335086d189d7f0238431.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[517,578,914,676]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 1. (a) Closed loop locomotion system schematic. Hexapod robot moving in the environment sends visual and gyros sensor signals to the raspberry pi processing unit to decide which legs to move during the next time instance (b) Gait learning with time. Black boxes indicate that the neuron spikes at that time instance. Initially the CPG neurons spikes randomly making the robot to lose balance which is corrected over time with the robot learning the correct gait \"]","image_footnote":"[]","img_path":"images/0399/3020f613d478082e4f0e1f1aff7194dd31608dc41dd814904c857a5ac905a0ca.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[504,767,926,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In prior work, a CPG based on digital implementation of phase patterns has been proposed and implemented on an FPGA [5]. However, the generated patterns are pre-programmed, to enable known walking patterns. Evolutionary algorithm-based approaches are also proposed for gait learning of hexapod robots [9], but the neural CPG is not discussed or related to control. [10-11] show reinforcement learning formulation in the context of SNNs. However, most of these works focus on image processing or task planning of wheeled robots. To the best of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[154,23,838,39]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2020 IEEE International Conference on Artificial Intelligence Circuits and Systems (AICAS) ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,64,870,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,958,391,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"978-1-7281-4922-620$31.00 ©2020 IEEE ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[484,959,512,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"208 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,980,867,994]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,99,487,127]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"our knowledge, SNN based CPG with autonomous learning ability has not been explored yet.. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,128,487,270]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this work, we demonstrate an end-to-end spiking neural network carrying out online processing of sensory information to generate gait learning in hexapod robots. Gyro sensor and camera provide the sensory inputs that are converted into reward signals reinforcing or depressing the weights to stochastically evolve the network to learn the tripod gait for locomotion. Thus we demonstrate a system where a legged robot learns to walk autonomously through interactions with the environment and by collecting data from its gyroscopic and camera sensors. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[201,286,359,298]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"II. PROPOSED SYSTEM ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[70,305,243,318]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. Network Architecture ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[141,324,418,465]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 3. Pseudo-code for the algorithm. For every time instance, the membrane voltages of neurons are updated to determine the neural spiking at the current time instance. After the corresponding legs are moved, the gyro sensor reading and visual sensor reading is updated to generate the reward signal for weight updates \"]","image_footnote":"[]","img_path":"images/0209/11cb7d2c6b61bc26f6a048b8f3e986a19f74f01a414fceb037589967b82742bc.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[68,486,489,532]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 2. Schematic of the neural connectivity within the network. The box forms the CPG driven by the input neuron and balance driven neuron. $\\mathrm{W}_{\\mathrm{in}}$ $\\mathrm{W_{Gyro}}$ and $\\mathrm{W_{CPG}}$ represent the weight matrices corresponding to the all-o-all connection. Only a few connections are shown in the figure due to space constraint ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,543,487,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The proposed CPG network consists of six leaky-integrate and fire (LIF) spiking neurons, each driving one leg of the hexapod robot shown in Fig. 1. In this work, we used a digital discretized version of LIF model [5]. The update of variables occurs at discrete time steps $t$ . The membrane voltage of LIF neurons take the injection current $I$ from spikes of other neuron and simultaneously decay with a leaky constant $\\alpha$ . When the membrane potential $V$ reaches a spiking threshold, a spike is issued and $V$ is reset to the resting potential (zero in our case). Thus, we have the discrete equation of membrane voltage: ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[213,685,487,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nV [ t + 1 ] = \\frac {V [ t ]}{\\alpha} + I \\tag {1}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[68,720,487,833]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The neurons are fully connected to each other with additive synapses. The CPG is driven by an input neuron with periodic input causing the CPG to fire and another neuron which fires only when the robots lose balance while walking. This neuron is a gyro sensor driven neuron referred as $\\mathrm{N}_{\\mathrm{Gyro}}$ . The CPG neurons have a refractory period of two time units. The compactness of the network enables its implementation on the Raspberry Pi board without any external infrastructural support. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,840,169,853]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. Algorithm ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,856,487,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 3 shows the pseudo-code for the algorithm. The weights are randomly initialized. Equations in step 7 and 8 show the voltage calculation for the LIF neurons where $\\alpha$ is the leak rate. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,99,924,218]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The voltages of all the LIF neurons in the CPG are calculated by calculating the current coming into each neuron from the input neuron, gyro sensor driven neuron and other CPG neurons. The current is assumed to be equal to the weight of the synapse if the pre-neuron has spiked and zero otherwise as shown in the equation of step 7. An output neuron fires when the voltage exceeds a predefined spiking threshold. At any time instance, the number of neurons firing result in movement of the corresponding legs in the forward direction. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,219,924,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For every time instance, visual and gyro inputs are received before and after the movement is completed. During the movement of the leg, gyro sensor reading provides information about the balance and at the completion of the movement the visual information from the camera conveys whether a forward movement has occurred. If the balance is lost, the gyro driven neuron fires in the next time instance and the moved leg is taken back to the initial position. If the balance is not lost the movement of the leg is completed making the body to move forward. The balance and movement are then fed into the reward calculation equation. The detailed experimental design for the weight updating is explained in the next section. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,396,700,409]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Algorithm 1 Learn to Walk ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[515,410,875,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1: Initialize weights randomly $W_{in}, W_{Gyro}, W_{CPG}$ \",\"2: Initialize CPG neuron voltages, $V_{CPG}[0] = 0$ \",\"3: Initialize Spikes $S_{in} = 1, S_{Gyro} = 0, S_{CPG} = 0$ \",\"4: for time $= 1$ to $T$ do \",\"5: Read camera and gyro sensor for initial reading \",\"6: for neuron $= 1$ to 6 do \",\"7: $I = W_{in}S_{in} + W_{Gyro}S_{Gyro} + W_{CPG}S_{CPG}$ \",\"8: $V_{neuron}[t] = V_{neuron}[t - 1] / \\\\alpha + I$ \",\"9: if $(V_{\\\\text{neuron}}[t] > V_{\\\\text{Thresh}})$ then \",\"10: Update Spike, $S_{CPG} = 1$ , $V_{neuron}[t] = 0$ \",\"11: Move Corresponding Leg \",\"12: end if \",\"13: end for \",\"14: Read camera and gyro sensor for final reading \",\"15: Calculate reward \",\"16: Update weights \",\"17: end for \"]","page_idx":"1","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[623,716,805,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"III. EXPERIMENTAL SETUP ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,736,675,749]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. Reward Calculation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,752,924,885]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The reward combines both visual and gyro sensor inputs. The gyro sensor reward is partitioned into three categories as shown in Fig. 4. In the first case the robot moves less than three legs losing its balance and not moving forward. This results in a small positive reward to encourage more neurons to fire in the next time instance. The other case is when four or more neurons in the CPG fire making the corresponding legs to be raised, which results the robot losing balance and gives a small negative reward to make sure that the weights are depressed and fewer number of neurons fire in the next iteration. The final case ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,65,868,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[484,959,512,971]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"209 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,982,867,994]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,99,489,138]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is when the correct three legs are raised, and the robot maintains its balance even when the legs are lifted up in the air. A high positive reward is given now to make sure the action is repeated. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,140,490,366]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The other component of the reward comes from the visual input. We use the scan line based odometry method from [13] because of its low computational cost. If the balance is maintained because no leg is raised, it gives an erroneous positive reward to the system. This error can be fixed by using a binary decision algorithm taking difference between the images before and after the movement to distinguish whether the forward movement has occurred or not. A positive reward accompanies the forward movement and lack of any movement is penalized. This allows the robot to simultaneously learn how to balance itself while moving forward. It is important to ensure that the negative reward is not very high in magnitude, particularly in the first few iterations so that the network has enough time to explore and learn. A linear correction is applied to the movement-based reward making it steeper as the algorithm progresses. Therefore, the total reward at time instance $t$ is given by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[95,378,489,423]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nR e w a r d _ {t o t a l} [ t ] = R e w a r d _ {g y r o} + R e w a r d _ {v i s u a l} \\left[ \\frac {t}{T _ {1}} \\right] (2)\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[82,453,386,712]","code_body":"1: for time = 1 to T do \n2: Ginitial = Read gyro sensor \n3: Complete the movement \n4: Gfinal = Read gyro sensor \n5: if (Gfinal - Ginitial > GThresh) then \n6: balance lost \n7: if (Number of legs moved > 3) then \n8: RewardGyro = -2 \n9: end if \n10: if (Number of legs moved < 3) then \n11: RewardGyro = +2 \n12: end if \n13: end if \n14: if (Gfinal - Ginitial < GThresh) then \n15: balance maintained \n16: RewardGyro = +5 \n17: end if \n18: end for ","code_caption":"[\"Algorithm 2 Gyroscope Reward Calculation \"]","image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":"algorithm","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"code"},{"bbox":"[68,714,489,760]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 4. Pseudo-code for calculating the reward corresponding to gyro sensor reading. If the balance is maintained high positive reward is given. If the balance is lost, the reward is given such that the cumulative weights evolve 3 legs at a time ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,766,275,780]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. Synaptic Weight Updating ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,782,490,876]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Combining synaptic reinforcement with reward function has been utilized previously [14] speculating dopamine release as the biological parallel of reward signals. The weights are updated only for synapses connected to the CPG neurons firing at the current time instance. If neuron $i$ spikes at time step $t$ , then for all pre-synaptic neurons spiking at time step $t-1$ , the change of weight is calculated as given below ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[576,100,924,121]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nW _ {i j} [ t + 1 ] = W _ {i j} [ t ] + \\theta \\eta R e w a r d _ {\\text {t o t a l}} [ t ] \\tag {3}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[504,130,924,175]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"where $\\theta$ is the learning rate and $\\eta = \\text{random}(0,1)$ is the stochastic term. The learning rate has to be chosen carefully to maximize the convergence rate of learning process. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,180,697,193]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Hardware Development ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,195,926,317]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The system described above is implemented in hardware for verification of the correct gait pattern in an office environment shown in Fig. 1. We use an Adept RaspClaws Hexapod Robot as the locomotion platform. It is equipped with a Gy-521 MPU6050 MPU6050 gyro sensor Module and a pi camera to provide balance and visual input to a Raspberry pi 3 Model B+ processing unit. The quad-core processor of Raspberry Pi operates at $1.5\\mathrm{GHz}$ frequency. The schematic of connections and block diagram of the operations is shown in Fig. 5. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,319,921,491]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 5. Block diagram of the system of computation. Sensory inputs are processed on the Raspberry Pi board and the movement signals are generated and send out to the hexapod. \"]","image_footnote":"[]","img_path":"images/0543/3ae7cf96c111233b7515c2f7618054ab5b97db14a7a074fcffa9c7ff65daecb1.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[608,549,821,562]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IV. RESULTS AND DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,571,660,584]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A. System Simulation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,587,926,712]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fig. 6 shows the simulation results of an example of learning process along the time. The robot starts its action with no movement and gradually begin to oscillate between moving 2 and 4 legs alternatively. When it finally enters the target gait (the tripod gait shown in Fig. 1), thereby earning a high reward, and the weights saturate thus sustaining the gait. Fig. 6(b) shows the total accumulated reward over time. The reward was initially negative before the correct gait is found. After that, it rapidly increases. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,716,921,838]","code_body":null,"code_caption":null,"image_caption":"[\"Fig. 6. The number of moving legs (a) and reward accumulated (b) during the learning process. \"]","image_footnote":"[]","img_path":"images/0347/2302c594ae1dc715027c78b4ce57be0774a9fde2fd3a7c3d7743eab438756070.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[68,65,868,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[484,958,512,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"210 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,980,867,994]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[70,100,201,112]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"B. Demonstration ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,116,492,264]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We apply the proposed method to an Adept hexpod robot with the hardware configuration depicted in section III.C. In the first experimental demonstration (demo-1)<sup>1</sup>, the learning process converged to the target gait pattern at the 66th cycle (4:10). We also note (demo 2) that the learning process converges to an unwanted alternative gait pattern at the 7th cycle (0:18). This gait pattern is a local minimum during the learning process. The hexapod can move also forward with this gait, but it is less efficient when compared to the bio-mimetic target gait. The occasional tremor of servos is caused by instantaneous drops in the current supply. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,269,238,282]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C. Parameter Selection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,286,492,540]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In order to identify the best learning rate, we simulated 100 iterations of the algorithm with different random seeds for different learning rates. This is shown in Fig. 7. Fig. 7(a) shows the percentage of simulations converging to the correct tripod gait. The results show that the convergence percentage remains similar over a range of learning rates. We choose 0.1 as the learning rate as it shows the lowest number of non-convergent cases. The non-convergent cases do not mean that no locomotion takes place. These cases correspond to an inefficient final gait, where the hexapod makes frequent turns and does not move forward in every step. Fig. 7(b) shows the convergence time for the iterations that converge to the desired gait. The median convergence time is 207 iterations for learning rate of 0.1. Fig. 7(c) shows the weight maps of synapses forming the connections between the CPG neurons before and after the completion of the learning. For the convergence to the global minima of tripod gait, the initially random weights between the neurons evolve into a pattern such that neurons 1,3,5 drive neurons 2,4,6 and vice versa. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[70,559,322,572]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"D. Comparison with the Prior Work ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,574,490,737]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The simple two-layer spiking network used in this network is expected to show high reduction in energy required in learning as opposed to conventional approaches involving artificial neural networks. We calculate the total number of spikes issued by the CPG in the course of learning to estimate the energy spent in learning. The median of total number of spikes issued is 503. If these dynamics were implemented in a specialized SNN processor, such as Intel's Loihi platform (1.7 nJ/spike [14]), then the total energy consumption in the learning process will be $855.1\\mathrm{nJ}$ . Along with the low energy consumption, this work also shows that online SNN training can enable a hexapod to learn how to walk by a simple reward mechanism. (Table. 1) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[218,749,341,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"V. CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[68,766,490,861]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We design a closed-loop end-to-end online training of central pattern generator based on a bio-plausible spiking neural network. We have applied the proposed neuromorphic CPG to a hexapod robot and achieve autonomous online reinforcement learning of biomimetic walking gaits in an energy efficient manner. This online learning system is implemented on a resource-constrained embedded system. The learning process ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,99,927,138]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"converges to the desired bio-observed tripod in $70\\%$ of the cases while in other cases it converges to suboptimal gaits that can still enable the locomotion. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,174,712,279]","code_body":null,"code_caption":null,"image_caption":"[\"(a) \"]","image_footnote":"[]","img_path":"images/0191/8fc1f7aad00fef397676ad2a495e37caf5adf68d9a2f899346c0bafba6fe7258.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[729,174,917,280]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \"]","image_footnote":"[]","img_path":"images/0275/761b8eebf9fa5ee9451677e915f5d87d8d75805611973ac5f6264dda415c9989.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[522,287,626,383]","code_body":null,"code_caption":null,"image_caption":"[\"(c) \"]","image_footnote":"[]","img_path":"images/0630/6a72e9315a7d5452b1d29b04becbd9a02d92d7ea53523893b31148e11d087f41.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[682,298,769,383]","code_body":null,"code_caption":null,"image_caption":"[\"Correct Convergence \"]","image_footnote":"[]","img_path":"images/0535/954cbf643f25fef1975f6bb31011d75a42a11b69fe7518ce7fe242d50a9c4449.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[818,298,902,383]","code_body":null,"code_caption":null,"image_caption":"[\"Incorrect Convergence \",\"Fig. 7(a) Distribution of convergence time with learning rate. Median convergence time is 207-time instances. (b) Percentage of simulations converging to bio-observed tripod gait is independent of the learning rate. Simulations not converging to tripod gait are trapped in local minima that still enabling the locomotion is shown in demo 2. (c) Weight matrices of the CPG connections before and after the training. With the convergence to the global minima exhibiting tripod gait as shown in video demo - 1. In this configuration the neurons form a group of 3 reinforcing each other. In the other case the weights evolve into a configuration with inefficient walking gait still ensuring locomotion as shown in demo - 2 \"]","image_footnote":"[]","img_path":"images/0764/0648ef907df4d8492a14fe332bd06d493c083f9d1430fd61c13a788238d0baa9.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[515,515,921,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0225/8151cd1d712990a584b6ae900262d85f98e412ed450d4c6fcc15e84e30a8ceb5.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Ref</td><td>Training Approach</td><td>Sensory Feedback</td><td>Online /Offline</td></tr><tr><td>[16]</td><td>Linear Programming</td><td>None</td><td>Offline</td></tr><tr><td>[17]</td><td>Grammar Evolution</td><td>None</td><td>Offline</td></tr><tr><td>[18]</td><td>Reward + STDP</td><td>Olfactory + visual</td><td>Offline</td></tr><tr><td>This Work</td><td>Stochastic RL</td><td>Balance + visual</td><td>Online</td></tr></table>","table_caption":"[\"Table. I Benchmarking Comparison to previous SNN CPG approaches \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[643,665,786,676]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGEMENT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,681,924,722]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was supported by C-BRIC, one of six centers in JUMP, a Semiconductor Research Corporation (SRC) program sponsored by DARPA. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[670,750,761,762]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,766,924,842]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] N. Bernstein. The Coordination and Regulation of Movements. Pergamon Press, Oxford, 1967. \",\"[2] T.G. Brown, “The intrinsic factors in the act of progression in the mammal.” Proc. R. Soc. Ser. B https://doi.org/10.1098/rspb.1911.0077 (1911). \",\"[3] A.I. Selverston, \\\"Invertebrate central pattern generator circuits.\\\" Philos Trans R Soc Lond B Biol Sci. 365(1551), pp.2329-2345. 2010 \"]","page_idx":"3","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[70,65,868,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[87,875,307,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Demo-1: https://youtu.be/1HqeISAkAs4 ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[89,887,307,899]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Demo-2: https://youtu.be/ypW0V23gEj0 ","text_format":null,"text_level":null,"type":"page_footnote"},{"bbox":"[484,959,510,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"211 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,982,867,994]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[72,99,489,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[4] D. Owaki, and A. Ishiguro. “A quadruped robot exhibiting spontaneous gait transitions from walking to trotting to galloping.” Scientific Reports, 7(1), p.277. \",\"[5] H. Rostro-Gonzalez, et al. “A CPG system based on spiking neurons for hexapod robot locomotion.” Neurocomputing, 170, pp.47-54. 2015 \",\"[6] X. Guo, L. Chen, Y. Zhang, P. Yang, and L. Zhang, \\\"A study on control mechanism of above knee robotic prosthesis based on CPG model.\\\" In Proc. IEEE International Conference on Robotics and Biomimetics (pp. 283-287). 2010. \",\"[7] P.A. Merolla, et al \\\"A million spiking-neuron integrated circuit with a scalable communication network and interface.\\\" Science, 345(6197), 668-673, 2014. \",\"[8] M. Davies, et al 2018. \\\"Loihi: A neuromorphic manycore processor with on-chip learning.\\\" IEEE Micro, 38(1), pp.82-99. 2018. \",\"[9] A. Espinal, H. Rostro-Gonzalez, M. Carpio, E.I. Guerra-Hernandez, M. Ornelas-Rodriguez, and M. Sotelo-Figueroa, \\\"Design of spiking central pattern generators for multiple locomotion gaits in hexapod robots by christiansen grammar evolution.\\\" Frontiers in neurorobotics, 10, p.6. 2016. \",\"[10] R.V. Florian, “Reinforcement learning through modulation of spike-timing-dependent synaptic plasticity.” *Neural Computation*, 19(6), pp.1468-1502. 2007 \",\"[11] E. Rueckert, D. Kappel, D. Tanneberg, D. Pecevski, and J. Peters, \\\"Recurrent spiking networks solve planning tasks.\\\" Sci. Rep. 6:21142. doi: 10.1038/srep21142.2016. \",\"[12] E. Nichols, L.J. McDaid, and N. Siddique, Biologically inspired snn for robot control. IEEE Trans. Cybern. 43, 115-128. 2013. \",\"[13] Milford, Michael, and Gordon Wyeth. \\\"Mapping a suburb with a single camera using a biologically inspired SLAM system.\\\" IEEE Transactions on Robotics 24.5 (2008): 1038-1053. \",\"[14] Izhikevich, Eugene M. \\\"Solving the distal reward problem through linkage of STDP and dopamine signaling.\\\" *Cerebral cortex* 17.10 (2007): 2443-2452. \",\"[15] Davies, Mike, et al. \\\"Loihi: A neuromorphic manycore processor with on-chip learning.\\\" IEEE Micro 38.1 (2018): 82-99. \",\"[16] Rostro-Gonzalez, Horacio, et al. \\\"A CPG system based on spiking neurons for hexapod robot locomotion.\\\" Neurocomputing 170 (2015): 47-54. \",\"[17] Espinal, Andres, et al. \\\"Design of spiking central pattern generators for multiple locomotion gaits in hexapod robots by christiansen grammar evolution.\\\" Frontiers in neurorobotics 10 (2016): 6. \",\"[18] Patanè, Luca, Roland Strauss, and Paolo Arena. Nonlinear Circuits and Systems for Neuro-inspired Robot Control. Springer, 2018 \"]","page_idx":"4","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[72,66,868,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT)< ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[484,959,512,969]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"212 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[122,982,867,992]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[127,112,868,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Learning to Walk: Spike Based Reinforcement Learning for Hexapod Robot Central Pattern Generation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[309,180,705,205]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Ashwin Sanjay Lele, Yan Fang, Justin Ting, Arijit Raychowdhury \\nSchool of Electrical and Computer Engineering \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[352,206,663,217]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Georgia Institute of Technology, Atlanta, GA, USA \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[280,217,739,229]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"{alele9, jting31, yan.fang}@gatech.edu, arijit.raychowdhury@ece.gatech.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,250,489,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Learning to walk - i.e., learning locomotion under performance and energy constraints continues to be a challenge in legged robotics. Methods such as stochastic gradient, deep reinforcement learning (RL) have been explored for bipeds, quadrupeds and hexapods. These techniques are computationally intensive and often prohibitive for edge applications. These methods rely on complex sensors and pre-processing of data, which further increases energy and latency. Recent advances in spiking neural networks (SNNs) promise significant reduction in computing owing to the sparse firing of neuros and has been shown to integrate reinforcement learning mechanisms with biologically observed spike time dependent plasticity (STDP). However, training a legged robot to walk by learning the synchronization patterns of central pattern generators (CPG) in an SNN framework has not been shown. This can marry the efficiency of SNNs with synchronized locomotion of CPG based systems - providing breakthrough end-to-end learning in mobile robotics. In this paper, we propose a reinforcement based stochastic weight update technique for training a spiking CPG. The whole system is implemented on a lightweight raspberry pi platform with integrated sensors, thus opening up exciting new possibilities. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,502,489,538]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Index Terms—Central pattern generator, spiking neural Networks, Spike time dependent plasticity, Stochastic Reinforcement based STDP, robotic locomotion \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[216,565,344,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"I. INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,581,489,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Locomotion of animals emerge from the biomechanical interaction between the environment and the body controlled by the nervous systems [1]. Locomotion of invertebrate and vertebrates with limbs is generated by Central pattern generators (CPGs), which are biological neural circuits that produce rhythmic outputs [2][3]. CPG-inspired control systems have been widely applied to the locomotion of legged robots and exoskeletal prosthetic systems [4-6]. Compared to a traditional centralized control that calculates the activity of each leg independently, a distributed CPG-based de-centralized approach can locally control each joint through a combination of local and global network dynamics. Thus, it decreases the dimensionality of the control signal and reduce the time delays in motor control loop. Researchers also discovered that CPG not only gives rise to complex rhythmic patterns for locomotion and seamless gait transition but also receives modulation from higher regions in the brain. Inspired by these findings in neurosciences, we develop an end-to-end autonomous system where sensory inputs can directly interface with CPG to not only provide a means of adaptive locomotion and gait; but also enable the agent to walk or run without any prior knowledge or model-based experience replay. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,252,927,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Besides enabling functional end-to-end learning, we also consider the energy consumption of such autonomous systems. This is particularly important for micro-robots for real-world tasks in energy-constrained environments. Recent advances in spiking neural networks (SNN) and neuromorphic computing hardware has tremendously improved the energy-efficiency of cognitive tasks thus bridging the gap between hardware and wetware [7][8]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,382,912,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0301/b34caa41101722820e2412580e4382424e76a986b046335086d189d7f0238431.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[517,578,914,676]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 1. (a) Closed loop locomotion system schematic. Hexapod robot moving in the environment sends visual and gyros sensor signals to the raspberry pi processing unit to decide which legs to move during the next time instance (b) Gait learning with time. Black boxes indicate that the neuron spikes at that time instance. Initially the CPG neurons spikes randomly making the robot to lose balance which is corrected over time with the robot learning the correct gait \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0399/3020f613d478082e4f0e1f1aff7194dd31608dc41dd814904c857a5ac905a0ca.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[504,767,926,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In prior work, a CPG based on digital implementation of phase patterns has been proposed and implemented on an FPGA [5]. However, the generated patterns are pre-programmed, to enable known walking patterns. Evolutionary algorithm-based approaches are also proposed for gait learning of hexapod robots [9], but the neural CPG is not discussed or related to control. [10-11] show reinforcement learning formulation in the context of SNNs. However, most of these works focus on image processing or task planning of wheeled robots. To the best of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[154,23,838,39]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2020 IEEE International Conference on Artificial Intelligence Circuits and Systems (AICAS) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,64,870,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,958,391,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"978-1-7281-4922-620$31.00 ©2020 IEEE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[484,959,512,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"208 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,980,867,994]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,99,487,127]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"our knowledge, SNN based CPG with autonomous learning ability has not been explored yet.. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,128,487,270]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this work, we demonstrate an end-to-end spiking neural network carrying out online processing of sensory information to generate gait learning in hexapod robots. Gyro sensor and camera provide the sensory inputs that are converted into reward signals reinforcing or depressing the weights to stochastically evolve the network to learn the tripod gait for locomotion. Thus we demonstrate a system where a legged robot learns to walk autonomously through interactions with the environment and by collecting data from its gyroscopic and camera sensors. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[201,286,359,298]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"II. PROPOSED SYSTEM \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,305,243,318]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. Network Architecture \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[141,324,418,465]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 3. Pseudo-code for the algorithm. For every time instance, the membrane voltages of neurons are updated to determine the neural spiking at the current time instance. After the corresponding legs are moved, the gyro sensor reading and visual sensor reading is updated to generate the reward signal for weight updates \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0209/11cb7d2c6b61bc26f6a048b8f3e986a19f74f01a414fceb037589967b82742bc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[68,486,489,532]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 2. Schematic of the neural connectivity within the network. The box forms the CPG driven by the input neuron and balance driven neuron. $\\\\mathrm{W}_{\\\\mathrm{in}}$ $\\\\mathrm{W_{Gyro}}$ and $\\\\mathrm{W_{CPG}}$ represent the weight matrices corresponding to the all-o-all connection. Only a few connections are shown in the figure due to space constraint \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,543,487,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The proposed CPG network consists of six leaky-integrate and fire (LIF) spiking neurons, each driving one leg of the hexapod robot shown in Fig. 1. In this work, we used a digital discretized version of LIF model [5]. The update of variables occurs at discrete time steps $t$ . The membrane voltage of LIF neurons take the injection current $I$ from spikes of other neuron and simultaneously decay with a leaky constant $\\\\alpha$ . When the membrane potential $V$ reaches a spiking threshold, a spike is issued and $V$ is reset to the resting potential (zero in our case). Thus, we have the discrete equation of membrane voltage: \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[213,685,487,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nV [ t + 1 ] = \\\\frac {V [ t ]}{\\\\alpha} + I \\\\tag {1}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[68,720,487,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The neurons are fully connected to each other with additive synapses. The CPG is driven by an input neuron with periodic input causing the CPG to fire and another neuron which fires only when the robots lose balance while walking. This neuron is a gyro sensor driven neuron referred as $\\\\mathrm{N}_{\\\\mathrm{Gyro}}$ . The CPG neurons have a refractory period of two time units. The compactness of the network enables its implementation on the Raspberry Pi board without any external infrastructural support. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,840,169,853]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. Algorithm \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,856,487,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 3 shows the pseudo-code for the algorithm. The weights are randomly initialized. Equations in step 7 and 8 show the voltage calculation for the LIF neurons where $\\\\alpha$ is the leak rate. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,99,924,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The voltages of all the LIF neurons in the CPG are calculated by calculating the current coming into each neuron from the input neuron, gyro sensor driven neuron and other CPG neurons. The current is assumed to be equal to the weight of the synapse if the pre-neuron has spiked and zero otherwise as shown in the equation of step 7. An output neuron fires when the voltage exceeds a predefined spiking threshold. At any time instance, the number of neurons firing result in movement of the corresponding legs in the forward direction. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,219,924,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For every time instance, visual and gyro inputs are received before and after the movement is completed. During the movement of the leg, gyro sensor reading provides information about the balance and at the completion of the movement the visual information from the camera conveys whether a forward movement has occurred. If the balance is lost, the gyro driven neuron fires in the next time instance and the moved leg is taken back to the initial position. If the balance is not lost the movement of the leg is completed making the body to move forward. The balance and movement are then fed into the reward calculation equation. The detailed experimental design for the weight updating is explained in the next section. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,396,700,409]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Algorithm 1 Learn to Walk \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,410,875,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1: Initialize weights randomly $W_{in}, W_{Gyro}, W_{CPG}$ \\\",\\\"2: Initialize CPG neuron voltages, $V_{CPG}[0] = 0$ \\\",\\\"3: Initialize Spikes $S_{in} = 1, S_{Gyro} = 0, S_{CPG} = 0$ \\\",\\\"4: for time $= 1$ to $T$ do \\\",\\\"5: Read camera and gyro sensor for initial reading \\\",\\\"6: for neuron $= 1$ to 6 do \\\",\\\"7: $I = W_{in}S_{in} + W_{Gyro}S_{Gyro} + W_{CPG}S_{CPG}$ \\\",\\\"8: $V_{neuron}[t] = V_{neuron}[t - 1] / \\\\\\\\alpha + I$ \\\",\\\"9: if $(V_{\\\\\\\\text{neuron}}[t] > V_{\\\\\\\\text{Thresh}})$ then \\\",\\\"10: Update Spike, $S_{CPG} = 1$ , $V_{neuron}[t] = 0$ \\\",\\\"11: Move Corresponding Leg \\\",\\\"12: end if \\\",\\\"13: end for \\\",\\\"14: Read camera and gyro sensor for final reading \\\",\\\"15: Calculate reward \\\",\\\"16: Update weights \\\",\\\"17: end for \\\"]\",\n \"page_idx\": \"1\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[623,716,805,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"III. EXPERIMENTAL SETUP \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,736,675,749]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. Reward Calculation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,752,924,885]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The reward combines both visual and gyro sensor inputs. The gyro sensor reward is partitioned into three categories as shown in Fig. 4. In the first case the robot moves less than three legs losing its balance and not moving forward. This results in a small positive reward to encourage more neurons to fire in the next time instance. The other case is when four or more neurons in the CPG fire making the corresponding legs to be raised, which results the robot losing balance and gives a small negative reward to make sure that the weights are depressed and fewer number of neurons fire in the next iteration. The final case \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,65,868,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[484,959,512,971]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"209 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,982,867,994]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,99,489,138]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is when the correct three legs are raised, and the robot maintains its balance even when the legs are lifted up in the air. A high positive reward is given now to make sure the action is repeated. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,140,490,366]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The other component of the reward comes from the visual input. We use the scan line based odometry method from [13] because of its low computational cost. If the balance is maintained because no leg is raised, it gives an erroneous positive reward to the system. This error can be fixed by using a binary decision algorithm taking difference between the images before and after the movement to distinguish whether the forward movement has occurred or not. A positive reward accompanies the forward movement and lack of any movement is penalized. This allows the robot to simultaneously learn how to balance itself while moving forward. It is important to ensure that the negative reward is not very high in magnitude, particularly in the first few iterations so that the network has enough time to explore and learn. A linear correction is applied to the movement-based reward making it steeper as the algorithm progresses. Therefore, the total reward at time instance $t$ is given by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[95,378,489,423]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nR e w a r d _ {t o t a l} [ t ] = R e w a r d _ {g y r o} + R e w a r d _ {v i s u a l} \\\\left[ \\\\frac {t}{T _ {1}} \\\\right] (2)\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[82,453,386,712]\",\n \"code_body\": \"1: for time = 1 to T do \\n2: Ginitial = Read gyro sensor \\n3: Complete the movement \\n4: Gfinal = Read gyro sensor \\n5: if (Gfinal - Ginitial > GThresh) then \\n6: balance lost \\n7: if (Number of legs moved > 3) then \\n8: RewardGyro = -2 \\n9: end if \\n10: if (Number of legs moved < 3) then \\n11: RewardGyro = +2 \\n12: end if \\n13: end if \\n14: if (Gfinal - Ginitial < GThresh) then \\n15: balance maintained \\n16: RewardGyro = +5 \\n17: end if \\n18: end for \",\n \"code_caption\": \"[\\\"Algorithm 2 Gyroscope Reward Calculation \\\"]\",\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": \"algorithm\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"code\"\n },\n {\n \"bbox\": \"[68,714,489,760]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 4. Pseudo-code for calculating the reward corresponding to gyro sensor reading. If the balance is maintained high positive reward is given. If the balance is lost, the reward is given such that the cumulative weights evolve 3 legs at a time \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,766,275,780]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. Synaptic Weight Updating \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,782,490,876]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Combining synaptic reinforcement with reward function has been utilized previously [14] speculating dopamine release as the biological parallel of reward signals. The weights are updated only for synapses connected to the CPG neurons firing at the current time instance. If neuron $i$ spikes at time step $t$ , then for all pre-synaptic neurons spiking at time step $t-1$ , the change of weight is calculated as given below \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[576,100,924,121]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nW _ {i j} [ t + 1 ] = W _ {i j} [ t ] + \\\\theta \\\\eta R e w a r d _ {\\\\text {t o t a l}} [ t ] \\\\tag {3}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[504,130,924,175]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"where $\\\\theta$ is the learning rate and $\\\\eta = \\\\text{random}(0,1)$ is the stochastic term. The learning rate has to be chosen carefully to maximize the convergence rate of learning process. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,180,697,193]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Hardware Development \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,195,926,317]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The system described above is implemented in hardware for verification of the correct gait pattern in an office environment shown in Fig. 1. We use an Adept RaspClaws Hexapod Robot as the locomotion platform. It is equipped with a Gy-521 MPU6050 MPU6050 gyro sensor Module and a pi camera to provide balance and visual input to a Raspberry pi 3 Model B+ processing unit. The quad-core processor of Raspberry Pi operates at $1.5\\\\mathrm{GHz}$ frequency. The schematic of connections and block diagram of the operations is shown in Fig. 5. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,319,921,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 5. Block diagram of the system of computation. Sensory inputs are processed on the Raspberry Pi board and the movement signals are generated and send out to the hexapod. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0543/3ae7cf96c111233b7515c2f7618054ab5b97db14a7a074fcffa9c7ff65daecb1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[608,549,821,562]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IV. RESULTS AND DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,571,660,584]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A. System Simulation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,587,926,712]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fig. 6 shows the simulation results of an example of learning process along the time. The robot starts its action with no movement and gradually begin to oscillate between moving 2 and 4 legs alternatively. When it finally enters the target gait (the tripod gait shown in Fig. 1), thereby earning a high reward, and the weights saturate thus sustaining the gait. Fig. 6(b) shows the total accumulated reward over time. The reward was initially negative before the correct gait is found. After that, it rapidly increases. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,716,921,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Fig. 6. The number of moving legs (a) and reward accumulated (b) during the learning process. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0347/2302c594ae1dc715027c78b4ce57be0774a9fde2fd3a7c3d7743eab438756070.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[68,65,868,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[484,958,512,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"210 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,980,867,994]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[70,100,201,112]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"B. Demonstration \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,116,492,264]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We apply the proposed method to an Adept hexpod robot with the hardware configuration depicted in section III.C. In the first experimental demonstration (demo-1)<sup>1</sup>, the learning process converged to the target gait pattern at the 66th cycle (4:10). We also note (demo 2) that the learning process converges to an unwanted alternative gait pattern at the 7th cycle (0:18). This gait pattern is a local minimum during the learning process. The hexapod can move also forward with this gait, but it is less efficient when compared to the bio-mimetic target gait. The occasional tremor of servos is caused by instantaneous drops in the current supply. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,269,238,282]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C. Parameter Selection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,286,492,540]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In order to identify the best learning rate, we simulated 100 iterations of the algorithm with different random seeds for different learning rates. This is shown in Fig. 7. Fig. 7(a) shows the percentage of simulations converging to the correct tripod gait. The results show that the convergence percentage remains similar over a range of learning rates. We choose 0.1 as the learning rate as it shows the lowest number of non-convergent cases. The non-convergent cases do not mean that no locomotion takes place. These cases correspond to an inefficient final gait, where the hexapod makes frequent turns and does not move forward in every step. Fig. 7(b) shows the convergence time for the iterations that converge to the desired gait. The median convergence time is 207 iterations for learning rate of 0.1. Fig. 7(c) shows the weight maps of synapses forming the connections between the CPG neurons before and after the completion of the learning. For the convergence to the global minima of tripod gait, the initially random weights between the neurons evolve into a pattern such that neurons 1,3,5 drive neurons 2,4,6 and vice versa. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[70,559,322,572]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"D. Comparison with the Prior Work \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,574,490,737]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The simple two-layer spiking network used in this network is expected to show high reduction in energy required in learning as opposed to conventional approaches involving artificial neural networks. We calculate the total number of spikes issued by the CPG in the course of learning to estimate the energy spent in learning. The median of total number of spikes issued is 503. If these dynamics were implemented in a specialized SNN processor, such as Intel's Loihi platform (1.7 nJ/spike [14]), then the total energy consumption in the learning process will be $855.1\\\\mathrm{nJ}$ . Along with the low energy consumption, this work also shows that online SNN training can enable a hexapod to learn how to walk by a simple reward mechanism. (Table. 1) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[218,749,341,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"V. CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,766,490,861]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We design a closed-loop end-to-end online training of central pattern generator based on a bio-plausible spiking neural network. We have applied the proposed neuromorphic CPG to a hexapod robot and achieve autonomous online reinforcement learning of biomimetic walking gaits in an energy efficient manner. This online learning system is implemented on a resource-constrained embedded system. The learning process \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,99,927,138]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"converges to the desired bio-observed tripod in $70\\\\%$ of the cases while in other cases it converges to suboptimal gaits that can still enable the locomotion. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,174,712,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(a) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0191/8fc1f7aad00fef397676ad2a495e37caf5adf68d9a2f899346c0bafba6fe7258.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[729,174,917,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(b) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0275/761b8eebf9fa5ee9451677e915f5d87d8d75805611973ac5f6264dda415c9989.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[522,287,626,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"(c) \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0630/6a72e9315a7d5452b1d29b04becbd9a02d92d7ea53523893b31148e11d087f41.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[682,298,769,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Correct Convergence \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0535/954cbf643f25fef1975f6bb31011d75a42a11b69fe7518ce7fe242d50a9c4449.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[818,298,902,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Incorrect Convergence \\\",\\\"Fig. 7(a) Distribution of convergence time with learning rate. Median convergence time is 207-time instances. (b) Percentage of simulations converging to bio-observed tripod gait is independent of the learning rate. Simulations not converging to tripod gait are trapped in local minima that still enabling the locomotion is shown in demo 2. (c) Weight matrices of the CPG connections before and after the training. With the convergence to the global minima exhibiting tripod gait as shown in video demo - 1. In this configuration the neurons form a group of 3 reinforcing each other. In the other case the weights evolve into a configuration with inefficient walking gait still ensuring locomotion as shown in demo - 2 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0764/0648ef907df4d8492a14fe332bd06d493c083f9d1430fd61c13a788238d0baa9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[515,515,921,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0225/8151cd1d712990a584b6ae900262d85f98e412ed450d4c6fcc15e84e30a8ceb5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Ref</td><td>Training Approach</td><td>Sensory Feedback</td><td>Online /Offline</td></tr><tr><td>[16]</td><td>Linear Programming</td><td>None</td><td>Offline</td></tr><tr><td>[17]</td><td>Grammar Evolution</td><td>None</td><td>Offline</td></tr><tr><td>[18]</td><td>Reward + STDP</td><td>Olfactory + visual</td><td>Offline</td></tr><tr><td>This Work</td><td>Stochastic RL</td><td>Balance + visual</td><td>Online</td></tr></table>\",\n \"table_caption\": \"[\\\"Table. I Benchmarking Comparison to previous SNN CPG approaches \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[643,665,786,676]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGEMENT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,681,924,722]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was supported by C-BRIC, one of six centers in JUMP, a Semiconductor Research Corporation (SRC) program sponsored by DARPA. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[670,750,761,762]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,766,924,842]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] N. Bernstein. The Coordination and Regulation of Movements. Pergamon Press, Oxford, 1967. \\\",\\\"[2] T.G. Brown, “The intrinsic factors in the act of progression in the mammal.” Proc. R. Soc. Ser. B https://doi.org/10.1098/rspb.1911.0077 (1911). \\\",\\\"[3] A.I. Selverston, \\\\\\\"Invertebrate central pattern generator circuits.\\\\\\\" Philos Trans R Soc Lond B Biol Sci. 365(1551), pp.2329-2345. 2010 \\\"]\",\n \"page_idx\": \"3\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[70,65,868,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[87,875,307,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Demo-1: https://youtu.be/1HqeISAkAs4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[89,887,307,899]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Demo-2: https://youtu.be/ypW0V23gEj0 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_footnote\"\n },\n {\n \"bbox\": \"[484,959,510,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"211 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,982,867,994]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[72,99,489,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[4] D. Owaki, and A. Ishiguro. “A quadruped robot exhibiting spontaneous gait transitions from walking to trotting to galloping.” Scientific Reports, 7(1), p.277. \\\",\\\"[5] H. Rostro-Gonzalez, et al. “A CPG system based on spiking neurons for hexapod robot locomotion.” Neurocomputing, 170, pp.47-54. 2015 \\\",\\\"[6] X. Guo, L. Chen, Y. Zhang, P. Yang, and L. Zhang, \\\\\\\"A study on control mechanism of above knee robotic prosthesis based on CPG model.\\\\\\\" In Proc. IEEE International Conference on Robotics and Biomimetics (pp. 283-287). 2010. \\\",\\\"[7] P.A. Merolla, et al \\\\\\\"A million spiking-neuron integrated circuit with a scalable communication network and interface.\\\\\\\" Science, 345(6197), 668-673, 2014. \\\",\\\"[8] M. Davies, et al 2018. \\\\\\\"Loihi: A neuromorphic manycore processor with on-chip learning.\\\\\\\" IEEE Micro, 38(1), pp.82-99. 2018. \\\",\\\"[9] A. Espinal, H. Rostro-Gonzalez, M. Carpio, E.I. Guerra-Hernandez, M. Ornelas-Rodriguez, and M. Sotelo-Figueroa, \\\\\\\"Design of spiking central pattern generators for multiple locomotion gaits in hexapod robots by christiansen grammar evolution.\\\\\\\" Frontiers in neurorobotics, 10, p.6. 2016. \\\",\\\"[10] R.V. Florian, “Reinforcement learning through modulation of spike-timing-dependent synaptic plasticity.” *Neural Computation*, 19(6), pp.1468-1502. 2007 \\\",\\\"[11] E. Rueckert, D. Kappel, D. Tanneberg, D. Pecevski, and J. Peters, \\\\\\\"Recurrent spiking networks solve planning tasks.\\\\\\\" Sci. Rep. 6:21142. doi: 10.1038/srep21142.2016. \\\",\\\"[12] E. Nichols, L.J. McDaid, and N. Siddique, Biologically inspired snn for robot control. IEEE Trans. Cybern. 43, 115-128. 2013. \\\",\\\"[13] Milford, Michael, and Gordon Wyeth. \\\\\\\"Mapping a suburb with a single camera using a biologically inspired SLAM system.\\\\\\\" IEEE Transactions on Robotics 24.5 (2008): 1038-1053. \\\",\\\"[14] Izhikevich, Eugene M. \\\\\\\"Solving the distal reward problem through linkage of STDP and dopamine signaling.\\\\\\\" *Cerebral cortex* 17.10 (2007): 2443-2452. \\\",\\\"[15] Davies, Mike, et al. \\\\\\\"Loihi: A neuromorphic manycore processor with on-chip learning.\\\\\\\" IEEE Micro 38.1 (2018): 82-99. \\\",\\\"[16] Rostro-Gonzalez, Horacio, et al. \\\\\\\"A CPG system based on spiking neurons for hexapod robot locomotion.\\\\\\\" Neurocomputing 170 (2015): 47-54. \\\",\\\"[17] Espinal, Andres, et al. \\\\\\\"Design of spiking central pattern generators for multiple locomotion gaits in hexapod robots by christiansen grammar evolution.\\\\\\\" Frontiers in neurorobotics 10 (2016): 6. \\\",\\\"[18] Patanè, Luca, Roland Strauss, and Paolo Arena. Nonlinear Circuits and Systems for Neuro-inspired Robot Control. Springer, 2018 \\\"]\",\n \"page_idx\": \"4\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[72,66,868,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"> REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT)< \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[484,959,512,969]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"212 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[122,982,867,992]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Authorized licensed use limited to: Macquarie University. Downloaded on May 31,2020 at 12:23:14 UTC from IEEE Xplore. Restrictions apply. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1109/aicas48895.2020.9073987"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Engineering and Manufacturing Science"},"sha256":{"kind":"string","value":"31729b51ef3f19e293a6b2143708223c0721abef78a69324abf0bbeccf56801e"},"title":{"kind":"string","value":"Learning to Walk: Spike Based Reinforcement Learning for Hexapod Robot Central Pattern Generation"}}},{"rowIdx":180,"cells":{"abstract":{"kind":"string","value":"Contextual fear conditioning (CFC) is mediated by a neural circuit that includes the hippocampus, prefrontal cortex, and amygdala, but the neurophysiological mechanisms underlying the regulation of CFC by neuromodulators remain unclear. Dopamine D1-like receptors (D1Rs) in this circuit regulate CFC and local synaptic plasticity, which is facilitated by synchronized oscillations between these areas. In rats, we determined the effects of systemic D1R blockade on CFC and oscillatory synchrony between dorsal hippocampus (DH), prelimbic (PL) cortex, basolateral amygdala (BLA), and ventral hippocampus (VH), which sends hippocampal projections to PL and BLA. D1R blockade altered DH-VH and reduced VH-PL and VH-BLA synchrony during CFC, as inferred from theta and gamma coherence and theta-gamma coupling. D1R blockade also impaired CFC, as indicated by decreased freezing at retrieval, which was characterized by altered DH-VH and reduced VH-PL, VH-BLA, and PL-BLA synchrony. This reduction in VH-PL-BLA synchrony was not fully accounted for by non-specific locomotor effects, as revealed by comparing between epochs of movement and freezing in the controls. These results suggest that D1Rs regulate CFC by modulating synchronized oscillations within the hippocampus-prefrontal-amygdala circuit. They also add to growing evidence indicating that this circuit synchrony at retrieval reflects a neural signature of learned fear."},"author":{"kind":"string","value":"Stubbendorff, Christine|Hale, Ed|Bast, Tobias|Cassaday, Helen J.|Martin, Stephen J.|Suwansawang, Sopapun|Halliday, David M.|Stevenson, Carl W."},"content_list":{"kind":"list like","value":[{"bbox":"[154,166,238,189]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,164,924,350]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dopamine D1-like receptors modulate synchronized oscillations in the hippocampal–prefrontal–amygdala circuit in contextual fear ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[255,360,912,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Christine Stubbendorff $^{1,6}$ , Ed Hale $^{1,7}$ , Tobias Bast $^{2,3}$ , Helen J. Cassaday $^{2,3}$ , Stephen J. Martin $^{4}$ , Sopapun Suwansawang $^{5,8}$ , David M. Halliday $^{5}$ & Carl W. Stevenson $^{1,3}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[258,402,929,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Contextual fear conditioning (CFC) is mediated by a neural circuit that includes the hippocampus, prefrontal cortex, and amygdala, but the neurophysiological mechanisms underlying the regulation of CFC by neuromodulators remain unclear. Dopamine D1-like receptors (D1Rs) in this circuit regulate CFC and local synaptic plasticity, which is facilitated by synchronized oscillations between these areas. In rats, we determined the effects of systemic D1R blockade on CFC and oscillatory synchrony between dorsal hippocampus (DH), prelimbic (PL) cortex, basolateral amygdala (BLA), and ventral hippocampus (VH), which sends hippocampal projections to PL and BLA. D1R blockade altered DH-VH and reduced VH-PL and VH-BLA synchrony during CFC, as inferred from theta and gamma coherence and theta-gamma coupling. D1R blockade also impaired CFC, as indicated by decreased freezing at retrieval, which was characterized by altered DH-VH and reduced VH-PL, VH-BLA, and PL-BLA synchrony. This reduction in VH-PL-BLA synchrony was not fully accounted for by non-specific locomotor effects, as revealed by comparing between epochs of movement and freezing in the controls. These results suggest that D1Rs regulate CFC by modulating synchronized oscillations within the hippocampus-prefrontal-amygdala circuit. They also add to growing evidence indicating that this circuit synchrony at retrieval reflects a neural signature of learned fear. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[253,638,931,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Learning that certain environments predict threat is adaptive and can be investigated using contextual fear conditioning (CFC) in rodents. During CFC, unsignalled presentation of an aversive unconditioned stimulus (US; e.g. footshock) typically occurs in a novel context. This results in the encoding of a representation of the context, which becomes associated with the US. Fear-related behavior (e.g. freezing) is then elicited in the conditioned context during later memory retrieval<sup>1</sup>. CFC provides a useful model for studying the neurobiological mechanisms underpinning emotional learning, which is also translationally relevant since aberrant emotional memory processing is a key feature of various anxiety-related disorders<sup>2,3</sup>. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[253,728,931,794]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CFC requires coordinated activity within a distributed neural network that includes the hippocampus, amygdala, and prefrontal cortex (PFC). The context representation is thought to be encoded in dorsal hippocampus (DH) and conveyed to basolateral amygdala (BLA) for association with the US representation $^{1,2,4,5}$ . Other evidence indicates that DH is also involved in forming and storing the context-US association $^{3,6}$ . Prelimbic (PL) PFC plays a role in processing the context and US representations through its inter-connections with DH and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[253,827,931,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK. $^{2}$ School of Psychology, University of Nottingham, University Park, Nottingham, UK. $^{3}$ Neuroscience@ Nottingham, University of Nottingham, Nottingham, UK. $^{4}$ Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. $^{5}$ School of Physics, Engineering and Technology, York Biomedical Research Institute, University of York, Heslington, York, UK. $^{6}$ Present address: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. $^{7}$ Present address: Envigo, Hillcrest, Dodgeford Lane, Belton LE12 9TE, UK. $^{8}$ Present address: Faculty of Science and Technology, Nakhon Pathom Rajabhat University, Nakhon Pathom, Thailand. $^{\\text{串}}$ email: christine.stubbendorff@ iit.it; carl.stevenson@nottingham.ac.uk ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[652,14,922,30]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[63,63,450,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"scientific reports ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[811,136,831,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"# ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[836,140,927,150]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,280,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[376,965,633,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"| https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[919,965,931,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[260,60,929,86]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"BLA $^{7-9}$ . Importantly, DH projects to BLA and PL indirectly through ventral hippocampus (VH), which is also involved in encoding representations of the context and US via its inter-connections with BLA and $\\mathrm{PL}^{10-16}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,86,931,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In contrast to the neural circuit basis of CFC, its regulation by neuromodulators remains unclear $^{17}$ . Dopamine regulates CFC via D1-like receptor (D1R) signalling in the hippocampal-prefrontal-amygdala circuit $^{18}$ . These brain areas receive midbrain dopamine projections and express D1Rs $^{19-21}$ . D1R signalling modulates activity in these areas by tuning the balance between excitatory and inhibitory inputs. D1R modulation of this excitability therefore exerts a strong influence on local activity and functional interactions in this circuit $^{18}$ . Systemic D1R blockade impairs the acquisition of contextual fear $^{22-24}$ . In terms of the brain areas involved, blocking D1Rs locally in DH, PL, or BLA, but not VH, disrupts $\\mathrm{CFC}^{23,24}$ . D1R blockade also interferes with in vitro and in vivo long-term potentiation (LTP), a model of synaptic plasticity that underpins learning, in these areas $^{25-27}$ . While it is hypothesized that D1Rs regulate CFC by modulating synaptic plasticity in this circuit $^{18}$ , the neurophysiological mechanisms linking D1R modulation of LTP and CFC remain unclear. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,214,931,318]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Synaptic plasticity underpinning learning is facilitated by synchronized rhythmic oscillations that mediate communication between inter-connected brain areas. Theta and gamma synchrony and phase-amplitude coupling (PAC) in the hippocampal–prefrontal–amygdala circuit are important for learned fear processing[28-33]. Interestingly, D1Rs modulate oscillatory activity in and synchrony between these areas[34-41], raising the possibility that D1R blockade impairs LTP and CFC by disrupting synchronized oscillations in this circuit. In this study we examined the effects of systemic D1R blockade on theta and gamma oscillations in DH, VH, PL, and BLA during CFC. Since synchronized oscillations and PAC in this circuit play a role in fear memory retrieval[28-32,42-44], we also examined the effects of impaired CFC by D1R blockade on oscillatory synchrony between these areas at retrieval. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,331,319,343]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,345,448,358]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"D1R blockade impairs CFC ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,358,931,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine if D1Rs regulate CFC, we examined the effects of the selective D1R antagonist SCH23390 given systemically $(0.1\\mathrm{mg / kg}$ i.p.) before CFC on freezing at retrieval (Fig. 1A-C). SCH23390 $(n = 20)$ impaired CFC, as indicated by reduced freezing during retrieval testing, compared to vehicle-treated controls $(n = 22)$ . For freezing throughout the test session (Fig. 1B), an unpaired t-test revealed that SCH23390 resulted in decreased freezing, compared to vehicle $(t_{(40)} = 2.65, P = 0.012)$ . This was confirmed by the time course analysis (Fig. 1C), which showed that SCH23390 resulted in decreased freezing throughout retrieval, compared to vehicle. Two-way ANOVA revealed a significant main effect of treatment $(F_{(1,40)} = 7.01, P = 0.012)$ but no main effect of time $(F_{(4,160)} = 2.32, P = 0.059)$ or treatment $\\times$ time interaction $(F_{(4,160)} = 0.74, P = 0.57)$ . This confirms previous results showing that SCH23390 impairs $\\mathrm{CFC}^{22-24}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,487,929,514]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acute D1R blockade alters intra-hippocampal and reduces hippocampal-prefrontal and hippocampal-amygdala synchrony during conditioning ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,514,931,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Examples of electrode placements in and local field potentials (LFPs) recorded from each area before US presentations during CFC are shown in Fig. 1D. Schematic representations of theta $(4 - 12\\mathrm{Hz})$ , low gamma $(30 - 45\\mathrm{Hz})$ and high gamma $(55 - 80\\mathrm{Hz})$ oscillations, and theta-gamma PAC, are shown in Fig. 1E. Compared to the behavioral data analysis, fewer rats were included in the electrophysiological data analyses because of missed electrode placements or electrical noise artefacts contained in the data. For the analyses comparing between epochs of movement and freezing at retrieval in vehicle-treated controls, the numbers of controls included in these comparisons were unequal because some animals had no movement or freezing epochs based on the criteria defined for their inclusion in the analyses (see Methods). The numbers of animals included in the final datasets for each comparison (SCH23390 vs. vehicle treatment; movement vs freezing in vehicle-treated controls) are indicated in Figs. 2, 3, 4, 5, 6, and 7. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,641,931,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine if D1Rs modulate theta oscillations in the hippocampus–prefrontal–amygdala circuit during the conditioning session, we examined the acute effects of SCH23390 on theta power in each area in the 2 min period before US presentations during CFC (Fig. 2A). Differences between SCH23390 and vehicle treatment in power at each individual frequency throughout the theta band were quantified using a log ratio test. In vehicle-treated controls there was a prominent peak $\\sim 7 - 8\\mathrm{Hz}$ in hippocampus, whereas this peak was less pronounced in PL and BLA. In DH, SCH23390 decreased peak theta power $(7 - 9\\mathrm{Hz})$ and increased power outside the peak $(4 - 6$ and $11 - 12\\mathrm{Hz})$ , compared to vehicle $(P < 0.001)$ . The largest effect of SCH23390 on theta power was observed in VH, where it reduced peak power $(7 - 9\\mathrm{Hz})$ while also increasing power at higher frequencies $(11 - 12\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . SCH23390 had no effect on theta power in PL or BLA. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,757,931,870]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine if D1Rs modulate theta synchrony before CFC, we examined the acute effects of SCH23390 on theta coherence in this circuit (Fig. 2B). Differences between SCH23390 and vehicle treatment in coherence between the areas sharing direct anatomical connections (i.e. DH-VH, VH-PL, VH-BLA, and PL-BLA) were quantified at each individual frequency throughout the theta band using a chi-squared difference of coherence test. Vehicle-treated controls showed peaks for theta coherence $\\sim 7 - 9\\mathrm{Hz}$ . SCH23390 decreased peak theta coherence between DH and VH $(7 - 8\\mathrm{Hz})$ , while increasing coherence outside the peak $(4 - 6$ and $11 - 12\\mathrm{Hz})$ , compared to vehicle $(P < 0.001)$ . The largest effects of SCH23390 were observed on VH-PL and VH-BLA theta coherence, where SCH23390 decreased coherence throughout the theta band, compared to vehicle $(P < 0.001)$ . SCH23390 had no effect on theta coherence between PL and BLA. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,872,929,936]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine if D1Rs modulate gamma oscillations in this circuit before CFC, we examined the acute effects of SCH23390 on gamma power in each area (Fig. 2C). Differences between SCH23390 and vehicle treatment in power at each individual frequency throughout the low and high gamma bands were quantified using a log ratio test. No obvious peak frequencies were observed for gamma power in any area in vehicle-treated controls. In DH, there was no effect of SCH23390 on gamma power. 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D1R blockade impairs CFC. (A) Schematic representation of the behavioral testing paradigm used. Rats received a systemic injection of SCH23390 (SCH) or vehicle (VEH) $30\\\\mathrm{min}$ before conditioning, and LFPs were recorded during conditioning and retrieval testing. (B) SCH given before CFC decreased freezing at retrieval, compared to $\\\\mathrm{VEH} (^{*}\\\\mathrm{P} < 0.05)$ . (C) A time course analysis showed that SCH resulted in decreased freezing throughout retrieval, compared to $\\\\mathrm{VEH} (^{*}\\\\mathrm{P} < 0.05)$ . (D) Illustrative examples of electrode placements in (left; white arrows) and LFP signals recorded from (right) DH, VH, PL, and BLA. (E) Schematic representations of theta $(8\\\\mathrm{Hz})$ , low gamma $(40\\\\mathrm{Hz})$ , and high gamma $(70\\\\mathrm{Hz})$ oscillations, and theta-gamma PAC at the low and high gamma frequencies. \"]","image_footnote":"[]","img_path":"images/0173/1a4379ac50bc3fbebd9fa58c12d3bc696658e1a4e776436d8983602e61120763.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,15,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ 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D1R blockade alters DH-VH and reduces VH-PL and VH-BLA synchrony before CFC. (A) Acute effects of SCH23390 (SCH) on theta power before CFC. Peak theta power occurred $\\\\sim 7 - 8\\\\mathrm{Hz}$ in controls treated with vehicle (VEH). Compared to VEH, SCH decreased peak theta power and increased power outside the peak in DH and VH ( $*P < 0.001$ ), but not PL or BLA. (B) Acute effects of SCH on theta coherence before CFC. Peak theta coherence occurred $\\\\sim 7 - 9\\\\mathrm{Hz}$ with VEH. Compared to VEH, SCH decreased DH-VH peak theta coherence and increased DH-VH coherence outside the peak ( $*P < 0.001$ ). SCH decreased VH-PL and VH-BLA theta coherence, compared to VEH ( $*P < 0.001$ ), without affecting PL-BLA theta coherence. (C) Acute effects of SCH on gamma power before CFC. SCH had no effect on gamma power in DH. Compared to VEH, SCH increased gamma power in VH and PL ( $*P < 0.001$ ). SCH decreased high gamma power in BLA, compared to VEH ( $*P < 0.001$ ). 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D1R blockade enhances theta-gamma coupling between DH and VH before CFC. (A) Theta-gamma PAC in each area after vehicle (VEH) treatment, with blue and red indicating lower and higher gamma amplitude, respectively. Peak PAC occurred at a theta frequency $\\\\sim 5\\\\mathrm{Hz}$ in each area. (B) SCH23390 (SCH) had no effects on theta-gamma PAC in DH, VH, PL or BLA. (C) Theta-gamma PAC between areas with VEH, showing that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ . (D) SCH increased DH theta coupling of VH gamma, compared to VEH ( $^{*}\\\\mathrm{P} < 0.05$ ). SCH had no effects on VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC. \"]","image_footnote":"[]","img_path":"images/0759/39cf7dcf5d2c5475d30a810dfe529a760ae05250d6bed21bda23a269aaa94581.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[255,900,932,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"was observed in VH, where power was increased throughout the low and high gamma bands, compared to vehicle $(P < 0.001)$ . In PL, SCH23390 increased power at some low (31-32 and $44 - 45\\mathrm{Hz}$ ) and high $(78 - 79\\mathrm{Hz})$ gamma frequencies, compared to vehicle $(P < 0.001)$ . 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Impaired CFC by D1R blockade is associated with altered DH-VH and reduced VH-PL-BLA synchrony at retrieval. (A) Effects of SCH23390 (SCH) given before CFC on theta power at retrieval. Peak theta power occurred $\\\\sim 6 - 7\\\\mathrm{Hz}$ in controls treated with vehicle (VEH), while SCH shifted the peak to $\\\\sim 7 - 8\\\\mathrm{Hz}$ . In DH, SCH decreased lower and increased peak theta power, compared to VEH ( $*P < 0.001$ ). In VH, SCH decreased lower and increased higher theta power, compared to VEH ( $*P < 0.001$ ). In PL and BLA, SCH increased theta power, compared to VEH ( $*P < 0.001$ ). (B) Effects of SCH given before CFC on theta coherence at retrieval. SCH increased DH-VH and decreased VH-PL, VH-BLA, and PL-BLA theta coherence, compared to VEH ( $*P < 0.001$ ). (C) Effects of SCH given before CFC on gamma power at retrieval. A peak in low gamma power occurred $\\\\sim 35 - 40\\\\mathrm{Hz}$ in DH, VH, and BLA, but not PL, with VEH. In DH, SCH decreased low and increased high gamma power, compared to VEH ( $*P < 0.001$ ). In VH, SCH decreased peak low gamma power and increased low gamma power outside the peak, while increasing or decreasing power at various high gamma frequencies, compared to VEH ( $*P < 0.001$ ). In PL and BLA, SCH decreased gamma power, compared to VEH ( $*P < 0.001$ ). (D) Effects of SCH given before CFC on gamma coherence at retrieval. Peak low gamma coherence between DH and VH occurred at $35 - 40\\\\mathrm{Hz}$ with VEH, but no peaks were observed for coherence between the other areas. SCH decreased DH-VH peak low gamma coherence and increased low gamma coherence outside the peak, while increasing or decreasing coherence at various high gamma frequencies, compared to VEH ( $*P < 0.001$ ). SCH decreased VH-PL, VH-BLA, and PL-BLA gamma coherence, compared to VEH ( $*P < 0.001$ ). \"]","image_footnote":"[]","img_path":"images/0445/d814a47ea5af5c3a9106b7ea2dbf41e1bd9eaf53ffd93175b85eedc285d0951a.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,15,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 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5. Impaired CFC by D1R blockade is associated with enhanced theta-gamma coupling between DH and VH at retrieval. (A) Theta-gamma PAC in each area after prior vehicle (VEH) treatment, with lower and higher gamma amplitude indicated by blue and red, respectively. Peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ in each area. (B) SCH23390 (SCH) given before CFC had no effects on theta-gamma PAC in DH, VH, PL or BLA. (C) Theta-gamma PAC between areas with prior VEH treatment, showing that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ . (D) SCH given before CFC increased DH theta phase coupling of gamma amplitude in VH, compared to VEH ( $*\\\\mathrm{P} < 0.05$ ). SCH given before CFC had no effects on VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC. \"]","image_footnote":"[]","img_path":"images/0094/665dbb8a5be65bc0f32b1e0d85cabc0fd409829d46838aed696700f1b3e1ae7f.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[255,891,929,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and decreased high gamma power at various frequencies (60-61, 64-65, and $67 - 79\\mathrm{Hz}$ , compared to vehicle $(P < 0.001)$ . 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6. Movement and freezing in vehicle-treated controls are associated with differences in DH-VH and VH-PL-BLA synchrony at retrieval. (A) Differences between movement (MOV) and freezing (FRE) in theta power at retrieval. Peak theta power occurred $\\\\sim 7 - 8\\\\mathrm{Hz}$ with MOV. Compared to FRE, MOV increased peak theta power and decreased theta power outside the peak in DH and VH ( $*P < 0.001$ ). In PL and BLA, MOV increased theta power, compared to FRE ( $*P < 0.001$ ). (B) Differences between MOV and FRE in theta coherence at retrieval. Compared to FRE, MOV increased DH-VH, VH-BLA, and PL-BLA theta coherence ( $*P < 0.001$ ). MOV decreased VH-PL theta coherence, compared to FRE ( $*P < 0.001$ ). (C) Differences between MOV and FRE in gamma power at retrieval. A peak in low gamma power occurred $\\\\sim 35 - 40\\\\mathrm{Hz}$ with FRE in DH and VH, but not PL or BLA. In DH, MOV decreased low and increased high gamma power, compared to FRE ( $*P < 0.001$ ). In VH, MOV decreased low gamma power, while power was increased or decreased at various high gamma frequencies, compared to FRE ( $*P < 0.001$ ). In PL, MOV increased high gamma power, compared to FRE ( $*P < 0.001$ ). In BLA, MOV increased gamma power, compared to FRE ( $*P < 0.001$ ). (D) Differences between MOV and FRE in gamma coherence at retrieval. Peak low gamma coherence between DH and VH occurred $\\\\sim 35 - 40\\\\mathrm{Hz}$ with FRE, but there were no peaks for gamma coherence between other areas. MOV decreased DH-VH low gamma coherence, compared to FRE ( $*P < 0.001$ ). MOV decreased VH-PL high gamma coherence, compared to FRE ( $*P < 0.001$ ). MOV had no effects on VH-BLA or PL-BLA gamma coherence. \"]","image_footnote":"[]","img_path":"images/0547/a69ac7e596dbbae4ad3e23089e8f60cbf38221071edcda4a7b6882e9760eb2d9.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,15,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 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7. Movement in vehicle-treated controls enhances theta-gamma coupling in BLA at retrieval. (A) Theta-gamma PAC in each area during freezing (FRE), with lower and higher gamma amplitude indicated by blue and red, respectively. Peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ in each area. (B) Movement (MOV) had no effect on theta-gamma PAC in DH, VH, or PL. MOV increased theta coupling of low gamma in BLA, compared to FRE ( $^*P < 0.05$ ). (C) Theta-gamma PAC between areas during FRE, showing that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ . (D) MOV had no effects on DH theta-VH gamma, VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC. \"]","image_footnote":"[]","img_path":"images/0960/ad74a021bc3e44c76e5b5ee43019e21c9675b43ed65795f576b6ba27f6a11657.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[255,897,931,938]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"were quantified at each individual frequency throughout the low and high gamma bands using a chi-squared difference of coherence test. There were no obvious peak frequencies observed for gamma coherence in vehicle-treated controls. SCH23390 increased coherence between DH and VH at low (37-39 and $41 - 45\\mathrm{Hz}$ ) and high ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,15,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,633,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[921,965,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"9 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[260,61,929,125]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(56-57 and $60 - 62\\mathrm{Hz}$ ) gamma frequencies, compared to the low levels of gamma coherence observed with vehicle $(P < 0.001)$ . In contrast, coherence between VH and PL was decreased by SCH23390 at some low (30-31 and $35 - 36\\mathrm{Hz}$ ) and high (74-75 Hz) gamma frequencies, compared to vehicle $(P < 0.001)$ . SCH23390 also decreased gamma coherence between VH and BLA at low (30-33 and $35 - 45\\mathrm{Hz}$ ; $P < 0.001$ ) but not high gamma frequencies, compared to vehicle. SCH23390 had no effect on gamma coherence between PL and BLA, compared to vehicle. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,126,929,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine if D1Rs modulate theta-gamma coupling in this circuit before CFC, we examined the acute effects of SCH23390 on theta-gamma phase-amplitude coupling (PAC) in each area (Fig. 3A,B). Theta-gamma PAC was quantified using a modulation index. Although peak theta power in each area occurred $\\sim 7 - 8\\mathrm{Hz}$ (Fig. 2A), color plots of theta-gamma PAC in each area showed that peak theta phase coupling of gamma amplitude occurred $\\sim 5\\mathrm{Hz}$ with vehicle (Fig. 3A) or SCH23390 (not shown). Therefore we focused the analysis on this theta frequency. The quantitative analysis using two-way ANOVA found no acute effects of SCH23390 on theta-gamma PAC in any area (Fig. 3B and Table S1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,214,929,342]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We also examined the acute effects of SCH23390 on theta-gamma PAC between the directly inter-connected areas before CFC (Fig. 3C,D). Color plots of theta-gamma PAC between areas showed that peak PAC occurred $\\sim 5\\mathrm{Hz}$ with vehicle (Fig. 3C) or SCH23390 (not shown), therefore the analysis was focused on this theta frequency. Compared to vehicle, SCH23390 increased DH theta coupling of VH gamma (Fig. 3D). Two-way ANOVA revealed a significant main effect of treatment $(\\mathrm{F}_{(1,24)} = 4.41, P = 0.046)$ but no treatment x frequency interaction $(\\mathrm{F}_{(1,24)} = 1.75, P = 0.20)$ . For VH theta coupling of PL gamma, two-way ANOVA found no main effect of treatment $(\\mathrm{F}_{(1,21)} = 1.61, P = 0.22)$ but revealed a significant treatment x frequency interaction $(\\mathrm{F}_{(1,21)} = 4.53, P = 0.045)$ ; however, post-hoc testing found no difference between vehicle and SCH23390 treatment at low or high gamma frequencies. There were also no effects of SCH23390 on VH or PL theta coupling of BLA gamma (Table S1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,356,929,383]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Impaired CFC by D1R blockade is associated with altered intra-hippocampal and reduced hippocampal–prefrontal–amygdala synchrony at retrieval ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,384,929,498]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the association between hippocampal–prefrontal–amygdala theta oscillations and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on theta power in each area during later retrieval tested drug-free (Fig. 4A). Compared to theta power before CFC, there was less of a peak that was shifted to $6 - 7\\mathrm{Hz}$ in hippocampus, with much less prominent peaks in PL or BLA, in vehicle-treated controls. Overall, SCH23390 shifted the peak to $7 - 8\\mathrm{Hz}$ in each area. SCH23390 resulted in the biggest increase in peak theta power in DH $(7 - 8\\mathrm{Hz})$ , while also decreasing power at lower frequencies $(4 - 6\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . In VH, SCH23390 decreased power at lower $(5 - 7\\mathrm{Hz})$ and increased power at higher $(11 - 12\\mathrm{Hz})$ theta frequencies, compared to vehicle $(P < 0.001)$ . SCH23390 increased peak theta power in PL $(8 - 9\\mathrm{Hz})$ and BLA $(7 - 9\\mathrm{Hz})$ , compared to vehicle $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,500,929,586]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the association between theta synchrony and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on theta coherence in this circuit at retrieval (Fig. 4B). Compared to theta power, peaks for theta coherence were less pronounced or absent. Overall, SCH23390 increased theta coherence within hippocampus and decreased theta coherence between VH, PL, and BLA. SCH23390 increased coherence between DH and VH at higher theta frequencies $(8 - 12\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . In contrast, SCH23390 caused a large decrease in VH-PL, VH-BLA, and PL-BLA coherence throughout the theta band, compared to vehicle $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,588,929,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the association between gamma oscillations and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on gamma power in each area at retrieval (Fig. 4C). Compared to low gamma power before CFC, there was a peak at $35 - 40\\mathrm{Hz}$ in hippocampus and, to a lesser extent, in BLA and PL in vehicle-treated controls. In DH, SCH23390 decreased peak low gamma power $(35 - 43\\mathrm{Hz})$ and increased power throughout the high gamma band, compared to vehicle $(P < 0.001)$ . In VH, SCH23390 decreased peak low gamma power $(36 - 43\\mathrm{Hz})$ but increased low gamma power outside the peak $(30 - 34\\mathrm{Hz})$ while increasing power at some $(55 - 57$ and $59 - 60\\mathrm{Hz})$ and decreasing power at other $(78 - 79\\mathrm{Hz})$ high gamma frequencies, compared to vehicle $(P < 0.001)$ . In PL, SCH23390 decreased power at some low $(41 - 42\\mathrm{Hz})$ and most high $(58 - 80\\mathrm{Hz})$ gamma frequencies, compared to vehicle $(P < 0.001)$ . In BLA, SCH23390 decreased peak low gamma power $(37 - 41\\mathrm{Hz})$ and high gamma power at most frequencies $(55 - 66$ and $68 - 80\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,728,929,868]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the association between gamma synchrony and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on gamma coherence in this circuit at retrieval (Fig. 4D). Vehicle-treated controls showed a peak for low gamma coherence within hippocampus at $35 - 40\\mathrm{Hz}$ but there were no obvious peaks observed for gamma coherence between any other areas. SCH23390 decreased peak low gamma coherence between DH and VH $(36 - 42\\mathrm{Hz})$ and increased low gamma coherence outside the peak $(30 - 33\\mathrm{Hz})$ , while increasing coherence at some $(55 - 56\\mathrm{Hz})$ and decreasing coherence at other $(65 - 80\\mathrm{Hz})$ high gamma frequencies, compared to vehicle $(P < 0.001)$ . SCH23390 caused a large decrease in coherence between VH and PL throughout the low and high gamma bands, compared to vehicle $(P < 0.001)$ . SCH23390 also decreased coherence between VH and BLA at most low $(30 - 44\\mathrm{Hz})$ and high $(61 - 80\\mathrm{Hz})$ gamma frequencies, compared to vehicle $(P < 0.001)$ . Similarly, SCH23390 resulted in a large decrease in coherence between PL and BLA across the low and high gamma bands, compared to vehicle $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,869,929,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the association between theta-gamma coupling and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on theta-gamma PAC in each area at retrieval (Fig. 5A,B). Color plots of theta-gamma PAC in each area showed that peak PAC occurred $\\sim 5\\mathrm{Hz}$ with vehicle (Fig. 5A) or SCH23390 (not shown), thus we focused the analysis on this frequency. The quantitative analysis ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[0,0,1000,33]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,631,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,965,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[255,61,931,86]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"found no effects of impaired CFC by SCH23390 on theta-gamma PAC in any area at retrieval (Fig. 5B and Table S2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,86,931,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We also examined the effects of impaired CFC by prior SCH23390 administration on theta-gamma PAC between these areas at retrieval (Fig. 5C,D). Color plots of theta-gamma PAC between areas showed that peak PAC occurred $\\sim 5\\mathrm{Hz}$ with vehicle (Fig. 5C) or SCH23390 (not shown), therefore we focused the analysis on this frequency. Compared to vehicle, SCH23390 increased DH theta coupling of VH gamma (Fig. 5D). Two-way ANOVA revealed a significant main effect of treatment $(\\mathrm{F}_{(1,27)} = 5.03, P = 0.033)$ but no treatment $\\times$ frequency interaction $(\\mathrm{F}_{(1,27)} = 1.70, P = 0.20)$ . SCH23390 had no effects on VH theta coupling of gamma in PL or BLA; similarly, there was no effect of SCH23390 on PL theta coupling of BLA gamma (Table S2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,190,931,218]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reduced hippocampal–prefrontal–amygdala synchrony associated with impaired CFC by D1R blockade is not fully accounted for by increased movement at retrieval ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[255,218,931,306]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Because theta and gamma oscillations in these areas are associated with movement[45-47], and contextual fear was inferred from freezing, we also compared synchronized oscillations between epochs of movement and freezing during retrieval testing in the vehicle-treated controls. We reasoned that if the reduced freezing and associated oscillatory synchrony resulting from SCH23390 given before CFC simply reflected increased movement at retrieval then we would find a similar synchrony profile with movement, compared to freezing, in the controls at retrieval. However, if we found differences between these synchrony profiles then this may instead reflect different neural signatures for movement and contextual fear memory. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,306,931,384]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of hippocampal–prefrontal–amygdala theta oscillations in the controls at retrieval, movement was associated with a peak in theta power at $7 - 8\\mathrm{Hz}$ in each area (Fig. 6A). In DH, movement increased peak theta power $(7 - 9\\mathrm{Hz})$ and decreased theta power outside the peak $(4 - 6$ and $11 - 12\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ . In VH, movement also increased peak theta power $(8 - 9\\mathrm{Hz})$ , while theta power was also decreased outside the peak $(4 - 6$ and $11 - 12\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ . Movement increased peak theta power in PL $(8 - 9\\mathrm{Hz})$ and BLA $(7 - 9\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,384,931,473]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of theta synchrony in this circuit in the controls at retrieval, there were less obvious peaks in theta coherence with movement in comparison to theta power (Fig. 6B). Movement increased coherence between DH and VH at higher theta frequencies $(11 - 12\\mathrm{Hz})$ compared to freezing $(P < 0.001)$ . In contrast, movement decreased peak theta coherence $(6 - 7\\mathrm{Hz})$ between VH and PL, compared to freezing $(P < 0.001)$ . Movement increased coherence between VH and BLA across most theta frequencies $(4 - 11\\mathrm{Hz})$ compared to freezing $(P < 0.001)$ . Movement also increased peak theta coherence $(8 - 9\\mathrm{Hz})$ between PL and BLA, compared to freezing $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,473,931,576]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of gamma oscillations in this circuit in the controls at retrieval, freezing was associated with a peak in low gamma power at $35 - 40\\mathrm{Hz}$ in hippocampus, but not in PL or BLA (Fig. 6C). In DH, movement decreased low $(30 - 42\\mathrm{Hz})$ and increased high (55-67, 71-75, and $77 - 80\\mathrm{Hz}$ ) gamma power, compared to freezing $(P < 0.001)$ . In VH, movement also decreased low gamma power (30-32 and $34 - 42\\mathrm{Hz}$ ), while power was increased $(56 - 59\\mathrm{Hz})$ or decreased $(74 - 77\\mathrm{Hz})$ at various high gamma frequencies, compared to freezing $(P < 0.001)$ . In PL, movement had no effect on low and increased high gamma power (56-59, 64-65, 67-69, 72-75, and 78-80), compared to freezing $(P < 0.001)$ . In BLA, movement increased both low $(30 - 34$ and $44 - 45\\mathrm{Hz}$ ) and high $(55 - 63$ and $65 - 80\\mathrm{Hz}$ ) gamma power, compared to freezing $(P < 0.001)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,575,931,652]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of gamma synchrony in this circuit in the controls at retrieval, freezing was associated with a peak in low gamma coherence at $35 - 40\\mathrm{Hz}$ within hippocampus but not between any other areas (Fig. 6D). Movement abolished peak low gamma coherence between DH and VH $(35 - 41\\mathrm{Hz};P < 0.001)$ but had no effect on high gamma coherence, compared to freezing. Movement had no effect on low gamma coherence between VH and PL but decreased coherence at some high gamma frequencies $(70 - 71\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ Movement had no effect on gamma coherence between VH and BLA, or between PL and BLA. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,652,931,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In terms of theta-gamma coupling in this circuit in the controls at retrieval, color plots of theta-gamma PAC in each area showed that peak PAC occurred $\\sim 5\\mathrm{Hz}$ with freezing (Fig. 7A) or movement (not shown), therefore the analysis was focused on this frequency. The quantitative analysis found no differences between movement and freezing in DH, VH, or PL (Fig. 7B and Table S3). However, compared to freezing, movement increased theta coupling of low gamma in BLA. Two-way ANOVA showed no main effect of locomotion $(\\mathrm{F}_{(1,7)} = 4.05$ , $P = 0.084)$ but revealed a marginally significant locomotion $\\times$ frequency interaction $(\\mathrm{F}_{(1,7)} = 5.59$ , $P = 0.050)$ . Post-hoc testing confirmed that theta coupling of low gamma was significantly increased with movement, compared to freezing $(P < 0.05)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,755,931,856]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We also examined differences between movement and freezing in theta-gamma coupling between these areas in the controls at retrieval (Fig. 7C,D). Color plots of theta-gamma PAC between areas showed that peak PAC occurred $\\sim 5\\mathrm{Hz}$ with freezing (Fig. 7C) or movement (not shown), therefore we focused our analysis at this frequency. The quantitative analysis found no differences between movement and freezing on theta-gamma PAC between any areas at retrieval (Fig. 7D and Table S3). For DH theta coupling of VH gamma, two-way ANOVA found no main effect of locomotion $(\\mathrm{F}_{(1,19)} = 0.69$ $P = 0.42)$ but revealed a significant locomotion $\\times$ frequency interaction $(\\mathrm{F}_{(1,19)} = 4.97$ $P = 0.038)$ ; however, post-hoc testing found no difference between movement and freezing at low or high gamma frequencies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,870,346,883]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[255,884,931,937]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We determined the effects of systemic D1R blockade on CFC and associated synchronized oscillations in the hippocampal-prefrontal-amygdala circuit. The selective D1R antagonist SCH23390 impaired CFC and acted acutely to alter intra-hippocampal and reduce hippocampal-prefrontal and hippocampal-amygdala synchrony during conditioning. SCH23390 decreased peak theta coherence and increased gamma coherence and theta-gamma PAC ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,16,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports| (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,633,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,966,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"11 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[255,61,931,202]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"between DH and VH, while VH-PL and VH-BLA theta and gamma coherence were decreased. Impaired CFC by SCH23390 was associated with altered intra-hippocampal and reduced hippocampal-prefrontal-amygdala synchrony at retrieval. Prior SCH23390 decreased peak low gamma coherence and increased theta coherence and theta-gamma PAC between DH and VH, while resulting in decreased VH-PL, VH-BLA, and PL-BLA theta and gamma coherence (Fig. 8). This reduction in hippocampal-prefrontal-amygdala synchrony was not fully accounted for by non-specific increases in movement occurring with decreased freezing at retrieval. This was revealed by comparing between epochs of movement and freezing in the vehicle-treated controls, which showed that movement increased VH-BLA and PL-BLA theta coherence and had no effect on VH-BLA or PL-BLA gamma coherence (Table 1). These results provide evidence that D1R signalling regulates CFC by modulating synchronized oscillations in the hippocampal-prefrontal-amygdala circuit, which also reflect a neural signature of contextual fear memory. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,202,931,242]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our finding that SCH23390 impaired CFC, as indicated by decreased freezing at retrieval in comparison to vehicle, replicates our previous results[23,24]. In those studies, we showed that SCH23390 impairs the acquisition, but not consolidation, of contextual fear since SCH23390 given before, but not immediately after, conditioning ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,265,653,434]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0423/b7df0fe1af9363cccc49cb18338055fbc74b23fa9d6b12efc17481158ef257d6.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[257,445,652,612]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0576/f58df776e06b2758fd65da095dcbcf8c8a5c326adf1a8bde917cb523eab35a8b.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[257,625,650,790]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 8. Summary of the key effects of D1R blockade before CFC on hippocampal–prefrontal–amygdala synchrony before conditioning and at retrieval tested drug-free. (A) Dopamine projections from the ventral tegmental area (VTA) to DH, PL, and BLA (green lines) regulate CFC and local synaptic plasticity via D1R signalling. DH projects to PL and BLA indirectly through VH (black lines). (B) SCH23390 acts acutely before conditioning to alter intra-hippocampal (solid red line; decreased peak theta coherence, increased gamma coherence and theta-gamma PAC) and reduce hippocampal–prefrontal and hippocampal–amygdala (dashed red lines; decreased theta and gamma coherence) synchrony. (C) Impaired CFC by SCH23390 is associated with altered intra-hippocampal (solid red line; decreased gamma coherence, increased theta coherence and theta-gamma PAC) and reduced hippocampal–prefrontal–amygdala (dashed red lines; decreased theta and gamma coherence) synchrony at retrieval. \"]","image_footnote":"[]","img_path":"images/0414/81c808599c5f8b7101191e031df701234463d1e3c99ed9ade81fd7a2991e7b84.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,16,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,631,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,966,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"12 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[255,61,931,113]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"reduced freezing at retrieval. Moreover, this effect of SCH23390 did not involve state dependency, acute drug effects on shock sensitivity during conditioning, or lasting drug effects on locomotion at retrieval $24\\mathrm{h}$ later. This latter finding is in keeping with the brief $(\\sim 25\\mathrm{min})$ half-life of SCH23390 in rats[48]. Taken together, these results indicate that D1R signalling at the time of conditioning is important for contextual fear learning. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,112,931,253]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Systemic or local D1R blockade has acute effects on hippocampal $^{34-38}$ , prefrontal $^{39,40}$ , and amygdala $^{41}$ oscillations. However, less is known about D1R modulation of synchronized oscillations between these inter-connected areas. Intra-cerebroventricular SCH23390 infusion reduces theta phase synchrony between VH and PL under anesthesia $^{36}$ . SCH23390 infused into VH prevents the increase in phase-locking of PFC spike firing to VH theta that occurs during learning $^{37}$ . Our results showing that SCH23390 decreased theta and gamma coherence between VH and PL before CFC broadly agrees with these previous findings. We also found that SCH23390 decreased theta and gamma coherence between VH and BLA before CFC without affecting PL-BLA synchrony. In contrast, the effects of SCH23390 on DH-VH synchrony were more complex. SCH23390 decreased peak theta coherence but increased gamma coherence and theta-gamma PAC. This suggests that D1R signalling has different effects on the modulation of intra-hippocampal coupling and synchrony between hippocampus and its projection areas. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,253,931,484]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Our finding that impaired CFC by SCH23390 was characterized by reduced hippocampal–prefrontal–amygdala synchrony at retrieval generally agrees with evidence indicating that synchronized oscillations in this circuit are crucial for fear memory. Theta synchrony between hippocampus and PFC $^{49}$ or amygdala $^{50-52}$ is enhanced during contextual fear retrieval. Moreover, hippocampal–amygdala theta synchrony is associated with long-term (24 h) but not short-term (30 min) contextual fear memory or fear expression per se. We examined VH–PL and VH–BLA synchrony since hippocampal projections to these areas occur through $\\mathrm{VH}^{10,11,13}$ . Our results showing that impaired CFC is associated with reduced VH–PL and VH–BLA theta coherence at retrieval confirm and extend these previous findings implicating hippocampal–prefrontal and hippocampal–amygdala theta synchrony in contextual fear memory. Our finding of reduced PL–BLA theta coherence with impaired CFC also broadly agrees with studies showing that prefrontal–amygdala theta synchrony is involved in auditory fear retrieval $^{53,54}$ . Similarly, we found reduced VH–PL, VH–BLA, and PL–BLA gamma coherence at retrieval with impaired CFC, suggesting that gamma synchrony between these areas also plays a role in contextual fear retrieval. This is compatible with evidence indicating that BLA gamma oscillations are important for contextual memory consolidation and that gamma coherence between BLA and various inter-connected areas is enhanced during learning $^{55-57}$ . However, impaired CFC was associated with more complex interactions between DH and VH at retrieval. While peak low gamma coherence between DH and VH was decreased, theta and higher gamma coherence and theta-gamma PAC were increased. This suggests that impaired CFC is characterized by differences in intra-hippocampal coupling and hippocampal–prefrontal–amygdala synchrony at retrieval. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,484,931,663]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A potential confounding issue for interpreting the effects of systemic D1R blockade on hippocampal–prefrontal–amygdala synchrony is that non-specific locomotor effects might be involved. SCH23390 acts acutely to decrease locomotion[22,23], while decreased freezing at retrieval resulting from impaired CFC by SCH23390 has the opposite effect to increase movement. Therefore opposing effects of SCH23390 acutely and during later retrieval might be expected if non-specific locomotor effects are involved. Although SCH23390 had the opposite effects on peak theta and low gamma coherence between DH and VH acutely and at retrieval, there were similar effects on DH-VH theta-gamma PAC, VH-PL theta and gamma coherence, and VH-BLA theta and gamma coherence under both conditions. To address this issue, we also compared hippocampal–prefrontal–amygdala synchrony between epochs of movement and freezing at retrieval in the vehicle-treated controls. If reduced freezing and VH-PL-BLA synchrony with impaired CFC by SCH23390 reflected a non-specific increase in locomotion at retrieval, then we expected to find a similar synchrony profile with movement in the controls, whereas differences between these synchrony profiles may indicate specific effects on contextual fear memory. Our results showed both similarities and differences in these synchrony profiles (Table 1). Movement increased theta and decreased peak low gamma coherence between DH and VH in controls, as we found with SCH23390. Movement ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[258,696,576,893]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0410/4fb4e34e435e435fbb9176be38d292a188a370af6054dd5ec395b7391c2936d3.jpg","list_items":null,"page_idx":"12","sub_type":null,"table_body":"<table><tr><td>Areas</td><td>Synchrony measure</td><td>SCH23390</td><td>Movement</td></tr><tr><td rowspan=\"3\">DH-VH</td><td>Theta coherence</td><td>↑</td><td>↑</td></tr><tr><td>Gamma coherence</td><td>↓/↑</td><td>↓</td></tr><tr><td>Theta-gamma PAC</td><td>↑</td><td>↔</td></tr><tr><td rowspan=\"3\">VH-PL</td><td>Theta coherence</td><td>↓</td><td>↓</td></tr><tr><td>Gamma coherence</td><td>↓</td><td>↓</td></tr><tr><td>Theta-gamma PAC</td><td>↔</td><td>↔</td></tr><tr><td rowspan=\"3\">VH-BLA</td><td>Theta coherence</td><td>↓</td><td>↑</td></tr><tr><td>Gamma coherence</td><td>↓</td><td>↔</td></tr><tr><td>Theta-gamma PAC</td><td>↔</td><td>↔</td></tr><tr><td rowspan=\"3\">PL-BLA</td><td>Theta coherence</td><td>↓</td><td>↑</td></tr><tr><td>Gamma coherence</td><td>↓</td><td>↔</td></tr><tr><td>Theta-gamma PAC</td><td>↔</td><td>↔</td></tr></table>","table_caption":"[\"Table 1. Comparison of effects of impaired CFC by SCH23390 versus movement in the vehicle-treated controls on hippocampal–prefrontal–amygdala synchrony at retrieval. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[65,16,337,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,633,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,966,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"13 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[260,61,931,150]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"also decreased VH-PL theta and gamma coherence in controls, albeit to a lesser extent than with SCH23390. However, VH-BLA and PL-BLA theta coherence were increased with movement in controls but decreased with SCH23390. Movement also had no effects on VH-BLA or PL-BLA gamma coherence in controls, whereas SCH23390 resulted in decreased gamma coherence between these areas. These results suggest that while the effects of SCH23390 on DH-VH and VH-PL synchrony at retrieval may have involved non-specific increases in movement, BLA synchrony with VH and PL during retrieval was instead more likely to have reflected a neural signature of contextual fear memory. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,152,931,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In summary, this study lends support to the idea that D1Rs regulate CFC by modulating hippocampal-prefrontal-amygdala synchrony. Synaptic plasticity in this circuitry, which is disrupted by local D1R blockade[25-27], is facilitated by synchronized oscillations[28,30,32]. Reduced synchrony between these areas is therefore a plausible neurophysiological mechanism by which D1R blockade disrupts the synaptic plasticity underlying CFC. This has implications for understanding how the various psychological processes involved are mediated by communication between these areas. D1R blockade locally in DH impairs CFC and LTP in this area[23,25], which may interfere with encoding the context representation and context-US association. Although blocking D1Rs locally in VH does not affect $\\mathrm{CFC^{24}}$ , our results suggest that altered synchrony between DH and VH by systemic D1R blockade may also play a role in disrupting CFC. Moreover, reduced VH-PL and VH-BLA synchrony with systemic D1R blockade may impair CFC by interfering with the context and US representations being conveyed from hippocampus to these areas[13,15]. In support of this idea, blocking D1Rs locally in PL impairs CFC and LTP in the VH-PL pathway[24,26]. Local D1R blockade in BLA also impairs CFC and LTP in this area[23,27], which may interfere with encoding the US representation and context-US association[58]. However, D1R modulation of VH-BLA plasticity[14,59] remains to be determined. It is worth noting that other areas inter-connected to this circuit may also play a role in D1R modulation of hippocampal-prefrontal-amygdala synchrony. The thalamic nucleus reuniens (RE) mediates hippocampal-prefrontal coupling via its reciprocal connections with these areas[60], while the PFC-RE and RE-BLA pathways have been implicated in various learned fear processes[32,61-63]. Moreover, D1Rs in RE regulate fear extinction memory and dopamine modulates theta oscillations in $\\mathrm{RE}^{64,65}$ , suggesting a potential role for RE in D1R modulation of synchrony in this circuit. Nevertheless, this study builds on our understanding of the hippocampal-prefrontal-amygdala circuit mechanisms underlying the neuromodulation of CFC by dopamine. It also confirms and adds to evidence indicating that communication within this circuitry is crucial for fear memory[28,30,32]. This may ultimately lead to novel insights on the neurobiological basis of anxiety-related disorders characterized by aberrant learned fear processing. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,457,332,471]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,473,319,484]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Animals ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,485,931,576]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"42 male Lister Hooded rats (Charles River, UK) weighing $280 - 390\\mathrm{g}$ before surgery were used. Rats were group housed in individually ventilated cages (2-3/cage) and kept on a $24\\mathrm{h}$ light/dark cycle (lights on at 7:00) with ad libitum access to food and water. All behavioral testing occurred during the rats' light cycle. All experimental procedures were performed with institutional ethical approval and under the UK Animals (Scientific Procedures) Act 1986 (Home Office Project Licence 30/3230). All experiments were performed in accordance with the relevant guidelines and regulations. All reporting for the study followed the recommendations in the ARRIVE guidelines (Essential 10;66). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,590,448,604]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Electrode implant surgery ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,604,931,809]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Anesthesia was induced with $\\sim 3\\%$ isoflurane in oxygen and analgesic (buprenorphine, $0.05\\mathrm{mg / kg}$ , s.c.) was administered immediately post-induction. Anesthesia was maintained with $1.5 - 2.5\\%$ isoflurane during surgery to ensure complete inhibition of the hindpaw withdrawal reflex. Rats were placed in a stereotaxic frame and the incisor bar was adjusted to maintain the skull horizontal. A homoeothermic heating pad was used to maintain body temperature at $36 - 37^{\\circ}C$ throughout surgery. A scalp incision was made along the midline, the periosteum was retracted, and 10 stainless steel anchoring screws were affixed to the top and sides of the skull. Small craniotomies were performed on the right side above the target coordinates and the dura mater was incised immediately before electrode implantation. Custom-made tungsten electrodes[67] were targeted at DH (CA1; $3.0\\mathrm{mm}$ posterior and $1.5\\mathrm{mm}$ lateral to bregma, $3.0\\mathrm{mm}$ ventral to the brain surface), VH (CA1; $5.0\\mathrm{mm}$ posterior and $4.8\\mathrm{mm}$ lateral to bregma, $6.3\\mathrm{mm}$ ventral to the brain surface), PL ( $2.5\\mathrm{mm}$ anterior and $0.5 - 0.8\\mathrm{mm}$ lateral to bregma, $3.0\\mathrm{mm}$ ventral to the brain surface), and BLA (basal nucleus; $2.8\\mathrm{mm}$ posterior and $4.7\\mathrm{mm}$ lateral to bregma, $7.2\\mathrm{mm}$ ventral to the brain surface)[68]. The electrodes were loaded into a microdrive (VersaDrive-8, Neuralynx, MT) and the implant was secured to the anchoring screws with light-cured dental cement (Henry Schein, UK). Another analgesic (meloxicam, $1\\mathrm{mg / kg}$ , s.c.) was given at the end of surgery. Rats were singly housed for 1-2 days after surgery, after which they were group housed as above. Buprenorphine and meloxicam were given once daily for 2-3 days after surgery. Behavioral testing commenced 6-8 days after surgery. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,823,363,837]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Drug injection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,837,931,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SCH23390 hydrochloride $(0.1\\mathrm{mg / kg},$ i.p.; Tocris Bioscience, UK) was dissolved in $0.9\\%$ sterile saline $(1\\mathrm{mL / kg})$ and injected 30 min before CFC (see below). We have previously shown that this dose impairs $\\mathrm{CFC}^{23,24}$ . Vehicle-treated controls received injections of $0.9\\%$ sterile saline $(1\\mathrm{mL / kg},$ i.p.). Animals were randomly assigned to receive SCH23390 or vehicle treatment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,902,393,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Behavioral testing ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,916,931,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The effects of systemic SCH23390 administration on CFC were investigated using a two-day conditioning and retrieval paradigm. Each rat was randomly allocated to receive SCH23390 or vehicle treatment before CFC. The ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[0,0,1000,33]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,631,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,966,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"14 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[260,58,931,202]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{apparatus}^{69}$ and experimental procedures $^{24}$ used have been described in detail elsewhere. On the first day rats underwent conditioning in a novel context that consisted of distinct visual, auditory, and olfactory cues present in the background during CFC. The US was a mild electric shock delivered through the chamber floor bars automatically via a PC running Med-PC IV software (Med Associates, VT). The rat was placed in the chamber and after 2 min was presented with four shocks (0.5 mA, 0.5 s, 1 min inter-trial interval). The rat was removed from the chamber 2 min after presentation of the last shock and returned to the home cage. On the second day the rat was returned to the same conditioning chamber for 5 min to test memory retrieval drug-free. The floor bars and waste tray were cleaned with $40\\%$ ethanol between each session. Rats were tested at approximately the same time of day on both days. Electrophysiological recordings (see below) were obtained during CFC and retrieval testing. Behavior during retrieval testing was recorded using a digital camera (ViewPoint, France) positioned above the chamber. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,216,487,231]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Electrophysiological recordings ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,231,931,294]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LFPs from the electrodes targeting each area were recorded during CFC and retrieval testing by connecting the microdrive via a headstage, cable, and pre-amplifier to an OmniPlex neural recording data acquisition system (Plexon Inc, TX). LFPs were band-pass filtered at $0.7 - 170\\mathrm{Hz}$ and digitized at $1.25\\mathrm{kHz}$ . A cable connecting the Med Associates and OmniPlex systems was used to record the start of the CFC and retrieval sessions, triggered by the Med-PC IV software, in the LFP data recording file. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,308,332,323]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Histology ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,322,931,411]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"After completing retrieval testing, rats were deeply anesthetized with sodium pentobarbital and current was passed through each electrode using an electrical stimulator to create a small lesion at the electrode tips. Rats were then perfused transcardially with $0.9\\%$ saline followed by $4\\%$ paraformaldehyde. The brains were removed, post-fixed in $4\\%$ paraformaldehyde, and kept at $4^{\\circ}\\mathrm{C}$ until slicing. Sections containing the relevant areas were obtained using a vibratome and stained for acetylcholinesterase (Fig. 1D). Only data from rats with histologically confirmed electrode placements in DH, VH, PL, and/or BLA were included in the electrophysiological data analysis. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,425,435,439]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Behavioral data analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,439,931,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Freezing, defined as the absence of movement except in relation to respiration, was taken as the behavioral measure of contextual fear during retrieval testing. Freezing was quantified automatically using VideoTrack software (ViewPoint, France) by setting the freezing detection threshold to 100 pixels change/frame (25 frames/sec), based on a comparison between automatically determined and manually scored freezing levels from our published data[24]. The cumulative duration of freezing during retrieval testing was calculated and expressed as a percentage of the 5 min test duration. Differences in freezing between the two groups were analyzed in two ways. Average freezing over the whole 5 min test session was analyzed using a two-tailed unpaired t-test, with the data presented in a bar graph as the mean + standard error of the mean (SEM). Freezing during each 1-min bin was also analyzed separately using two-way analysis of variance (ANOVA) with repeated measures, with treatment as the between-subjects factor and time as the within-subjects factor. Freezing during each 1-min bin was presented in a line graph as the mean + SEM. The level of significance for both analyses was set at $P < 0.05$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,594,505,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Electrophysiological data analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,609,931,710]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"LFP activity was analyzed using multi-taper spectral analysis as described elsewhere[70-72]. LFP recordings were inspected visually and data containing obvious electrical noise artefacts were omitted from the analysis. LFP signals were normalized to unit variance in each segment prior to spectral analysis. Normalization removes effects of changes in absolute power due to changes in electrode impedance, therefore we report on differences in relative power. Spectral estimates for LFP data from each area in the 2 min period before US presentations during CFC and in the 5 min retrieval test were generated using custom Matlab scripts. LFP recordings from all areas contained many electrical noise artefacts in the 2 min period after US presentations during CFC, which precluded analysis of the data from this period. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,710,931,875]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We first examined the acute effects of SCH23390 on theta (4–12 Hz), low gamma (30–45 Hz), and high gamma (55–80 Hz) power in each area during CFC. The gamma frequency band was divided into low and high frequencies to omit electrical mains noise ~ 50 Hz. Differences between SCH23390 and vehicle treatment in power at each individual frequency throughout the theta and gamma bands were quantified using the log ratio test. The acute effects of SCH23390 on theta, low gamma, and high gamma coherence between the areas sharing direct anatomical connections (i.e. DH–VH, VH–PL, VH–BLA, and PL–BLA) were then determined during CFC as measures of synchrony between these areas. Differences between SCH23390 and vehicle treatment in coherence at each individual frequency throughout the theta and gamma bands were quantified using the chi-squared difference of coherence test. Power and coherence data are presented as the mean +/− 95% pointwise confidence intervals. The level of significance for the statistical comparisons of power and coherence was set at $P < 0.001$ to correct for multiple comparisons across individual frequencies. Differences at individual frequencies were also considered as chance effects, therefore differences were only deemed significant where they were found for two or more adjacent frequencies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[260,877,931,941]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The acute effects of SCH23390 on theta-gamma PAC during CFC were quantified as described elsewhere[73-75] using custom Matlab scripts. Theta-gamma PAC was determined using a modulation index from the normalised mean vector length. Estimates were constructed using analytic Morse wavelets, with significance determined using surrogate data[75-77]. Amplitude information in each trial was split into five blocks, which were randomly permuted to yield a surrogate dataset for amplitude. Phases were shuffled randomly between the different ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[0,0,1000,33]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,631,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,966,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"15 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[255,61,931,240]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frequency components $^{78}$ . Each shuffled phase information obtained from the $i$ th frequency was randomly matched with the shuffled amplitude data from the $j$ th frequency, with $i$ and $j$ random integers. We examined theta-gamma PAC within each area and between the directly inter-connected areas. Specifically, we examined DH theta-VH gamma PAC since theta oscillations propagate from DH to $\\mathrm{VH}^{79,80}$ . We also examined VH theta-PL gamma PAC since hippocampal-prefrontal theta synchrony is mediated by $\\mathrm{VH}^{81,82}$ . Similarly, we examined VH theta-BLA gamma PAC since theta burst stimulation of VH modulates BLA activity and plasticity $^{83}$ . Finally, we examined PL theta-BLA gamma PAC since learned fear inhibition is associated with prefrontal theta coupling of BLA $\\mathrm{gamma}^{29}$ . Color plots of theta-gamma PAC within each area and between the directly inter-connected areas showed that peak theta phase coupling of gamma amplitude occurred at a theta frequency $\\sim 5\\mathrm{Hz}$ after vehicle or SCH23390 treatment, therefore we focused the analyses at this theta frequency. Theta-gamma PAC was analyzed using two-way ANOVA with repeated measures, with treatment as the between-subjects factor and gamma frequency band as the within-subjects factor. Post-hoc comparisons were conducted using the Sidak test where indicated. Theta-gamma PAC was presented in bar graphs as the mean + SEM and the level of significance for the analyses was set at $P < 0.05$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,241,931,381]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The effects of SCH23390 given before CFC on theta power and coherence, low and high gamma power and coherence, and theta-gamma PAC during retrieval testing drug-free were determined as above. We also examined differences in these neurophysiological measures between epochs of movement and freezing during retrieval testing in the vehicle-treated controls to determine if decreased freezing resulting from SCH23390 treatment before CFC was related specifically to impaired contextual fear or non-specifically to increased movement at retrieval. Freezing epochs were determined by considering intervals of a minimum of $0.5\\mathrm{s}$ where $< 100$ pixels change/frame (i.e. the freezing detection threshold) was detected, while movement epochs were determined by considering intervals of a minimum of $0.5\\mathrm{s}$ where $>500$ pixels change/frame was detected. The resulting LFP data from these intervals were then pooled within and between rats. Differences between movement and freezing in theta power and coherence, low and high gamma power and coherence, and theta-gamma PAC during retrieval testing were determined as above. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,392,394,407]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data availability ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[255,407,831,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All electrophysiology data and analysis code are freely available online (https://osf.io/km2s7/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,430,561,445]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received: 25 June 2023; Accepted: 12 October 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,446,460,457]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published online: 17 October 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[258,471,349,485]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[260,487,929,943]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. 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Neuron 87, 1290-1303 (2015). \"]","page_idx":"17","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[258,453,421,469]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgements ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[257,469,931,494]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was funded by a research grant from the Biotechnology and Biological Sciences Research Council [Grant Number BB/P001149/1]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,505,430,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author contributions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[255,519,931,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"C.S. and E.H. conducted the experiments. C.S., S.S., and D.M.H. analyzed the data. T.B., H.J.C., S.J.M., and C.W.S. conceived the study and designed the experiments. C.S. and C.W.S. drafted the manuscript. C.S., T.B., H.J.C., S.J.M., D.M.H., and C.W.S. revised the manuscript. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,570,425,585]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Competing interests ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[257,585,524,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors declare no competing interests. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,608,445,622]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Additional information ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[255,622,931,648]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Supplementary Information The online version contains supplementary material available at https://doi.org/10.1038/s41598-023-44772-6. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,654,752,668]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Correspondence and requests for materials should be addressed to C.S. or C.W.S. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,673,747,687]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reprints and permissions information is available at www.nature.com/reprints. 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","text_format":null,"text_level":null,"type":"text"},{"bbox":"[257,725,332,746]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0805/89b68b2a8fa4be53cc8939f839ecbd246651b720f1c21486ef9aa0cc2873e474.jpg","list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[334,725,931,751]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[255,751,931,828]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[258,838,394,852]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© The Author(s) 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,16,341,31]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.nature.com/scientificreports/ ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[65,965,290,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scientific Reports (2023) 13:17631 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[381,965,633,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"https://doi.org/10.1038/s41598-023-44772-6 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[786,964,880,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"natureportfolio ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[914,966,929,976]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"18 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[154,166,238,189]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,164,924,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dopamine D1-like receptors modulate synchronized oscillations in the hippocampal–prefrontal–amygdala circuit in contextual fear \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,360,912,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Christine Stubbendorff $^{1,6}$ , Ed Hale $^{1,7}$ , Tobias Bast $^{2,3}$ , Helen J. Cassaday $^{2,3}$ , Stephen J. Martin $^{4}$ , Sopapun Suwansawang $^{5,8}$ , David M. Halliday $^{5}$ & Carl W. Stevenson $^{1,3}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[258,402,929,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Contextual fear conditioning (CFC) is mediated by a neural circuit that includes the hippocampus, prefrontal cortex, and amygdala, but the neurophysiological mechanisms underlying the regulation of CFC by neuromodulators remain unclear. Dopamine D1-like receptors (D1Rs) in this circuit regulate CFC and local synaptic plasticity, which is facilitated by synchronized oscillations between these areas. In rats, we determined the effects of systemic D1R blockade on CFC and oscillatory synchrony between dorsal hippocampus (DH), prelimbic (PL) cortex, basolateral amygdala (BLA), and ventral hippocampus (VH), which sends hippocampal projections to PL and BLA. D1R blockade altered DH-VH and reduced VH-PL and VH-BLA synchrony during CFC, as inferred from theta and gamma coherence and theta-gamma coupling. D1R blockade also impaired CFC, as indicated by decreased freezing at retrieval, which was characterized by altered DH-VH and reduced VH-PL, VH-BLA, and PL-BLA synchrony. This reduction in VH-PL-BLA synchrony was not fully accounted for by non-specific locomotor effects, as revealed by comparing between epochs of movement and freezing in the controls. These results suggest that D1Rs regulate CFC by modulating synchronized oscillations within the hippocampus-prefrontal-amygdala circuit. They also add to growing evidence indicating that this circuit synchrony at retrieval reflects a neural signature of learned fear. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[253,638,931,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Learning that certain environments predict threat is adaptive and can be investigated using contextual fear conditioning (CFC) in rodents. During CFC, unsignalled presentation of an aversive unconditioned stimulus (US; e.g. footshock) typically occurs in a novel context. This results in the encoding of a representation of the context, which becomes associated with the US. Fear-related behavior (e.g. freezing) is then elicited in the conditioned context during later memory retrieval<sup>1</sup>. CFC provides a useful model for studying the neurobiological mechanisms underpinning emotional learning, which is also translationally relevant since aberrant emotional memory processing is a key feature of various anxiety-related disorders<sup>2,3</sup>. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[253,728,931,794]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CFC requires coordinated activity within a distributed neural network that includes the hippocampus, amygdala, and prefrontal cortex (PFC). The context representation is thought to be encoded in dorsal hippocampus (DH) and conveyed to basolateral amygdala (BLA) for association with the US representation $^{1,2,4,5}$ . Other evidence indicates that DH is also involved in forming and storing the context-US association $^{3,6}$ . Prelimbic (PL) PFC plays a role in processing the context and US representations through its inter-connections with DH and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[253,827,931,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK. $^{2}$ School of Psychology, University of Nottingham, University Park, Nottingham, UK. $^{3}$ Neuroscience@ Nottingham, University of Nottingham, Nottingham, UK. $^{4}$ Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. $^{5}$ School of Physics, Engineering and Technology, York Biomedical Research Institute, University of York, Heslington, York, UK. $^{6}$ Present address: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. $^{7}$ Present address: Envigo, Hillcrest, Dodgeford Lane, Belton LE12 9TE, UK. $^{8}$ Present address: Faculty of Science and Technology, Nakhon Pathom Rajabhat University, Nakhon Pathom, Thailand. $^{\\\\text{串}}$ email: christine.stubbendorff@ iit.it; carl.stevenson@nottingham.ac.uk \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[652,14,922,30]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[63,63,450,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"scientific reports \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[811,136,831,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"# \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[836,140,927,150]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Check for updates \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,280,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[376,965,633,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"| https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[919,965,931,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[260,60,929,86]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"BLA $^{7-9}$ . Importantly, DH projects to BLA and PL indirectly through ventral hippocampus (VH), which is also involved in encoding representations of the context and US via its inter-connections with BLA and $\\\\mathrm{PL}^{10-16}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,86,931,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In contrast to the neural circuit basis of CFC, its regulation by neuromodulators remains unclear $^{17}$ . Dopamine regulates CFC via D1-like receptor (D1R) signalling in the hippocampal-prefrontal-amygdala circuit $^{18}$ . These brain areas receive midbrain dopamine projections and express D1Rs $^{19-21}$ . D1R signalling modulates activity in these areas by tuning the balance between excitatory and inhibitory inputs. D1R modulation of this excitability therefore exerts a strong influence on local activity and functional interactions in this circuit $^{18}$ . Systemic D1R blockade impairs the acquisition of contextual fear $^{22-24}$ . In terms of the brain areas involved, blocking D1Rs locally in DH, PL, or BLA, but not VH, disrupts $\\\\mathrm{CFC}^{23,24}$ . D1R blockade also interferes with in vitro and in vivo long-term potentiation (LTP), a model of synaptic plasticity that underpins learning, in these areas $^{25-27}$ . While it is hypothesized that D1Rs regulate CFC by modulating synaptic plasticity in this circuit $^{18}$ , the neurophysiological mechanisms linking D1R modulation of LTP and CFC remain unclear. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,214,931,318]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Synaptic plasticity underpinning learning is facilitated by synchronized rhythmic oscillations that mediate communication between inter-connected brain areas. Theta and gamma synchrony and phase-amplitude coupling (PAC) in the hippocampal–prefrontal–amygdala circuit are important for learned fear processing[28-33]. Interestingly, D1Rs modulate oscillatory activity in and synchrony between these areas[34-41], raising the possibility that D1R blockade impairs LTP and CFC by disrupting synchronized oscillations in this circuit. In this study we examined the effects of systemic D1R blockade on theta and gamma oscillations in DH, VH, PL, and BLA during CFC. Since synchronized oscillations and PAC in this circuit play a role in fear memory retrieval[28-32,42-44], we also examined the effects of impaired CFC by D1R blockade on oscillatory synchrony between these areas at retrieval. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,331,319,343]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,345,448,358]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"D1R blockade impairs CFC \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,358,931,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine if D1Rs regulate CFC, we examined the effects of the selective D1R antagonist SCH23390 given systemically $(0.1\\\\mathrm{mg / kg}$ i.p.) before CFC on freezing at retrieval (Fig. 1A-C). SCH23390 $(n = 20)$ impaired CFC, as indicated by reduced freezing during retrieval testing, compared to vehicle-treated controls $(n = 22)$ . For freezing throughout the test session (Fig. 1B), an unpaired t-test revealed that SCH23390 resulted in decreased freezing, compared to vehicle $(t_{(40)} = 2.65, P = 0.012)$ . This was confirmed by the time course analysis (Fig. 1C), which showed that SCH23390 resulted in decreased freezing throughout retrieval, compared to vehicle. Two-way ANOVA revealed a significant main effect of treatment $(F_{(1,40)} = 7.01, P = 0.012)$ but no main effect of time $(F_{(4,160)} = 2.32, P = 0.059)$ or treatment $\\\\times$ time interaction $(F_{(4,160)} = 0.74, P = 0.57)$ . This confirms previous results showing that SCH23390 impairs $\\\\mathrm{CFC}^{22-24}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,487,929,514]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acute D1R blockade alters intra-hippocampal and reduces hippocampal-prefrontal and hippocampal-amygdala synchrony during conditioning \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,514,931,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Examples of electrode placements in and local field potentials (LFPs) recorded from each area before US presentations during CFC are shown in Fig. 1D. Schematic representations of theta $(4 - 12\\\\mathrm{Hz})$ , low gamma $(30 - 45\\\\mathrm{Hz})$ and high gamma $(55 - 80\\\\mathrm{Hz})$ oscillations, and theta-gamma PAC, are shown in Fig. 1E. Compared to the behavioral data analysis, fewer rats were included in the electrophysiological data analyses because of missed electrode placements or electrical noise artefacts contained in the data. For the analyses comparing between epochs of movement and freezing at retrieval in vehicle-treated controls, the numbers of controls included in these comparisons were unequal because some animals had no movement or freezing epochs based on the criteria defined for their inclusion in the analyses (see Methods). The numbers of animals included in the final datasets for each comparison (SCH23390 vs. vehicle treatment; movement vs freezing in vehicle-treated controls) are indicated in Figs. 2, 3, 4, 5, 6, and 7. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,641,931,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine if D1Rs modulate theta oscillations in the hippocampus–prefrontal–amygdala circuit during the conditioning session, we examined the acute effects of SCH23390 on theta power in each area in the 2 min period before US presentations during CFC (Fig. 2A). Differences between SCH23390 and vehicle treatment in power at each individual frequency throughout the theta band were quantified using a log ratio test. In vehicle-treated controls there was a prominent peak $\\\\sim 7 - 8\\\\mathrm{Hz}$ in hippocampus, whereas this peak was less pronounced in PL and BLA. In DH, SCH23390 decreased peak theta power $(7 - 9\\\\mathrm{Hz})$ and increased power outside the peak $(4 - 6$ and $11 - 12\\\\mathrm{Hz})$ , compared to vehicle $(P < 0.001)$ . The largest effect of SCH23390 on theta power was observed in VH, where it reduced peak power $(7 - 9\\\\mathrm{Hz})$ while also increasing power at higher frequencies $(11 - 12\\\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . SCH23390 had no effect on theta power in PL or BLA. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,757,931,870]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine if D1Rs modulate theta synchrony before CFC, we examined the acute effects of SCH23390 on theta coherence in this circuit (Fig. 2B). Differences between SCH23390 and vehicle treatment in coherence between the areas sharing direct anatomical connections (i.e. DH-VH, VH-PL, VH-BLA, and PL-BLA) were quantified at each individual frequency throughout the theta band using a chi-squared difference of coherence test. Vehicle-treated controls showed peaks for theta coherence $\\\\sim 7 - 9\\\\mathrm{Hz}$ . SCH23390 decreased peak theta coherence between DH and VH $(7 - 8\\\\mathrm{Hz})$ , while increasing coherence outside the peak $(4 - 6$ and $11 - 12\\\\mathrm{Hz})$ , compared to vehicle $(P < 0.001)$ . The largest effects of SCH23390 were observed on VH-PL and VH-BLA theta coherence, where SCH23390 decreased coherence throughout the theta band, compared to vehicle $(P < 0.001)$ . SCH23390 had no effect on theta coherence between PL and BLA. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,872,929,936]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine if D1Rs modulate gamma oscillations in this circuit before CFC, we examined the acute effects of SCH23390 on gamma power in each area (Fig. 2C). Differences between SCH23390 and vehicle treatment in power at each individual frequency throughout the low and high gamma bands were quantified using a log ratio test. No obvious peak frequencies were observed for gamma power in any area in vehicle-treated controls. In DH, there was no effect of SCH23390 on gamma power. The largest effect of SCH23390 on gamma power \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,16,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,631,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[922,965,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[171,61,480,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0703/6324b40e294d55b7776e334359bb12dc61823141d3d50fcffb4d5687da5cc7de.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[507,61,695,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0426/361d141708e1aea62a125e8cf41dd2f20808e661c539b8b74daff5033603153a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[717,61,910,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0611/7f25bc79091f07eeabc3c5b3b50fd9623f1224b3fe6c98d4845f43f6e8849e36.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[171,241,778,533]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0640/83655a4776261019bf0aeac3a37c644ad7591877463837afc1739b8dc8d46eb8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[171,557,934,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. D1R blockade impairs CFC. (A) Schematic representation of the behavioral testing paradigm used. Rats received a systemic injection of SCH23390 (SCH) or vehicle (VEH) $30\\\\\\\\mathrm{min}$ before conditioning, and LFPs were recorded during conditioning and retrieval testing. (B) SCH given before CFC decreased freezing at retrieval, compared to $\\\\\\\\mathrm{VEH} (^{*}\\\\\\\\mathrm{P} < 0.05)$ . (C) A time course analysis showed that SCH resulted in decreased freezing throughout retrieval, compared to $\\\\\\\\mathrm{VEH} (^{*}\\\\\\\\mathrm{P} < 0.05)$ . (D) Illustrative examples of electrode placements in (left; white arrows) and LFP signals recorded from (right) DH, VH, PL, and BLA. 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null,\n \"image_caption\": \"[\\\"VH-BLA \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0757/84a2e70db4c3ae6f84e8ea1bd0a27ecf0aca9fe92bde495207857e2e47102a7b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[744,631,929,773]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"PL-BLA \\\",\\\"Figure 2. D1R blockade alters DH-VH and reduces VH-PL and VH-BLA synchrony before CFC. (A) Acute effects of SCH23390 (SCH) on theta power before CFC. Peak theta power occurred $\\\\\\\\sim 7 - 8\\\\\\\\mathrm{Hz}$ in controls treated with vehicle (VEH). Compared to VEH, SCH decreased peak theta power and increased power outside the peak in DH and VH ( $*P < 0.001$ ), but not PL or BLA. (B) Acute effects of SCH on theta coherence before CFC. Peak theta coherence occurred $\\\\\\\\sim 7 - 9\\\\\\\\mathrm{Hz}$ with VEH. Compared to VEH, SCH decreased DH-VH peak theta coherence and increased DH-VH coherence outside the peak ( $*P < 0.001$ ). SCH decreased VH-PL and VH-BLA theta coherence, compared to VEH ( $*P < 0.001$ ), without affecting PL-BLA theta coherence. (C) Acute effects of SCH on gamma power before CFC. SCH had no effect on gamma power in DH. Compared to VEH, SCH increased gamma power in VH and PL ( $*P < 0.001$ ). SCH decreased high gamma power in BLA, compared to VEH ( $*P < 0.001$ ). (D) Acute effects of SCH on gamma coherence before CFC. SCH increased DH-VH and decreased VH-PL gamma coherence, compared to VEH ( $*P < 0.001$ ). SCH decreased VH-BLA low gamma coherence, compared to VEH ( $*P < 0.001$ ), without affecting PL-BLA gamma coherence. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0180/4fcee76fd8b6d28accd13eb2ae9c3050f60720752c0916c25b4c0cc79d740422.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,15,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": 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D1R blockade enhances theta-gamma coupling between DH and VH before CFC. (A) Theta-gamma PAC in each area after vehicle (VEH) treatment, with blue and red indicating lower and higher gamma amplitude, respectively. Peak PAC occurred at a theta frequency $\\\\\\\\sim 5\\\\\\\\mathrm{Hz}$ in each area. (B) SCH23390 (SCH) had no effects on theta-gamma PAC in DH, VH, PL or BLA. (C) Theta-gamma PAC between areas with VEH, showing that peak PAC occurred $\\\\\\\\sim 5\\\\\\\\mathrm{Hz}$ . (D) SCH increased DH theta coupling of VH gamma, compared to VEH ( $^{*}\\\\\\\\mathrm{P} < 0.05$ ). SCH had no effects on VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0759/39cf7dcf5d2c5475d30a810dfe529a760ae05250d6bed21bda23a269aaa94581.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[255,900,932,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"was observed in VH, where power was increased throughout the low and high gamma bands, compared to vehicle $(P < 0.001)$ . In PL, SCH23390 increased power at some low (31-32 and $44 - 45\\\\mathrm{Hz}$ ) and high $(78 - 79\\\\mathrm{Hz})$ gamma frequencies, compared to vehicle $(P < 0.001)$ . 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\"image_caption\": \"[\\\"VH-PL \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0326/d5e8381d71bf7b86e89f4e069902797957121526744b0860c65b7d009c4ab9fc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[539,601,724,746]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"VH-BLA \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0504/57c620b96677d6bfa8620db717effff8acaa47e3315bc06b6ecdc20814929276.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[742,601,929,746]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"PL-BLA \\\",\\\"Figure 4. Impaired CFC by D1R blockade is associated with altered DH-VH and reduced VH-PL-BLA synchrony at retrieval. (A) Effects of SCH23390 (SCH) given before CFC on theta power at retrieval. Peak theta power occurred $\\\\\\\\sim 6 - 7\\\\\\\\mathrm{Hz}$ in controls treated with vehicle (VEH), while SCH shifted the peak to $\\\\\\\\sim 7 - 8\\\\\\\\mathrm{Hz}$ . In DH, SCH decreased lower and increased peak theta power, compared to VEH ( $*P < 0.001$ ). In VH, SCH decreased lower and increased higher theta power, compared to VEH ( $*P < 0.001$ ). In PL and BLA, SCH increased theta power, compared to VEH ( $*P < 0.001$ ). (B) Effects of SCH given before CFC on theta coherence at retrieval. SCH increased DH-VH and decreased VH-PL, VH-BLA, and PL-BLA theta coherence, compared to VEH ( $*P < 0.001$ ). (C) Effects of SCH given before CFC on gamma power at retrieval. A peak in low gamma power occurred $\\\\\\\\sim 35 - 40\\\\\\\\mathrm{Hz}$ in DH, VH, and BLA, but not PL, with VEH. In DH, SCH decreased low and increased high gamma power, compared to VEH ( $*P < 0.001$ ). In VH, SCH decreased peak low gamma power and increased low gamma power outside the peak, while increasing or decreasing power at various high gamma frequencies, compared to VEH ( $*P < 0.001$ ). In PL and BLA, SCH decreased gamma power, compared to VEH ( $*P < 0.001$ ). (D) Effects of SCH given before CFC on gamma coherence at retrieval. Peak low gamma coherence between DH and VH occurred at $35 - 40\\\\\\\\mathrm{Hz}$ with VEH, but no peaks were observed for coherence between the other areas. SCH decreased DH-VH peak low gamma coherence and increased low gamma coherence outside the peak, while increasing or decreasing coherence at various high gamma frequencies, compared to VEH ( $*P < 0.001$ ). SCH decreased VH-PL, VH-BLA, and PL-BLA gamma coherence, compared to VEH ( $*P < 0.001$ ). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0445/d814a47ea5af5c3a9106b7ea2dbf41e1bd9eaf53ffd93175b85eedc285d0951a.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,15,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": 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Impaired CFC by D1R blockade is associated with enhanced theta-gamma coupling between DH and VH at retrieval. (A) Theta-gamma PAC in each area after prior vehicle (VEH) treatment, with lower and higher gamma amplitude indicated by blue and red, respectively. Peak PAC occurred $\\\\\\\\sim 5\\\\\\\\mathrm{Hz}$ in each area. (B) SCH23390 (SCH) given before CFC had no effects on theta-gamma PAC in DH, VH, PL or BLA. (C) Theta-gamma PAC between areas with prior VEH treatment, showing that peak PAC occurred $\\\\\\\\sim 5\\\\\\\\mathrm{Hz}$ . (D) SCH given before CFC increased DH theta phase coupling of gamma amplitude in VH, compared to VEH ( $*\\\\\\\\mathrm{P} < 0.05$ ). SCH given before CFC had no effects on VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0094/665dbb8a5be65bc0f32b1e0d85cabc0fd409829d46838aed696700f1b3e1ae7f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[255,891,929,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and decreased high gamma power at various frequencies (60-61, 64-65, and $67 - 79\\\\mathrm{Hz}$ , compared to vehicle $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,916,931,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine if D1Rs modulate gamma synchrony before CFC, we examined the acute effects of SCH23390 on gamma coherence in this circuit (Fig. 2D). Differences between SCH23390 and vehicle treatment in coherence \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,16,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n 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Movement and freezing in vehicle-treated controls are associated with differences in DH-VH and VH-PL-BLA synchrony at retrieval. (A) Differences between movement (MOV) and freezing (FRE) in theta power at retrieval. Peak theta power occurred $\\\\\\\\sim 7 - 8\\\\\\\\mathrm{Hz}$ with MOV. Compared to FRE, MOV increased peak theta power and decreased theta power outside the peak in DH and VH ( $*P < 0.001$ ). In PL and BLA, MOV increased theta power, compared to FRE ( $*P < 0.001$ ). (B) Differences between MOV and FRE in theta coherence at retrieval. Compared to FRE, MOV increased DH-VH, VH-BLA, and PL-BLA theta coherence ( $*P < 0.001$ ). MOV decreased VH-PL theta coherence, compared to FRE ( $*P < 0.001$ ). (C) Differences between MOV and FRE in gamma power at retrieval. A peak in low gamma power occurred $\\\\\\\\sim 35 - 40\\\\\\\\mathrm{Hz}$ with FRE in DH and VH, but not PL or BLA. In DH, MOV decreased low and increased high gamma power, compared to FRE ( $*P < 0.001$ ). In VH, MOV decreased low gamma power, while power was increased or decreased at various high gamma frequencies, compared to FRE ( $*P < 0.001$ ). In PL, MOV increased high gamma power, compared to FRE ( $*P < 0.001$ ). In BLA, MOV increased gamma power, compared to FRE ( $*P < 0.001$ ). (D) Differences between MOV and FRE in gamma coherence at retrieval. Peak low gamma coherence between DH and VH occurred $\\\\\\\\sim 35 - 40\\\\\\\\mathrm{Hz}$ with FRE, but there were no peaks for gamma coherence between other areas. MOV decreased DH-VH low gamma coherence, compared to FRE ( $*P < 0.001$ ). MOV decreased VH-PL high gamma coherence, compared to FRE ( $*P < 0.001$ ). MOV had no effects on VH-BLA or PL-BLA gamma coherence. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0547/a69ac7e596dbbae4ad3e23089e8f60cbf38221071edcda4a7b6882e9760eb2d9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,15,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n 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Movement in vehicle-treated controls enhances theta-gamma coupling in BLA at retrieval. (A) Theta-gamma PAC in each area during freezing (FRE), with lower and higher gamma amplitude indicated by blue and red, respectively. Peak PAC occurred $\\\\\\\\sim 5\\\\\\\\mathrm{Hz}$ in each area. (B) Movement (MOV) had no effect on theta-gamma PAC in DH, VH, or PL. MOV increased theta coupling of low gamma in BLA, compared to FRE ( $^*P < 0.05$ ). (C) Theta-gamma PAC between areas during FRE, showing that peak PAC occurred $\\\\\\\\sim 5\\\\\\\\mathrm{Hz}$ . (D) MOV had no effects on DH theta-VH gamma, VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0960/ad74a021bc3e44c76e5b5ee43019e21c9675b43ed65795f576b6ba27f6a11657.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[255,897,931,938]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"were quantified at each individual frequency throughout the low and high gamma bands using a chi-squared difference of coherence test. There were no obvious peak frequencies observed for gamma coherence in vehicle-treated controls. SCH23390 increased coherence between DH and VH at low (37-39 and $41 - 45\\\\mathrm{Hz}$ ) and high \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,15,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,633,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[921,965,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"9 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[260,61,929,125]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(56-57 and $60 - 62\\\\mathrm{Hz}$ ) gamma frequencies, compared to the low levels of gamma coherence observed with vehicle $(P < 0.001)$ . In contrast, coherence between VH and PL was decreased by SCH23390 at some low (30-31 and $35 - 36\\\\mathrm{Hz}$ ) and high (74-75 Hz) gamma frequencies, compared to vehicle $(P < 0.001)$ . SCH23390 also decreased gamma coherence between VH and BLA at low (30-33 and $35 - 45\\\\mathrm{Hz}$ ; $P < 0.001$ ) but not high gamma frequencies, compared to vehicle. SCH23390 had no effect on gamma coherence between PL and BLA, compared to vehicle. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,126,929,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine if D1Rs modulate theta-gamma coupling in this circuit before CFC, we examined the acute effects of SCH23390 on theta-gamma phase-amplitude coupling (PAC) in each area (Fig. 3A,B). Theta-gamma PAC was quantified using a modulation index. Although peak theta power in each area occurred $\\\\sim 7 - 8\\\\mathrm{Hz}$ (Fig. 2A), color plots of theta-gamma PAC in each area showed that peak theta phase coupling of gamma amplitude occurred $\\\\sim 5\\\\mathrm{Hz}$ with vehicle (Fig. 3A) or SCH23390 (not shown). Therefore we focused the analysis on this theta frequency. The quantitative analysis using two-way ANOVA found no acute effects of SCH23390 on theta-gamma PAC in any area (Fig. 3B and Table S1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,214,929,342]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We also examined the acute effects of SCH23390 on theta-gamma PAC between the directly inter-connected areas before CFC (Fig. 3C,D). Color plots of theta-gamma PAC between areas showed that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ with vehicle (Fig. 3C) or SCH23390 (not shown), therefore the analysis was focused on this theta frequency. Compared to vehicle, SCH23390 increased DH theta coupling of VH gamma (Fig. 3D). Two-way ANOVA revealed a significant main effect of treatment $(\\\\mathrm{F}_{(1,24)} = 4.41, P = 0.046)$ but no treatment x frequency interaction $(\\\\mathrm{F}_{(1,24)} = 1.75, P = 0.20)$ . For VH theta coupling of PL gamma, two-way ANOVA found no main effect of treatment $(\\\\mathrm{F}_{(1,21)} = 1.61, P = 0.22)$ but revealed a significant treatment x frequency interaction $(\\\\mathrm{F}_{(1,21)} = 4.53, P = 0.045)$ ; however, post-hoc testing found no difference between vehicle and SCH23390 treatment at low or high gamma frequencies. There were also no effects of SCH23390 on VH or PL theta coupling of BLA gamma (Table S1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,356,929,383]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Impaired CFC by D1R blockade is associated with altered intra-hippocampal and reduced hippocampal–prefrontal–amygdala synchrony at retrieval \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,384,929,498]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the association between hippocampal–prefrontal–amygdala theta oscillations and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on theta power in each area during later retrieval tested drug-free (Fig. 4A). Compared to theta power before CFC, there was less of a peak that was shifted to $6 - 7\\\\mathrm{Hz}$ in hippocampus, with much less prominent peaks in PL or BLA, in vehicle-treated controls. Overall, SCH23390 shifted the peak to $7 - 8\\\\mathrm{Hz}$ in each area. SCH23390 resulted in the biggest increase in peak theta power in DH $(7 - 8\\\\mathrm{Hz})$ , while also decreasing power at lower frequencies $(4 - 6\\\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . In VH, SCH23390 decreased power at lower $(5 - 7\\\\mathrm{Hz})$ and increased power at higher $(11 - 12\\\\mathrm{Hz})$ theta frequencies, compared to vehicle $(P < 0.001)$ . SCH23390 increased peak theta power in PL $(8 - 9\\\\mathrm{Hz})$ and BLA $(7 - 9\\\\mathrm{Hz})$ , compared to vehicle $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,500,929,586]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the association between theta synchrony and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on theta coherence in this circuit at retrieval (Fig. 4B). Compared to theta power, peaks for theta coherence were less pronounced or absent. Overall, SCH23390 increased theta coherence within hippocampus and decreased theta coherence between VH, PL, and BLA. SCH23390 increased coherence between DH and VH at higher theta frequencies $(8 - 12\\\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . In contrast, SCH23390 caused a large decrease in VH-PL, VH-BLA, and PL-BLA coherence throughout the theta band, compared to vehicle $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,588,929,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the association between gamma oscillations and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on gamma power in each area at retrieval (Fig. 4C). Compared to low gamma power before CFC, there was a peak at $35 - 40\\\\mathrm{Hz}$ in hippocampus and, to a lesser extent, in BLA and PL in vehicle-treated controls. In DH, SCH23390 decreased peak low gamma power $(35 - 43\\\\mathrm{Hz})$ and increased power throughout the high gamma band, compared to vehicle $(P < 0.001)$ . In VH, SCH23390 decreased peak low gamma power $(36 - 43\\\\mathrm{Hz})$ but increased low gamma power outside the peak $(30 - 34\\\\mathrm{Hz})$ while increasing power at some $(55 - 57$ and $59 - 60\\\\mathrm{Hz})$ and decreasing power at other $(78 - 79\\\\mathrm{Hz})$ high gamma frequencies, compared to vehicle $(P < 0.001)$ . In PL, SCH23390 decreased power at some low $(41 - 42\\\\mathrm{Hz})$ and most high $(58 - 80\\\\mathrm{Hz})$ gamma frequencies, compared to vehicle $(P < 0.001)$ . In BLA, SCH23390 decreased peak low gamma power $(37 - 41\\\\mathrm{Hz})$ and high gamma power at most frequencies $(55 - 66$ and $68 - 80\\\\mathrm{Hz})$ compared to vehicle $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,728,929,868]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the association between gamma synchrony and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on gamma coherence in this circuit at retrieval (Fig. 4D). Vehicle-treated controls showed a peak for low gamma coherence within hippocampus at $35 - 40\\\\mathrm{Hz}$ but there were no obvious peaks observed for gamma coherence between any other areas. SCH23390 decreased peak low gamma coherence between DH and VH $(36 - 42\\\\mathrm{Hz})$ and increased low gamma coherence outside the peak $(30 - 33\\\\mathrm{Hz})$ , while increasing coherence at some $(55 - 56\\\\mathrm{Hz})$ and decreasing coherence at other $(65 - 80\\\\mathrm{Hz})$ high gamma frequencies, compared to vehicle $(P < 0.001)$ . SCH23390 caused a large decrease in coherence between VH and PL throughout the low and high gamma bands, compared to vehicle $(P < 0.001)$ . SCH23390 also decreased coherence between VH and BLA at most low $(30 - 44\\\\mathrm{Hz})$ and high $(61 - 80\\\\mathrm{Hz})$ gamma frequencies, compared to vehicle $(P < 0.001)$ . Similarly, SCH23390 resulted in a large decrease in coherence between PL and BLA across the low and high gamma bands, compared to vehicle $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,869,929,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the association between theta-gamma coupling and contextual fear memory, we examined the effects of impaired CFC by prior SCH23390 administration on theta-gamma PAC in each area at retrieval (Fig. 5A,B). Color plots of theta-gamma PAC in each area showed that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ with vehicle (Fig. 5A) or SCH23390 (not shown), thus we focused the analysis on this frequency. The quantitative analysis \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[0,0,1000,33]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,631,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[914,965,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[255,61,931,86]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"found no effects of impaired CFC by SCH23390 on theta-gamma PAC in any area at retrieval (Fig. 5B and Table S2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,86,931,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We also examined the effects of impaired CFC by prior SCH23390 administration on theta-gamma PAC between these areas at retrieval (Fig. 5C,D). Color plots of theta-gamma PAC between areas showed that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ with vehicle (Fig. 5C) or SCH23390 (not shown), therefore we focused the analysis on this frequency. Compared to vehicle, SCH23390 increased DH theta coupling of VH gamma (Fig. 5D). Two-way ANOVA revealed a significant main effect of treatment $(\\\\mathrm{F}_{(1,27)} = 5.03, P = 0.033)$ but no treatment $\\\\times$ frequency interaction $(\\\\mathrm{F}_{(1,27)} = 1.70, P = 0.20)$ . SCH23390 had no effects on VH theta coupling of gamma in PL or BLA; similarly, there was no effect of SCH23390 on PL theta coupling of BLA gamma (Table S2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,190,931,218]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reduced hippocampal–prefrontal–amygdala synchrony associated with impaired CFC by D1R blockade is not fully accounted for by increased movement at retrieval \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,218,931,306]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Because theta and gamma oscillations in these areas are associated with movement[45-47], and contextual fear was inferred from freezing, we also compared synchronized oscillations between epochs of movement and freezing during retrieval testing in the vehicle-treated controls. We reasoned that if the reduced freezing and associated oscillatory synchrony resulting from SCH23390 given before CFC simply reflected increased movement at retrieval then we would find a similar synchrony profile with movement, compared to freezing, in the controls at retrieval. However, if we found differences between these synchrony profiles then this may instead reflect different neural signatures for movement and contextual fear memory. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,306,931,384]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of hippocampal–prefrontal–amygdala theta oscillations in the controls at retrieval, movement was associated with a peak in theta power at $7 - 8\\\\mathrm{Hz}$ in each area (Fig. 6A). In DH, movement increased peak theta power $(7 - 9\\\\mathrm{Hz})$ and decreased theta power outside the peak $(4 - 6$ and $11 - 12\\\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ . In VH, movement also increased peak theta power $(8 - 9\\\\mathrm{Hz})$ , while theta power was also decreased outside the peak $(4 - 6$ and $11 - 12\\\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ . Movement increased peak theta power in PL $(8 - 9\\\\mathrm{Hz})$ and BLA $(7 - 9\\\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,384,931,473]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of theta synchrony in this circuit in the controls at retrieval, there were less obvious peaks in theta coherence with movement in comparison to theta power (Fig. 6B). Movement increased coherence between DH and VH at higher theta frequencies $(11 - 12\\\\mathrm{Hz})$ compared to freezing $(P < 0.001)$ . In contrast, movement decreased peak theta coherence $(6 - 7\\\\mathrm{Hz})$ between VH and PL, compared to freezing $(P < 0.001)$ . Movement increased coherence between VH and BLA across most theta frequencies $(4 - 11\\\\mathrm{Hz})$ compared to freezing $(P < 0.001)$ . Movement also increased peak theta coherence $(8 - 9\\\\mathrm{Hz})$ between PL and BLA, compared to freezing $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,473,931,576]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of gamma oscillations in this circuit in the controls at retrieval, freezing was associated with a peak in low gamma power at $35 - 40\\\\mathrm{Hz}$ in hippocampus, but not in PL or BLA (Fig. 6C). In DH, movement decreased low $(30 - 42\\\\mathrm{Hz})$ and increased high (55-67, 71-75, and $77 - 80\\\\mathrm{Hz}$ ) gamma power, compared to freezing $(P < 0.001)$ . In VH, movement also decreased low gamma power (30-32 and $34 - 42\\\\mathrm{Hz}$ ), while power was increased $(56 - 59\\\\mathrm{Hz})$ or decreased $(74 - 77\\\\mathrm{Hz})$ at various high gamma frequencies, compared to freezing $(P < 0.001)$ . In PL, movement had no effect on low and increased high gamma power (56-59, 64-65, 67-69, 72-75, and 78-80), compared to freezing $(P < 0.001)$ . In BLA, movement increased both low $(30 - 34$ and $44 - 45\\\\mathrm{Hz}$ ) and high $(55 - 63$ and $65 - 80\\\\mathrm{Hz}$ ) gamma power, compared to freezing $(P < 0.001)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,575,931,652]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of gamma synchrony in this circuit in the controls at retrieval, freezing was associated with a peak in low gamma coherence at $35 - 40\\\\mathrm{Hz}$ within hippocampus but not between any other areas (Fig. 6D). Movement abolished peak low gamma coherence between DH and VH $(35 - 41\\\\mathrm{Hz};P < 0.001)$ but had no effect on high gamma coherence, compared to freezing. Movement had no effect on low gamma coherence between VH and PL but decreased coherence at some high gamma frequencies $(70 - 71\\\\mathrm{Hz})$ , compared to freezing $(P < 0.001)$ Movement had no effect on gamma coherence between VH and BLA, or between PL and BLA. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,652,931,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In terms of theta-gamma coupling in this circuit in the controls at retrieval, color plots of theta-gamma PAC in each area showed that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ with freezing (Fig. 7A) or movement (not shown), therefore the analysis was focused on this frequency. The quantitative analysis found no differences between movement and freezing in DH, VH, or PL (Fig. 7B and Table S3). However, compared to freezing, movement increased theta coupling of low gamma in BLA. Two-way ANOVA showed no main effect of locomotion $(\\\\mathrm{F}_{(1,7)} = 4.05$ , $P = 0.084)$ but revealed a marginally significant locomotion $\\\\times$ frequency interaction $(\\\\mathrm{F}_{(1,7)} = 5.59$ , $P = 0.050)$ . Post-hoc testing confirmed that theta coupling of low gamma was significantly increased with movement, compared to freezing $(P < 0.05)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,755,931,856]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We also examined differences between movement and freezing in theta-gamma coupling between these areas in the controls at retrieval (Fig. 7C,D). Color plots of theta-gamma PAC between areas showed that peak PAC occurred $\\\\sim 5\\\\mathrm{Hz}$ with freezing (Fig. 7C) or movement (not shown), therefore we focused our analysis at this frequency. The quantitative analysis found no differences between movement and freezing on theta-gamma PAC between any areas at retrieval (Fig. 7D and Table S3). For DH theta coupling of VH gamma, two-way ANOVA found no main effect of locomotion $(\\\\mathrm{F}_{(1,19)} = 0.69$ $P = 0.42)$ but revealed a significant locomotion $\\\\times$ frequency interaction $(\\\\mathrm{F}_{(1,19)} = 4.97$ $P = 0.038)$ ; however, post-hoc testing found no difference between movement and freezing at low or high gamma frequencies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,870,346,883]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,884,931,937]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We determined the effects of systemic D1R blockade on CFC and associated synchronized oscillations in the hippocampal-prefrontal-amygdala circuit. The selective D1R antagonist SCH23390 impaired CFC and acted acutely to alter intra-hippocampal and reduce hippocampal-prefrontal and hippocampal-amygdala synchrony during conditioning. SCH23390 decreased peak theta coherence and increased gamma coherence and theta-gamma PAC \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,16,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports| (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,633,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[914,966,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"11 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[255,61,931,202]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"between DH and VH, while VH-PL and VH-BLA theta and gamma coherence were decreased. Impaired CFC by SCH23390 was associated with altered intra-hippocampal and reduced hippocampal-prefrontal-amygdala synchrony at retrieval. Prior SCH23390 decreased peak low gamma coherence and increased theta coherence and theta-gamma PAC between DH and VH, while resulting in decreased VH-PL, VH-BLA, and PL-BLA theta and gamma coherence (Fig. 8). This reduction in hippocampal-prefrontal-amygdala synchrony was not fully accounted for by non-specific increases in movement occurring with decreased freezing at retrieval. This was revealed by comparing between epochs of movement and freezing in the vehicle-treated controls, which showed that movement increased VH-BLA and PL-BLA theta coherence and had no effect on VH-BLA or PL-BLA gamma coherence (Table 1). These results provide evidence that D1R signalling regulates CFC by modulating synchronized oscillations in the hippocampal-prefrontal-amygdala circuit, which also reflect a neural signature of contextual fear memory. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,202,931,242]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our finding that SCH23390 impaired CFC, as indicated by decreased freezing at retrieval in comparison to vehicle, replicates our previous results[23,24]. In those studies, we showed that SCH23390 impairs the acquisition, but not consolidation, of contextual fear since SCH23390 given before, but not immediately after, conditioning \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,265,653,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0423/b7df0fe1af9363cccc49cb18338055fbc74b23fa9d6b12efc17481158ef257d6.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[257,445,652,612]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0576/f58df776e06b2758fd65da095dcbcf8c8a5c326adf1a8bde917cb523eab35a8b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[257,625,650,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 8. Summary of the key effects of D1R blockade before CFC on hippocampal–prefrontal–amygdala synchrony before conditioning and at retrieval tested drug-free. (A) Dopamine projections from the ventral tegmental area (VTA) to DH, PL, and BLA (green lines) regulate CFC and local synaptic plasticity via D1R signalling. DH projects to PL and BLA indirectly through VH (black lines). (B) SCH23390 acts acutely before conditioning to alter intra-hippocampal (solid red line; decreased peak theta coherence, increased gamma coherence and theta-gamma PAC) and reduce hippocampal–prefrontal and hippocampal–amygdala (dashed red lines; decreased theta and gamma coherence) synchrony. (C) Impaired CFC by SCH23390 is associated with altered intra-hippocampal (solid red line; decreased gamma coherence, increased theta coherence and theta-gamma PAC) and reduced hippocampal–prefrontal–amygdala (dashed red lines; decreased theta and gamma coherence) synchrony at retrieval. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0414/81c808599c5f8b7101191e031df701234463d1e3c99ed9ade81fd7a2991e7b84.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,16,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,631,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[914,966,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"12 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[255,61,931,113]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"reduced freezing at retrieval. Moreover, this effect of SCH23390 did not involve state dependency, acute drug effects on shock sensitivity during conditioning, or lasting drug effects on locomotion at retrieval $24\\\\mathrm{h}$ later. This latter finding is in keeping with the brief $(\\\\sim 25\\\\mathrm{min})$ half-life of SCH23390 in rats[48]. Taken together, these results indicate that D1R signalling at the time of conditioning is important for contextual fear learning. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,112,931,253]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Systemic or local D1R blockade has acute effects on hippocampal $^{34-38}$ , prefrontal $^{39,40}$ , and amygdala $^{41}$ oscillations. However, less is known about D1R modulation of synchronized oscillations between these inter-connected areas. Intra-cerebroventricular SCH23390 infusion reduces theta phase synchrony between VH and PL under anesthesia $^{36}$ . SCH23390 infused into VH prevents the increase in phase-locking of PFC spike firing to VH theta that occurs during learning $^{37}$ . Our results showing that SCH23390 decreased theta and gamma coherence between VH and PL before CFC broadly agrees with these previous findings. We also found that SCH23390 decreased theta and gamma coherence between VH and BLA before CFC without affecting PL-BLA synchrony. In contrast, the effects of SCH23390 on DH-VH synchrony were more complex. SCH23390 decreased peak theta coherence but increased gamma coherence and theta-gamma PAC. This suggests that D1R signalling has different effects on the modulation of intra-hippocampal coupling and synchrony between hippocampus and its projection areas. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,253,931,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Our finding that impaired CFC by SCH23390 was characterized by reduced hippocampal–prefrontal–amygdala synchrony at retrieval generally agrees with evidence indicating that synchronized oscillations in this circuit are crucial for fear memory. Theta synchrony between hippocampus and PFC $^{49}$ or amygdala $^{50-52}$ is enhanced during contextual fear retrieval. Moreover, hippocampal–amygdala theta synchrony is associated with long-term (24 h) but not short-term (30 min) contextual fear memory or fear expression per se. We examined VH–PL and VH–BLA synchrony since hippocampal projections to these areas occur through $\\\\mathrm{VH}^{10,11,13}$ . Our results showing that impaired CFC is associated with reduced VH–PL and VH–BLA theta coherence at retrieval confirm and extend these previous findings implicating hippocampal–prefrontal and hippocampal–amygdala theta synchrony in contextual fear memory. Our finding of reduced PL–BLA theta coherence with impaired CFC also broadly agrees with studies showing that prefrontal–amygdala theta synchrony is involved in auditory fear retrieval $^{53,54}$ . Similarly, we found reduced VH–PL, VH–BLA, and PL–BLA gamma coherence at retrieval with impaired CFC, suggesting that gamma synchrony between these areas also plays a role in contextual fear retrieval. This is compatible with evidence indicating that BLA gamma oscillations are important for contextual memory consolidation and that gamma coherence between BLA and various inter-connected areas is enhanced during learning $^{55-57}$ . However, impaired CFC was associated with more complex interactions between DH and VH at retrieval. While peak low gamma coherence between DH and VH was decreased, theta and higher gamma coherence and theta-gamma PAC were increased. This suggests that impaired CFC is characterized by differences in intra-hippocampal coupling and hippocampal–prefrontal–amygdala synchrony at retrieval. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,484,931,663]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A potential confounding issue for interpreting the effects of systemic D1R blockade on hippocampal–prefrontal–amygdala synchrony is that non-specific locomotor effects might be involved. SCH23390 acts acutely to decrease locomotion[22,23], while decreased freezing at retrieval resulting from impaired CFC by SCH23390 has the opposite effect to increase movement. Therefore opposing effects of SCH23390 acutely and during later retrieval might be expected if non-specific locomotor effects are involved. Although SCH23390 had the opposite effects on peak theta and low gamma coherence between DH and VH acutely and at retrieval, there were similar effects on DH-VH theta-gamma PAC, VH-PL theta and gamma coherence, and VH-BLA theta and gamma coherence under both conditions. To address this issue, we also compared hippocampal–prefrontal–amygdala synchrony between epochs of movement and freezing at retrieval in the vehicle-treated controls. If reduced freezing and VH-PL-BLA synchrony with impaired CFC by SCH23390 reflected a non-specific increase in locomotion at retrieval, then we expected to find a similar synchrony profile with movement in the controls, whereas differences between these synchrony profiles may indicate specific effects on contextual fear memory. Our results showed both similarities and differences in these synchrony profiles (Table 1). Movement increased theta and decreased peak low gamma coherence between DH and VH in controls, as we found with SCH23390. Movement \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[258,696,576,893]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0410/4fb4e34e435e435fbb9176be38d292a188a370af6054dd5ec395b7391c2936d3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Areas</td><td>Synchrony measure</td><td>SCH23390</td><td>Movement</td></tr><tr><td rowspan=\\\"3\\\">DH-VH</td><td>Theta coherence</td><td>↑</td><td>↑</td></tr><tr><td>Gamma coherence</td><td>↓/↑</td><td>↓</td></tr><tr><td>Theta-gamma PAC</td><td>↑</td><td>↔</td></tr><tr><td rowspan=\\\"3\\\">VH-PL</td><td>Theta coherence</td><td>↓</td><td>↓</td></tr><tr><td>Gamma coherence</td><td>↓</td><td>↓</td></tr><tr><td>Theta-gamma PAC</td><td>↔</td><td>↔</td></tr><tr><td rowspan=\\\"3\\\">VH-BLA</td><td>Theta coherence</td><td>↓</td><td>↑</td></tr><tr><td>Gamma coherence</td><td>↓</td><td>↔</td></tr><tr><td>Theta-gamma PAC</td><td>↔</td><td>↔</td></tr><tr><td rowspan=\\\"3\\\">PL-BLA</td><td>Theta coherence</td><td>↓</td><td>↑</td></tr><tr><td>Gamma coherence</td><td>↓</td><td>↔</td></tr><tr><td>Theta-gamma PAC</td><td>↔</td><td>↔</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1. Comparison of effects of impaired CFC by SCH23390 versus movement in the vehicle-treated controls on hippocampal–prefrontal–amygdala synchrony at retrieval. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[65,16,337,31]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,633,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[914,966,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"13 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[260,61,931,150]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"also decreased VH-PL theta and gamma coherence in controls, albeit to a lesser extent than with SCH23390. However, VH-BLA and PL-BLA theta coherence were increased with movement in controls but decreased with SCH23390. Movement also had no effects on VH-BLA or PL-BLA gamma coherence in controls, whereas SCH23390 resulted in decreased gamma coherence between these areas. These results suggest that while the effects of SCH23390 on DH-VH and VH-PL synchrony at retrieval may have involved non-specific increases in movement, BLA synchrony with VH and PL during retrieval was instead more likely to have reflected a neural signature of contextual fear memory. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,152,931,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In summary, this study lends support to the idea that D1Rs regulate CFC by modulating hippocampal-prefrontal-amygdala synchrony. Synaptic plasticity in this circuitry, which is disrupted by local D1R blockade[25-27], is facilitated by synchronized oscillations[28,30,32]. Reduced synchrony between these areas is therefore a plausible neurophysiological mechanism by which D1R blockade disrupts the synaptic plasticity underlying CFC. This has implications for understanding how the various psychological processes involved are mediated by communication between these areas. D1R blockade locally in DH impairs CFC and LTP in this area[23,25], which may interfere with encoding the context representation and context-US association. Although blocking D1Rs locally in VH does not affect $\\\\mathrm{CFC^{24}}$ , our results suggest that altered synchrony between DH and VH by systemic D1R blockade may also play a role in disrupting CFC. Moreover, reduced VH-PL and VH-BLA synchrony with systemic D1R blockade may impair CFC by interfering with the context and US representations being conveyed from hippocampus to these areas[13,15]. In support of this idea, blocking D1Rs locally in PL impairs CFC and LTP in the VH-PL pathway[24,26]. Local D1R blockade in BLA also impairs CFC and LTP in this area[23,27], which may interfere with encoding the US representation and context-US association[58]. However, D1R modulation of VH-BLA plasticity[14,59] remains to be determined. It is worth noting that other areas inter-connected to this circuit may also play a role in D1R modulation of hippocampal-prefrontal-amygdala synchrony. The thalamic nucleus reuniens (RE) mediates hippocampal-prefrontal coupling via its reciprocal connections with these areas[60], while the PFC-RE and RE-BLA pathways have been implicated in various learned fear processes[32,61-63]. Moreover, D1Rs in RE regulate fear extinction memory and dopamine modulates theta oscillations in $\\\\mathrm{RE}^{64,65}$ , suggesting a potential role for RE in D1R modulation of synchrony in this circuit. Nevertheless, this study builds on our understanding of the hippocampal-prefrontal-amygdala circuit mechanisms underlying the neuromodulation of CFC by dopamine. It also confirms and adds to evidence indicating that communication within this circuitry is crucial for fear memory[28,30,32]. This may ultimately lead to novel insights on the neurobiological basis of anxiety-related disorders characterized by aberrant learned fear processing. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,457,332,471]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,473,319,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Animals \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,485,931,576]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"42 male Lister Hooded rats (Charles River, UK) weighing $280 - 390\\\\mathrm{g}$ before surgery were used. Rats were group housed in individually ventilated cages (2-3/cage) and kept on a $24\\\\mathrm{h}$ light/dark cycle (lights on at 7:00) with ad libitum access to food and water. All behavioral testing occurred during the rats' light cycle. All experimental procedures were performed with institutional ethical approval and under the UK Animals (Scientific Procedures) Act 1986 (Home Office Project Licence 30/3230). All experiments were performed in accordance with the relevant guidelines and regulations. All reporting for the study followed the recommendations in the ARRIVE guidelines (Essential 10;66). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,590,448,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Electrode implant surgery \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,604,931,809]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Anesthesia was induced with $\\\\sim 3\\\\%$ isoflurane in oxygen and analgesic (buprenorphine, $0.05\\\\mathrm{mg / kg}$ , s.c.) was administered immediately post-induction. Anesthesia was maintained with $1.5 - 2.5\\\\%$ isoflurane during surgery to ensure complete inhibition of the hindpaw withdrawal reflex. Rats were placed in a stereotaxic frame and the incisor bar was adjusted to maintain the skull horizontal. A homoeothermic heating pad was used to maintain body temperature at $36 - 37^{\\\\circ}C$ throughout surgery. A scalp incision was made along the midline, the periosteum was retracted, and 10 stainless steel anchoring screws were affixed to the top and sides of the skull. Small craniotomies were performed on the right side above the target coordinates and the dura mater was incised immediately before electrode implantation. Custom-made tungsten electrodes[67] were targeted at DH (CA1; $3.0\\\\mathrm{mm}$ posterior and $1.5\\\\mathrm{mm}$ lateral to bregma, $3.0\\\\mathrm{mm}$ ventral to the brain surface), VH (CA1; $5.0\\\\mathrm{mm}$ posterior and $4.8\\\\mathrm{mm}$ lateral to bregma, $6.3\\\\mathrm{mm}$ ventral to the brain surface), PL ( $2.5\\\\mathrm{mm}$ anterior and $0.5 - 0.8\\\\mathrm{mm}$ lateral to bregma, $3.0\\\\mathrm{mm}$ ventral to the brain surface), and BLA (basal nucleus; $2.8\\\\mathrm{mm}$ posterior and $4.7\\\\mathrm{mm}$ lateral to bregma, $7.2\\\\mathrm{mm}$ ventral to the brain surface)[68]. The electrodes were loaded into a microdrive (VersaDrive-8, Neuralynx, MT) and the implant was secured to the anchoring screws with light-cured dental cement (Henry Schein, UK). Another analgesic (meloxicam, $1\\\\mathrm{mg / kg}$ , s.c.) was given at the end of surgery. Rats were singly housed for 1-2 days after surgery, after which they were group housed as above. Buprenorphine and meloxicam were given once daily for 2-3 days after surgery. Behavioral testing commenced 6-8 days after surgery. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,823,363,837]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Drug injection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,837,931,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SCH23390 hydrochloride $(0.1\\\\mathrm{mg / kg},$ i.p.; Tocris Bioscience, UK) was dissolved in $0.9\\\\%$ sterile saline $(1\\\\mathrm{mL / kg})$ and injected 30 min before CFC (see below). We have previously shown that this dose impairs $\\\\mathrm{CFC}^{23,24}$ . Vehicle-treated controls received injections of $0.9\\\\%$ sterile saline $(1\\\\mathrm{mL / kg},$ i.p.). Animals were randomly assigned to receive SCH23390 or vehicle treatment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,902,393,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Behavioral testing \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,916,931,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The effects of systemic SCH23390 administration on CFC were investigated using a two-day conditioning and retrieval paradigm. Each rat was randomly allocated to receive SCH23390 or vehicle treatment before CFC. The \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[0,0,1000,33]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,631,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[914,966,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"14 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[260,58,931,202]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{apparatus}^{69}$ and experimental procedures $^{24}$ used have been described in detail elsewhere. On the first day rats underwent conditioning in a novel context that consisted of distinct visual, auditory, and olfactory cues present in the background during CFC. The US was a mild electric shock delivered through the chamber floor bars automatically via a PC running Med-PC IV software (Med Associates, VT). The rat was placed in the chamber and after 2 min was presented with four shocks (0.5 mA, 0.5 s, 1 min inter-trial interval). The rat was removed from the chamber 2 min after presentation of the last shock and returned to the home cage. On the second day the rat was returned to the same conditioning chamber for 5 min to test memory retrieval drug-free. The floor bars and waste tray were cleaned with $40\\\\%$ ethanol between each session. Rats were tested at approximately the same time of day on both days. Electrophysiological recordings (see below) were obtained during CFC and retrieval testing. Behavior during retrieval testing was recorded using a digital camera (ViewPoint, France) positioned above the chamber. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,216,487,231]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Electrophysiological recordings \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,231,931,294]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LFPs from the electrodes targeting each area were recorded during CFC and retrieval testing by connecting the microdrive via a headstage, cable, and pre-amplifier to an OmniPlex neural recording data acquisition system (Plexon Inc, TX). LFPs were band-pass filtered at $0.7 - 170\\\\mathrm{Hz}$ and digitized at $1.25\\\\mathrm{kHz}$ . A cable connecting the Med Associates and OmniPlex systems was used to record the start of the CFC and retrieval sessions, triggered by the Med-PC IV software, in the LFP data recording file. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,308,332,323]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Histology \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,322,931,411]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"After completing retrieval testing, rats were deeply anesthetized with sodium pentobarbital and current was passed through each electrode using an electrical stimulator to create a small lesion at the electrode tips. Rats were then perfused transcardially with $0.9\\\\%$ saline followed by $4\\\\%$ paraformaldehyde. The brains were removed, post-fixed in $4\\\\%$ paraformaldehyde, and kept at $4^{\\\\circ}\\\\mathrm{C}$ until slicing. Sections containing the relevant areas were obtained using a vibratome and stained for acetylcholinesterase (Fig. 1D). Only data from rats with histologically confirmed electrode placements in DH, VH, PL, and/or BLA were included in the electrophysiological data analysis. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,425,435,439]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Behavioral data analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,439,931,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Freezing, defined as the absence of movement except in relation to respiration, was taken as the behavioral measure of contextual fear during retrieval testing. Freezing was quantified automatically using VideoTrack software (ViewPoint, France) by setting the freezing detection threshold to 100 pixels change/frame (25 frames/sec), based on a comparison between automatically determined and manually scored freezing levels from our published data[24]. The cumulative duration of freezing during retrieval testing was calculated and expressed as a percentage of the 5 min test duration. Differences in freezing between the two groups were analyzed in two ways. Average freezing over the whole 5 min test session was analyzed using a two-tailed unpaired t-test, with the data presented in a bar graph as the mean + standard error of the mean (SEM). Freezing during each 1-min bin was also analyzed separately using two-way analysis of variance (ANOVA) with repeated measures, with treatment as the between-subjects factor and time as the within-subjects factor. Freezing during each 1-min bin was presented in a line graph as the mean + SEM. The level of significance for both analyses was set at $P < 0.05$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,594,505,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Electrophysiological data analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,609,931,710]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"LFP activity was analyzed using multi-taper spectral analysis as described elsewhere[70-72]. LFP recordings were inspected visually and data containing obvious electrical noise artefacts were omitted from the analysis. LFP signals were normalized to unit variance in each segment prior to spectral analysis. Normalization removes effects of changes in absolute power due to changes in electrode impedance, therefore we report on differences in relative power. Spectral estimates for LFP data from each area in the 2 min period before US presentations during CFC and in the 5 min retrieval test were generated using custom Matlab scripts. LFP recordings from all areas contained many electrical noise artefacts in the 2 min period after US presentations during CFC, which precluded analysis of the data from this period. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,710,931,875]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We first examined the acute effects of SCH23390 on theta (4–12 Hz), low gamma (30–45 Hz), and high gamma (55–80 Hz) power in each area during CFC. The gamma frequency band was divided into low and high frequencies to omit electrical mains noise ~ 50 Hz. Differences between SCH23390 and vehicle treatment in power at each individual frequency throughout the theta and gamma bands were quantified using the log ratio test. The acute effects of SCH23390 on theta, low gamma, and high gamma coherence between the areas sharing direct anatomical connections (i.e. DH–VH, VH–PL, VH–BLA, and PL–BLA) were then determined during CFC as measures of synchrony between these areas. Differences between SCH23390 and vehicle treatment in coherence at each individual frequency throughout the theta and gamma bands were quantified using the chi-squared difference of coherence test. Power and coherence data are presented as the mean +/− 95% pointwise confidence intervals. The level of significance for the statistical comparisons of power and coherence was set at $P < 0.001$ to correct for multiple comparisons across individual frequencies. Differences at individual frequencies were also considered as chance effects, therefore differences were only deemed significant where they were found for two or more adjacent frequencies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,877,931,941]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The acute effects of SCH23390 on theta-gamma PAC during CFC were quantified as described elsewhere[73-75] using custom Matlab scripts. Theta-gamma PAC was determined using a modulation index from the normalised mean vector length. Estimates were constructed using analytic Morse wavelets, with significance determined using surrogate data[75-77]. Amplitude information in each trial was split into five blocks, which were randomly permuted to yield a surrogate dataset for amplitude. Phases were shuffled randomly between the different \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[0,0,1000,33]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.nature.com/scientificreports/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[65,965,290,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scientific Reports (2023) 13:17631 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[381,965,631,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"https://doi.org/10.1038/s41598-023-44772-6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[786,964,880,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"natureportfolio \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[914,966,929,976]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"15 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[255,61,931,240]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frequency components $^{78}$ . Each shuffled phase information obtained from the $i$ th frequency was randomly matched with the shuffled amplitude data from the $j$ th frequency, with $i$ and $j$ random integers. We examined theta-gamma PAC within each area and between the directly inter-connected areas. Specifically, we examined DH theta-VH gamma PAC since theta oscillations propagate from DH to $\\\\mathrm{VH}^{79,80}$ . We also examined VH theta-PL gamma PAC since hippocampal-prefrontal theta synchrony is mediated by $\\\\mathrm{VH}^{81,82}$ . Similarly, we examined VH theta-BLA gamma PAC since theta burst stimulation of VH modulates BLA activity and plasticity $^{83}$ . Finally, we examined PL theta-BLA gamma PAC since learned fear inhibition is associated with prefrontal theta coupling of BLA $\\\\mathrm{gamma}^{29}$ . Color plots of theta-gamma PAC within each area and between the directly inter-connected areas showed that peak theta phase coupling of gamma amplitude occurred at a theta frequency $\\\\sim 5\\\\mathrm{Hz}$ after vehicle or SCH23390 treatment, therefore we focused the analyses at this theta frequency. Theta-gamma PAC was analyzed using two-way ANOVA with repeated measures, with treatment as the between-subjects factor and gamma frequency band as the within-subjects factor. Post-hoc comparisons were conducted using the Sidak test where indicated. Theta-gamma PAC was presented in bar graphs as the mean + SEM and the level of significance for the analyses was set at $P < 0.05$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,241,931,381]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The effects of SCH23390 given before CFC on theta power and coherence, low and high gamma power and coherence, and theta-gamma PAC during retrieval testing drug-free were determined as above. We also examined differences in these neurophysiological measures between epochs of movement and freezing during retrieval testing in the vehicle-treated controls to determine if decreased freezing resulting from SCH23390 treatment before CFC was related specifically to impaired contextual fear or non-specifically to increased movement at retrieval. Freezing epochs were determined by considering intervals of a minimum of $0.5\\\\mathrm{s}$ where $< 100$ pixels change/frame (i.e. the freezing detection threshold) was detected, while movement epochs were determined by considering intervals of a minimum of $0.5\\\\mathrm{s}$ where $>500$ pixels change/frame was detected. The resulting LFP data from these intervals were then pooled within and between rats. Differences between movement and freezing in theta power and coherence, low and high gamma power and coherence, and theta-gamma PAC during retrieval testing were determined as above. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,392,394,407]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data availability \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,407,831,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All electrophysiology data and analysis code are freely available online (https://osf.io/km2s7/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,430,561,445]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Received: 25 June 2023; Accepted: 12 October 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,446,460,457]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published online: 17 October 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[258,471,349,485]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[260,487,929,943]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Patel, J., Fujisawa, S., Berenyi, A., Royer, S. & Buzsaki, G. Traveling theta waves along the entire septotemporal axis of the hippocampus. Neuron 75, 410-417 (2012). \\\",\\\"81. Adhikari, A., Topiwala, M. A. & Gordon, J. A. Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron 65, 257-269 (2010). \\\",\\\"82. O'Neill, P. K., Gordon, J. A. & Sigurdsson, T. Theta oscillations in the medial prefrontal cortex are modulated by spatial working memory and synchronize with the hippocampus through its ventral subregion. J. Neurosci. 33, 14211-14224 (2013). \\\",\\\"83. Bazelot, M. et al. Hippocampal theta input to the amygdala shapes feedforward inhibition to gate heterosynaptic plasticity. Neuron 87, 1290-1303 (2015). \\\"]\",\n \"page_idx\": \"17\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[258,453,421,469]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgements \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,469,931,494]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was funded by a research grant from the Biotechnology and Biological Sciences Research Council [Grant Number BB/P001149/1]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,505,430,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Author contributions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,519,931,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"C.S. and E.H. conducted the experiments. C.S., S.S., and D.M.H. analyzed the data. T.B., H.J.C., S.J.M., and C.W.S. conceived the study and designed the experiments. C.S. and C.W.S. drafted the manuscript. C.S., T.B., H.J.C., S.J.M., D.M.H., and C.W.S. revised the manuscript. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,570,425,585]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Competing interests \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,585,524,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors declare no competing interests. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[257,608,445,622]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Additional information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[255,622,931,648]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Supplementary Information The online version contains supplementary material available at https://doi.org/10.1038/s41598-023-44772-6. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n 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This work is made available under the terms of a Creative Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[91,933,243,949]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"eScholarship.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[540,931,906,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Powered by the California Digital Library University of California ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[52,69,473,133]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"role in applicant choice. Conversely, we did not find support for the hypothesis that acuity and competitiveness are correlated (fig1). We still see a strong correlation between competitiveness and DR (fig2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[52,133,488,247]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions: Despite EM leadership repeatedly criticizing the use of DR, they continue to correlate with competitive EM applicants' preferences. This will continue until we provide our applicants compelling data on the clinical environment of programs. We should therefore consider making an objective score, such as the AAAEM methodology and rankings available to applicants. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,287,434,498]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. \"]","image_footnote":"[]","img_path":"images/0427/bde011ac765daa5cfac0c4f63cc595a41ed6b0c38f7923da69bc9371d741007c.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[117,541,419,731]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2. \"]","image_footnote":"[]","img_path":"images/0069/fde30d46b4033e9aee464a7c87b967451b89965abd3b9438da1485a3d656d036.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[53,787,485,851]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"50 Simulation in Emergency Medicine Residency Training Programs: A National Survey Andrew Bloom, Briana Miller, Jaron Raper, Charles Khoury ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[52,867,450,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: The use of simulation-based medical education (SBME) has been proven to be an effective instructional strategy both procedurally and clinically. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[501,69,936,148]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Emergency Medicine (EM) residency programs utilize SBME in a variety of ways and settings. Simulation (sim) in EM has not been recently evaluated in light of the expansion of residency programs and fellowships. The current state of SBME utilization in EM is unknown. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[503,150,939,196]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objectives: To assess the current state and utilization of sim in ACGME-approved EM residencies given the growth of the field of sim and expansion of EM training. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[501,198,924,339]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: This was a national survey study performed from July through September 2022. The survey was sent to the residency program directors of all 277 ACGME-accredited EM residency programs in the United States. A literature search identified existing publications discussing the state of SBME in EM. From this, a 17-question survey was developed and focused on technology, types of sim (procedural vs. case-based), barriers to growth, and overall sentiments of sim in EM. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[501,340,934,547]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Of the 277 EM programs at the time of this abstract, 244 programs were successfully contacted, with a total of responses. Nearly all programs reported access to a dedicated sim center (98%), with available high-fidelity mannequin simulators (94%) and task trainers (91%). Most programs engage in sim didactics monthly (54%), followed by more than monthly (24%) and quarterly (21%). Few programs reported barriers in sim implementation (15%). Of those, funding (35%), sim lab availability (24%), and equipment (21%) were identified most frequently. Programs frequently used sim (82%) to perform the majority of rare but required procedures. Finally, half (50%) of the programs have simulation fellowship-trained faculty on staff. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[503,547,931,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions: SBME is an important aspect of EM residency and training. A majority of residency programs report dedication and resources to developing and integrating sim into their curriculum. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,614,933,662]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"51 Strong Correlation Between Depression/ Stress and Self-Reported Microaggressions in Emergency Medicine Residents ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[504,676,890,709]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Brian Walsh, Claire Delong, Frederick Fiesseler, Nicole Riley, Marc Wheaton ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[503,724,936,756]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: Residents' well-being and their perceptions of microaggression may be correlated. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[503,757,921,820]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objective: We sought to measure resident wellness objectively and determine if it is correlated with a resident's perception of how frequently they are victimized by microaggressions. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[501,820,939,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: All the residents at a three-year EM program were surveyed using an anonymous questionnaire in Google Forms. Resident wellness was assessed using the Depression, Anxiety and Stress Scale (DASS), a validated psychometric scale that is used across multiple industries. Using a 5-point Likert scale, residents were also asked how often they feel like ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[746,37,942,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CORD Abstracts Issue 2023 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[53,952,295,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Volume 24, Supplement : May 2023 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[485,953,511,965]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S35 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[674,952,942,968]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Western Journal of Emergency Medicine ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[57,70,480,162]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"they are the victim of microaggressions: 1: never or almost never to 5: very frequently. The term \"microaggressions\" was not defined, allowing residents to determine what they feel it to be. Pearson product moment correlation between the two variables was calculated and statistical significance to $p < 0.05$ was determined. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,165,478,354]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: 20 out of 27 residents responded to the questionnaire. Seven residents scored for at least mild depression (three severe), nine residents scored for at least mild anxiety (five severe), and 11 residents scored for at least mild stress (one severe). The average rating on the frequency of being the victim of microaggressions was 2.2 (95%CI: 1.6, 2.7), suggesting residents infrequently felt victimized by microaggressions. The Pearson correlation between Depression and the frequency of microaggressions is $r = 0.56$ ( $p = 0.01$ ), between Anxiety and microaggressions is $r = 0.41$ ( $p = 0.07$ , NS), and between Stress and microaggressions is $r = 0.63$ ( $p = 0.004$ ) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,357,480,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion: This study suggests there is a correlation between depression/stress and a residents' perception of being victimized by microaggressions. It is unclear whether being the victim of microaggression leads to more depression/stress or if residents with more depression/stress view comments as being more insulting. Certainly, this subject merits further study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,470,444,517]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"52 Take-Home Naloxone in the Emergency Department: Assessing Residents' Attitudes and Practices ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[57,534,450,550]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Aaron Dora-Laskey, Brittany Ladson, Brett Gerstner ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,566,485,630]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: Take-home naloxone may mitigate opioid overdose risk in emergency department (ED) patients who use drugs, yet little is known about emergency medicine (EM) resident dispensing practices. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,631,462,662]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objective: To identify factors associated with resident take-home naloxone dispensing. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,662,485,787]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: We analyzed ED take-home naloxone kit data retrospectively from a single Michigan community ED (100k/yr) convenience sample between 3/11/2020 and 10/30/2021, comparing dispensing rates to resident shift type (morning, midday, night) and training year (PGY-1 to 3) using the Kruskal Wallis test. Current residents' attitudes regarding naloxone were assessed using a validated tool, the Naloxone-Related Risk Compensation Belief survey. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,789,486,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Of 274 kits, 76 could be linked with one of 2,409 resident shifts, yielding a dispensing rate of 3.15 kits/100 shifts. Of 34 residents scheduled, 12 (35.3%) ordered no kits, 7 (20.6%) ordered 1 kit, and 15 (44.1%) ordered $\\geq 2$ kits. Dispensing rates were highest among PGY-3 (4.35 kits/100 shifts) compared to PGY-2 (2.20) and PGY-1 (1.06) residents $(p = 0.006)$ . Kit dispensing was more frequent during night (3.82 kits/100 shifts) compared to midday (3.23) and day ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,70,939,212]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(2.20) shifts; this was not statistically significant $(p = 0.09)$ . Of 25 EM residents surveyed, 21 responded $(84\\%)$ . Fewer than $10\\%$ believed dispensing naloxone to people who used opioids would result in greater drug use or decreased treatment-seeking, and only 1 resident agreed that there should be a limit to the number of times a person receives naloxone. None reported that naloxone was enabling for people who used drugs, or that dispensing naloxone sends the message that residents condone risky opioid use. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,214,921,292]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusions: EM resident take-home naloxone dispensing was associated with more senior year of training, suggesting a need to better educate junior residents. Few residents expressed concern that naloxone would increase risky drug use or decrease treatment-seeking. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[516,311,913,359]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"53 Targeted Procedure Lab to Improve Self-Identified Deficiencies Among Graduating Emergency Medicine Residents ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,376,906,407]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Andrew Bobbett, Stephanie Cohen, Andrew Bobbett, Jeffrey Thompson, Robert Pell, Latha Ganti ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,424,937,502]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Background: Simulation is the artificial recreation of an experience for the purpose of education. This study focuses on the usefulness of targeted procedural labs in correcting self-identified deficiencies and increasing procedural confidence in emergency medicine (EM) resident procedural skills. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,503,921,565]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objectives: To determine whether a procedure lab targeting procedures that EM residents do not feel proficient in can increase feelings of confidence prior to residency graduation. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,566,937,741]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: A survey was performed comparing EM residents that participated in a targeted procedure lab versus residents that did not. The sample included 31 EM residents delineated by program year at onset of study—Group A: Class of 2021 (15 residents, year 2), Group B: Class of 2020 (16 residents, year 3). In June 2020, groups A and B filled out a survey indicating procedural confidence. A procedure lab was made based on the top 12 procedures group A felt they needed practice in. Group A participated in the procedure lab in March 2021. Group B did not receive the targeted treatment lab. Group A completed the post intervention survey in May 2021. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,742,937,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Group A self-reported a decreased need for more procedural support training and increased confidence in procedural skills compared to Group B in nine out of twelve procedures. Results from an inference for two proportions indicate a statistically significant difference between the percent of Group A compared to Group B participants wanting more experience performing Subclavian Line (TS = -2.102, p < .05; 95%CI (-0.68, -0.02) and Thoracotomy (TS = -2.01, p < .05; 95%CI (-0.603, -0.007) procedures, indicating Group A reported significantly increased confidence in the Subclavian Line and Thoracotomy procedures. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[57,37,248,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CORD Abstracts Issue 2023 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[57,953,323,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Western Journal of Emergency Medicine ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[486,954,511,964]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"S36 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[707,953,939,967]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Volume 24, Supplement : May2023 ","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[80,69,217,90]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"UC Irvine \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,94,911,136]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": 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null,\n \"table_footnote\": null,\n \"text\": \"Delong, Claire \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,455,256,486]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fiesseler, Frederick et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,502,264,518]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Publication Date \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n 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null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.5811/westjem.61114 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,607,326,625]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright Information \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,627,900,661]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright 2023 by the author(s). This work is made available under the terms of a Creative Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[91,933,243,949]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"eScholarship.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[540,931,906,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Powered by the California Digital Library University of California \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[52,69,473,133]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"role in applicant choice. Conversely, we did not find support for the hypothesis that acuity and competitiveness are correlated (fig1). We still see a strong correlation between competitiveness and DR (fig2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[52,133,488,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions: Despite EM leadership repeatedly criticizing the use of DR, they continue to correlate with competitive EM applicants' preferences. This will continue until we provide our applicants compelling data on the clinical environment of programs. We should therefore consider making an objective score, such as the AAAEM methodology and rankings available to applicants. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,287,434,498]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0427/bde011ac765daa5cfac0c4f63cc595a41ed6b0c38f7923da69bc9371d741007c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[117,541,419,731]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0069/fde30d46b4033e9aee464a7c87b967451b89965abd3b9438da1485a3d656d036.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[53,787,485,851]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"50 Simulation in Emergency Medicine Residency Training Programs: A National Survey Andrew Bloom, Briana Miller, Jaron Raper, Charles Khoury \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[52,867,450,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: The use of simulation-based medical education (SBME) has been proven to be an effective instructional strategy both procedurally and clinically. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[501,69,936,148]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Emergency Medicine (EM) residency programs utilize SBME in a variety of ways and settings. Simulation (sim) in EM has not been recently evaluated in light of the expansion of residency programs and fellowships. The current state of SBME utilization in EM is unknown. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[503,150,939,196]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objectives: To assess the current state and utilization of sim in ACGME-approved EM residencies given the growth of the field of sim and expansion of EM training. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[501,198,924,339]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: This was a national survey study performed from July through September 2022. The survey was sent to the residency program directors of all 277 ACGME-accredited EM residency programs in the United States. A literature search identified existing publications discussing the state of SBME in EM. From this, a 17-question survey was developed and focused on technology, types of sim (procedural vs. case-based), barriers to growth, and overall sentiments of sim in EM. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[501,340,934,547]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Of the 277 EM programs at the time of this abstract, 244 programs were successfully contacted, with a total of responses. Nearly all programs reported access to a dedicated sim center (98%), with available high-fidelity mannequin simulators (94%) and task trainers (91%). Most programs engage in sim didactics monthly (54%), followed by more than monthly (24%) and quarterly (21%). Few programs reported barriers in sim implementation (15%). Of those, funding (35%), sim lab availability (24%), and equipment (21%) were identified most frequently. Programs frequently used sim (82%) to perform the majority of rare but required procedures. Finally, half (50%) of the programs have simulation fellowship-trained faculty on staff. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[503,547,931,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions: SBME is an important aspect of EM residency and training. A majority of residency programs report dedication and resources to developing and integrating sim into their curriculum. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,614,933,662]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"51 Strong Correlation Between Depression/ Stress and Self-Reported Microaggressions in Emergency Medicine Residents \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,676,890,709]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Brian Walsh, Claire Delong, Frederick Fiesseler, Nicole Riley, Marc Wheaton \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[503,724,936,756]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: Residents' well-being and their perceptions of microaggression may be correlated. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[503,757,921,820]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objective: We sought to measure resident wellness objectively and determine if it is correlated with a resident's perception of how frequently they are victimized by microaggressions. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[501,820,939,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: All the residents at a three-year EM program were surveyed using an anonymous questionnaire in Google Forms. Resident wellness was assessed using the Depression, Anxiety and Stress Scale (DASS), a validated psychometric scale that is used across multiple industries. Using a 5-point Likert scale, residents were also asked how often they feel like \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[746,37,942,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CORD Abstracts Issue 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[53,952,295,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Volume 24, Supplement : May 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[485,953,511,965]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S35 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[674,952,942,968]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Western Journal of Emergency Medicine \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[57,70,480,162]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"they are the victim of microaggressions: 1: never or almost never to 5: very frequently. The term \\\"microaggressions\\\" was not defined, allowing residents to determine what they feel it to be. Pearson product moment correlation between the two variables was calculated and statistical significance to $p < 0.05$ was determined. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,165,478,354]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: 20 out of 27 residents responded to the questionnaire. Seven residents scored for at least mild depression (three severe), nine residents scored for at least mild anxiety (five severe), and 11 residents scored for at least mild stress (one severe). The average rating on the frequency of being the victim of microaggressions was 2.2 (95%CI: 1.6, 2.7), suggesting residents infrequently felt victimized by microaggressions. The Pearson correlation between Depression and the frequency of microaggressions is $r = 0.56$ ( $p = 0.01$ ), between Anxiety and microaggressions is $r = 0.41$ ( $p = 0.07$ , NS), and between Stress and microaggressions is $r = 0.63$ ( $p = 0.004$ ) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,357,480,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusion: This study suggests there is a correlation between depression/stress and a residents' perception of being victimized by microaggressions. It is unclear whether being the victim of microaggression leads to more depression/stress or if residents with more depression/stress view comments as being more insulting. Certainly, this subject merits further study. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,470,444,517]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"52 Take-Home Naloxone in the Emergency Department: Assessing Residents' Attitudes and Practices \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,534,450,550]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Aaron Dora-Laskey, Brittany Ladson, Brett Gerstner \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,566,485,630]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: Take-home naloxone may mitigate opioid overdose risk in emergency department (ED) patients who use drugs, yet little is known about emergency medicine (EM) resident dispensing practices. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,631,462,662]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objective: To identify factors associated with resident take-home naloxone dispensing. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,662,485,787]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: We analyzed ED take-home naloxone kit data retrospectively from a single Michigan community ED (100k/yr) convenience sample between 3/11/2020 and 10/30/2021, comparing dispensing rates to resident shift type (morning, midday, night) and training year (PGY-1 to 3) using the Kruskal Wallis test. Current residents' attitudes regarding naloxone were assessed using a validated tool, the Naloxone-Related Risk Compensation Belief survey. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,789,486,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Of 274 kits, 76 could be linked with one of 2,409 resident shifts, yielding a dispensing rate of 3.15 kits/100 shifts. Of 34 residents scheduled, 12 (35.3%) ordered no kits, 7 (20.6%) ordered 1 kit, and 15 (44.1%) ordered $\\\\geq 2$ kits. Dispensing rates were highest among PGY-3 (4.35 kits/100 shifts) compared to PGY-2 (2.20) and PGY-1 (1.06) residents $(p = 0.006)$ . Kit dispensing was more frequent during night (3.82 kits/100 shifts) compared to midday (3.23) and day \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,70,939,212]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(2.20) shifts; this was not statistically significant $(p = 0.09)$ . Of 25 EM residents surveyed, 21 responded $(84\\\\%)$ . Fewer than $10\\\\%$ believed dispensing naloxone to people who used opioids would result in greater drug use or decreased treatment-seeking, and only 1 resident agreed that there should be a limit to the number of times a person receives naloxone. None reported that naloxone was enabling for people who used drugs, or that dispensing naloxone sends the message that residents condone risky opioid use. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,214,921,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conclusions: EM resident take-home naloxone dispensing was associated with more senior year of training, suggesting a need to better educate junior residents. Few residents expressed concern that naloxone would increase risky drug use or decrease treatment-seeking. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[516,311,913,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"53 Targeted Procedure Lab to Improve Self-Identified Deficiencies Among Graduating Emergency Medicine Residents \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,376,906,407]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Andrew Bobbett, Stephanie Cohen, Andrew Bobbett, Jeffrey Thompson, Robert Pell, Latha Ganti \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,424,937,502]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Background: Simulation is the artificial recreation of an experience for the purpose of education. This study focuses on the usefulness of targeted procedural labs in correcting self-identified deficiencies and increasing procedural confidence in emergency medicine (EM) resident procedural skills. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,503,921,565]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objectives: To determine whether a procedure lab targeting procedures that EM residents do not feel proficient in can increase feelings of confidence prior to residency graduation. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,566,937,741]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: A survey was performed comparing EM residents that participated in a targeted procedure lab versus residents that did not. The sample included 31 EM residents delineated by program year at onset of study—Group A: Class of 2021 (15 residents, year 2), Group B: Class of 2020 (16 residents, year 3). In June 2020, groups A and B filled out a survey indicating procedural confidence. A procedure lab was made based on the top 12 procedures group A felt they needed practice in. Group A participated in the procedure lab in March 2021. Group B did not receive the targeted treatment lab. Group A completed the post intervention survey in May 2021. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,742,937,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Group A self-reported a decreased need for more procedural support training and increased confidence in procedural skills compared to Group B in nine out of twelve procedures. Results from an inference for two proportions indicate a statistically significant difference between the percent of Group A compared to Group B participants wanting more experience performing Subclavian Line (TS = -2.102, p < .05; 95%CI (-0.68, -0.02) and Thoracotomy (TS = -2.01, p < .05; 95%CI (-0.603, -0.007) procedures, indicating Group A reported significantly increased confidence in the Subclavian Line and Thoracotomy procedures. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[57,37,248,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CORD Abstracts Issue 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[57,953,323,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Western Journal of Emergency Medicine \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[486,954,511,964]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"S36 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[707,953,939,967]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Volume 24, Supplement : May2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.5811/westjem.61114"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"8f560a2bcc3fea981faed081bbb7be156d406122afc94d45b79e481645e0bf59"},"title":{"kind":"string","value":"Strong Correlation Between Depression/Stress and Self-Reported Microaggressions in Emergency Medicine Residents"}}},{"rowIdx":182,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Harikishore Kakarla|Udari. Gnaneshwara chary"},"content_list":{"kind":"list like","value":[{"bbox":"[60,131,243,144]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PAPER $\\cdot$ OPEN ACCESS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,157,697,181]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Low Power Analog Multiplexers for ECG Applications ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[60,195,721,209]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To cite this article: Udari. Gnaneshwara chary and Harikishore Kakarla 2021 J. Phys.: Conf. Ser. 1804 012177 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[60,251,389,264]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"View the article online for updates and enhancements. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,785,144,823]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0770/5fa33a06f60f3fb50ca546fdc6be63b4723e87ba03f85e2791ecc41c92a1b588.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[144,790,408,808]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Electrochemical Society ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[147,808,408,817]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Advancing solid state & electrochemical science & technology ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[144,832,556,853]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"239th ECS Meeting with IMCS18 ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[146,863,554,881]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DIGITAL MEETING May 30-June 3, 2021 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[146,891,512,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Live events daily • Free to register ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[579,771,937,940]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0726/5b6337e2703a478883b7178d9aa3ea25855118eeb5896d382e704a930694f49a.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[60,42,410,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[236,942,759,956]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This content was downloaded from IP address 181.199.62.255 on 21/05/2021 at 20:10 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[115,229,789,252]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Low Power Analog Multiplexers for ECG Applications ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[233,283,653,301]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Udari. Gnaneshwara chary $^{1}$ , Harikishore Kakarla $^{2}$ , ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[231,306,880,338]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Research Scholar, Koneru Lakhmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India-5225022. E-mail: gnaneshwarchary@gmail.com ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[231,350,882,382]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{2}$ Professor, Koneru Lakhmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India-522502. E-mail: kakarla.harikishore@kluniversity.in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[231,395,880,491]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract. This paper demonstrates the design of the 8 channel and 16 channel biomedical data selector with passtransistor switches. Pass transistor switches are designed with NMOS switch logic in $45\\mathrm{nm}$ technology. Data selectors are the important input circuitry to instrumentation amplifier in the Electrocardiogram (ECG). Generally, Inputs for ECG are very low voltages in terms of millivolts and frequency also in HZs. The proposed designs are useful in 3 lead 6 lead and 12 lead ECGs. The power dissipation is $11.055\\mathrm{pW}$ at 1HZ and its calculated for supply voltages of $0.5\\mathrm{V}$ and frequency analysis are done in between 1HZ to $10\\mathrm{KHZ}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[233,517,605,532]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keyword: ECG, Analog multiplexer, data acquisition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,559,243,572]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1. Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,587,880,707]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the instruments that are very much helpful for the cardiac patients is Electrocardiogram (ECG). At the time of cardiac cycle ECG will produce wave forms in the display. Based on waveform doctors will monitor and observe the heart functionality. ECG consists of Data selector, instrumentation amplifier, filter and ADC[1,2]. Instrumentation amplifier consist of inverting and non inverting terminals[5, 6]. These inputs are acquired by the analog data selector which was fed by the different sensing leads connected to the body. Most of the biomedical circuits are implemented with the NMOS, PMOS and CMOS logic circuits for low power and Low noise advantages[7, 8, 9]. FINFETs are the emerging technology for low power applications[10]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,722,880,768]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1.1. Biomedical Data Transmission System Electrodes are placed on the various locations of the body, It is the best way to measure and diagnose abnormal rhythms of the heart[3], Electrodes connected to the body in order to record ECG are called leads. These leads are divided into three types ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,781,645,796]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(i) Bipolar limb leads (ii) Unipolar limb leads (iii) Unipolar chest leads ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,811,880,857]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"These leads collect information which is in the analog form having less amplitude. In order to process these signal it has to be amplified and hence instrumentation amplifier is required. Two different analog data selectors are used to acquire the inputs for both the terminals of an instrumentation amplifier[4]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,880,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,913,198,934]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CC BY ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[198,913,880,935]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[112,938,369,950]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Published under licence by IOP Publishing Ltd ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[497,940,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,163,410,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2. Analog Multiplexer (Data Selector) ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,193,884,285]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pass transistor is nothing but series of NMOS transistors or series of PMOS transistors[11, 13]. Here we are designed pass transistor based analog multiplexer. Multiplexer is a digital circuit which to select one output from many inputs. In this work 8 to 1 analog multiplexer to select 8 various amplitudes and frequency inputs. MOSFETs are working as switches and based on selection lines MOSFET transmits input signals to output. NMOS based analog multiplexers are designed and analyzed with power, frequency parameters[12]. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[112,298,884,404]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The 8:1 analog multiplexer design uses 24 Pass transistors in the logic and 6 transistors for three selection lines. The 16:1 analog multiplexer design use 54 transistors and for selection lines 8 transistors are required. Power dissipation is calculated at the VDD node and equation for power $\\mathrm{P} = \\mathrm{VDD} * \\mathrm{ID}$ . The design works with the 0.5v and power dissipation is low in terms of pico watts. Here on resistance plays a key role in power consumption at transistors[14,15]. ON resistance of each transistor is measured with the equation $\\mathrm{RON} = \\mathrm{VDD} / \\mathrm{ID}$ . Here ID is the drain to source current and equation for ID current in saturation is $\\mathrm{ID} = (\\mathrm{VGS} - \\mathrm{Vth}) / 2$ (1) VGS is gate to source voltage and Vth is threshold voltage. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[191,433,821,714]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1: Testbench of 8:1 Analog Multiplexer for Biomedical signal transmission \"]","image_footnote":"[]","img_path":"images/0418/da1721a4a07d3c26ec27244b3cc3727f4dda90340a26ad01097a0f6cad8e9c03.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[112,747,882,809]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The figure1 represents the testbench setup for analog multiplexer. Alphabets A to H are considered as inputs and S0,S1,S2 are selection lines. All eight inputs are aranged with different analog signals with different voltages and also frequencies. Selectionlines are pulse waveforms which will generate the selection lines form 0 to 8. Supply voltage for this 8:1 analog multiplexer is $500\\mathrm{mV}$ or $0.5\\mathrm{V}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,880,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[149,140,796,388]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2: Schematic diagram of 8:1 Analog Multiplexer for Biomedical signal transmission \"]","image_footnote":"[]","img_path":"images/0097/ce9bcb6b08d0314e7f7ec2f6281b3915e435e223af0907617f6f4c48fbbf66ef.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[164,507,835,767]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 2 is the schematic diagram of 8:1 multiplexer circuit. Here NMOS transistors are working as a switches to pass the Analog information from eight inputs. Three CMOS inverters are used in selection line system. \",\"Figure 3: Testbench of 16:1 Analog Multiplexer for Biomedical signal transmission \",\"The figure3 is the testbench of 16:1 analog multiplexer. In this testbench 16 different analog inputs are applied with varying frequencies. Four selection lines are used to select 16 different input lines. \"]","image_footnote":"[]","img_path":"images/0145/ef4bf5dcc5596b689957712c2662141acca5cf540d8b9b379e81121baa637862.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[114,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,882,80]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[203,130,845,394]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4: Schematic diagram of 16:1 Analog Multiplexer for Biomedical signal transmission \",\"Figure 4 is the schematic diagram of 16:1 multiplexer circuit. Here NMOS transistors are working as a switches to pass the Analog information from sixteen inputs. Four CMOS inverters are used in selection line system. \"]","image_footnote":"[]","img_path":"images/0805/0eb567c11888794501a5cfc7467c2d24b1f2f44cd77ceb93cf9ccbf25ab6f753.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[114,492,319,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3\\.Results and Discussions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[124,522,884,732]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 5: Output wave form of 8 to 1 mux at 1HZ frequency \",\"The figure 5 shows output waveform of one of the input signal which consist of $1\\\\mathrm{HZ}$ frequency with amplitude $2\\\\mathrm{mv}$ . By varying Selection line inputs from 0 to 8 are amplitude signalse are transferred to output V0. We also plotted current signals to measure the current and with this we measured power dissipation for 8:1 multiplexer. Figure 6 represents the 8:1 analog multiplexers at 500HZ, 200HZ, 100HZ and 50HZ. \"]","image_footnote":"[]","img_path":"images/0530/84a00a22f9b5e29e0360df505cd59f816eaf70270bad01767ac7c4972317a0bd.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[114,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,882,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing 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","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[139,108,884,283]","code_body":null,"code_caption":null,"image_caption":"[\"(b) \",\"Figure 7: 16:1 Analog multiplexer output waveform at a) 50HZ b) 100HZ \"]","image_footnote":"[]","img_path":"images/0408/dec2a6bd74910b1fec7fd27d312198ce8af69d03f3ba34b13c9644dc2401a193.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[114,342,878,374]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The figure 7 shows output waveform of 16:1 analog multiplexer at various frequencies like $50\\mathrm{Hz}$ and $100\\mathrm{HZ}$ frequencies at $1\\mathrm{uV}$ of input signal voltage. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[119,385,223,400]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ANALYSIS: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[290,415,707,595]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0451/58626b45d276ad4bb779272432d9f4a3ef9d10ca33d5a19fe59984c2c379561d.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td>Switching frequencies</td><td>current</td><td>Power</td></tr><tr><td>1HZ</td><td>21.91PA</td><td>10.955 pW</td></tr><tr><td>50HZ</td><td>22.03PA</td><td>11.015 pW</td></tr><tr><td>100HZ</td><td>22.11PA</td><td>11.055 pW</td></tr><tr><td>500HZ</td><td>22.18PA</td><td>11.09pW</td></tr><tr><td>1KHZ</td><td>22.55PA</td><td>11.275 pW</td></tr><tr><td>10KHZ</td><td>33.79PA</td><td>16.895pW</td></tr></table>","table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[287,663,709,864]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0548/f9b1373f2e15531f937b5878d3e80241812e51f663a72124ddf8bdbfc8d24dc5.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td>Switching frequencies</td><td>current</td><td>Power</td></tr><tr><td>1HZ</td><td>24.71PA</td><td>12.55 pW</td></tr><tr><td>50HZ</td><td>26.13PA</td><td>14.15 pW</td></tr><tr><td>100HZ</td><td>26.11PA</td><td>14.03 pW</td></tr><tr><td>500HZ</td><td>26.81PA</td><td>15.9pW</td></tr><tr><td>1KHZ</td><td>26.75PA</td><td>15.275 pW</td></tr><tr><td>10KHZ</td><td>37.79PA</td><td>18.895pW</td></tr></table>","table_caption":"[\"Table 1: 8:1 Analog multiplexer with Supply voltage ${0.5}\\\\mathrm{\\\\;V}{45}\\\\mathrm{\\\\;{nm}}$ Technology \",\"Table 2: 16:1 Analog multiplexer with Supply voltage ${0.5}\\\\mathrm{\\\\;V}{45}\\\\mathrm{\\\\;{nm}}$ Technology \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[114,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,880,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,940,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[112,134,878,180]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Table 1 and Table 2 represent the current and power results at various frequencies of 8:1 and 16:1 analog multiplexers. The average power of 8:1 analog multiplexer is $11.055\\mathrm{pW}$ and average power of 16:1 analog multiplexer is $14.15\\mathrm{pW}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,193,231,207]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4. Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[112,207,882,269]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This proposed 8:1 and 16:1 analog multiplexers are useful in biomedical transmission and these are designed to transmit mV volts of voltages and these circuits can transmit the signals with various frequencies like 1Hz to 10KHz signals without any distortion at the output. Power consumption of the Signal are attained in the result analysis. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,283,205,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,298,882,900]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[1] K Hari Kishore “Implementation of Low Power and Area Efficient 7-Bit Flash Analog to Digital Converter” Journal of Nanoscience and Nanotechnology, ISSN: 1546-1955, Volume-16, Issue No: (5-6), Page No: 22132217, June 2019. \",\"[2] K Hari Kishore “A Low Power 8-Bit Current-Steering DAC Using CMOS Technology” International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6, Page No: 137-140, April 2019. \",\"[3] Sheng-Cheng Lee; Tsan-Jieh Chen; HermingChiueh, \\\"A multichannel multi-mode physiological signals acquisition and analysis platform,\\\" Circuits and Systems (ISCAS), 2013 IEEE International Symposium on vol., no., pp.397,400, 19-23 May 2013. \",\"[4] Mahesh Madavath, K Hari Kishore \\\"Design and Analysis of Receiver Front-End of CMOS Cascode Common Source Stage with Inductive Degeneration Low Noise Amplifier on 65 nm Technology Process\\\" Journal of Nanoscience and Nanotechnology, ISSN: 1546-1955, Volume-16, Issue No: (5-6), Page No: 2628-2634, June 2019. \",\"[5] Mahesh Madavath, K Hari Kishore“Design and Analysis of Receiver Front-End of CMOS Cascode Common Source Stage with Inductive Degeneration Low Noise Amplifier on 65 nm Technology Process” Journal of Nanoscience and Nanotechnology, ISSN: 1546-1955, Volume-16, Issue No: (5-6), Page No: 2628-2634, June 2019. \",\"[6] Mahesh Madavath, K Hari Kishore “RF Front-End Design of Inductorless CMOS LNA Circuit with Noise Cancellation Method for IoT Applications” International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6, Page No: 176-183, April 2019. \",\"[7] Avinash Yadlapati, Hari Kishore Kakarla \\\"Low-power design-for-test implementation on phase-locked loop design\\\" Measurement and Control, ISSN: 0020-2940, Volume-52, Issue No: (7-8), Page No: 995-1001, June 2019. \",\"[8] Avinash Yadlapati, K Hari Kishore “Implementation of Asynchronous FIFO using Low Power DFT” International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6S, Page No: 152-156, April 2019. \",\"[9] Mahesh Madavath, Hari Kishore Kakarla, Azham Hussain, C.S. Boopathy “Design and Analysis of CMOS RF Receiver Front-End of LNA for Wireless Applications” Microprocessors and Microsystems, ISSN: 0141-9331, Volume-75, Article: 102999, June 2020. \",\"[10] K.Sarath Chandra, K Hari Kishore \\\"Electrical Characteristics of Double Gate FINFET under Different Modes of Operation\\\" International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6, Page No: 172-175, April 2019. \",\"[11] Liqiong Wei; Roy, K.; De, V.K., \\\"Low voltage low power CMOS design techniques for deep submicron ICs,\\\" VLSI Design, 2000. Thirteenth International Conference on, vol., no., pp.24,29, 2000. \",\"[12] Zimmermann, Reto; Fichtner, Wolfgang, \\\"Low-power logic styles: CMOS versus pass-transistor logic,\\\" SolidState Circuits, IEEE Journal of, vol.32, no.7, pp.1079,1090, Jul 1997. \",\"[13] K. Yano, Y. Sasaki, K. Rikino, and K. Seki, \\\"Top-down passtransistor logic design\\\", IEEE J. Solid-State Circuits, vol. 31, pp. 792-803, June1996. \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[114,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,880,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,939,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"7 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[114,134,882,210]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"[14] Galup-Montoro, C.; Schneider, M.C.; Coitinho, R.M., \\\"Resizing rules for MOS analog-design reuse,\\\" Design Test of Computers, IEEE, vol.19, no.2, pp.50,58, Mar-Apr 2002. \",\"[15] Galup-Montoro, C.; Schneider, M.C., \\\"Resizing rules for the reuse of MOS analog designs,\\\" Integrated Circuits and Systems Design, 2000. Proceedings. 13th Symposium on, vol., no., pp.89,93, 20 \"]","page_idx":"8","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[114,65,226,78]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ICMAICT 2020 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[774,65,880,79]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOP Publishing ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[112,81,373,96]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Journal of Physics: Conference Series ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[457,81,882,93]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[497,940,507,948]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[60,131,243,144]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PAPER $\\\\cdot$ OPEN ACCESS \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,157,697,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Low Power Analog Multiplexers for ECG Applications \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,195,721,209]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To cite this article: Udari. Gnaneshwara chary and Harikishore Kakarla 2021 J. Phys.: Conf. Ser. 1804 012177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[60,251,389,264]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"View the article online for updates and enhancements. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,785,144,823]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0770/5fa33a06f60f3fb50ca546fdc6be63b4723e87ba03f85e2791ecc41c92a1b588.jpg\",\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n 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null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[236,942,759,956]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This content was downloaded from IP address 181.199.62.255 on 21/05/2021 at 20:10 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[115,229,789,252]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Low Power Analog Multiplexers for ECG Applications \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,283,653,301]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Udari. Gnaneshwara chary $^{1}$ , Harikishore Kakarla $^{2}$ , \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[231,306,880,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Research Scholar, Koneru Lakhmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India-5225022. E-mail: gnaneshwarchary@gmail.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[231,350,882,382]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{2}$ Professor, Koneru Lakhmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India-522502. E-mail: kakarla.harikishore@kluniversity.in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[231,395,880,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract. This paper demonstrates the design of the 8 channel and 16 channel biomedical data selector with passtransistor switches. Pass transistor switches are designed with NMOS switch logic in $45\\\\mathrm{nm}$ technology. Data selectors are the important input circuitry to instrumentation amplifier in the Electrocardiogram (ECG). Generally, Inputs for ECG are very low voltages in terms of millivolts and frequency also in HZs. The proposed designs are useful in 3 lead 6 lead and 12 lead ECGs. The power dissipation is $11.055\\\\mathrm{pW}$ at 1HZ and its calculated for supply voltages of $0.5\\\\mathrm{V}$ and frequency analysis are done in between 1HZ to $10\\\\mathrm{KHZ}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[233,517,605,532]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keyword: ECG, Analog multiplexer, data acquisition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,559,243,572]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1. Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,587,880,707]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the instruments that are very much helpful for the cardiac patients is Electrocardiogram (ECG). At the time of cardiac cycle ECG will produce wave forms in the display. Based on waveform doctors will monitor and observe the heart functionality. ECG consists of Data selector, instrumentation amplifier, filter and ADC[1,2]. Instrumentation amplifier consist of inverting and non inverting terminals[5, 6]. These inputs are acquired by the analog data selector which was fed by the different sensing leads connected to the body. Most of the biomedical circuits are implemented with the NMOS, PMOS and CMOS logic circuits for low power and Low noise advantages[7, 8, 9]. FINFETs are the emerging technology for low power applications[10]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,722,880,768]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1.1. Biomedical Data Transmission System Electrodes are placed on the various locations of the body, It is the best way to measure and diagnose abnormal rhythms of the heart[3], Electrodes connected to the body in order to record ECG are called leads. These leads are divided into three types \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,781,645,796]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(i) Bipolar limb leads (ii) Unipolar limb leads (iii) Unipolar chest leads \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,811,880,857]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"These leads collect information which is in the analog form having less amplitude. In order to process these signal it has to be amplified and hence instrumentation amplifier is required. Two different analog data selectors are used to acquire the inputs for both the terminals of an instrumentation amplifier[4]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,65,226,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ICMAICT 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,880,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,373,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[457,81,882,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,913,198,934]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CC BY \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[198,913,880,935]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[112,938,369,950]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Published under licence by IOP Publishing Ltd \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[497,940,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,163,410,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2. Analog Multiplexer (Data Selector) \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,193,884,285]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pass transistor is nothing but series of NMOS transistors or series of PMOS transistors[11, 13]. Here we are designed pass transistor based analog multiplexer. Multiplexer is a digital circuit which to select one output from many inputs. In this work 8 to 1 analog multiplexer to select 8 various amplitudes and frequency inputs. MOSFETs are working as switches and based on selection lines MOSFET transmits input signals to output. NMOS based analog multiplexers are designed and analyzed with power, frequency parameters[12]. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,298,884,404]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The 8:1 analog multiplexer design uses 24 Pass transistors in the logic and 6 transistors for three selection lines. The 16:1 analog multiplexer design use 54 transistors and for selection lines 8 transistors are required. Power dissipation is calculated at the VDD node and equation for power $\\\\mathrm{P} = \\\\mathrm{VDD} * \\\\mathrm{ID}$ . The design works with the 0.5v and power dissipation is low in terms of pico watts. Here on resistance plays a key role in power consumption at transistors[14,15]. ON resistance of each transistor is measured with the equation $\\\\mathrm{RON} = \\\\mathrm{VDD} / \\\\mathrm{ID}$ . Here ID is the drain to source current and equation for ID current in saturation is $\\\\mathrm{ID} = (\\\\mathrm{VGS} - \\\\mathrm{Vth}) / 2$ (1) VGS is gate to source voltage and Vth is threshold voltage. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[191,433,821,714]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1: Testbench of 8:1 Analog Multiplexer for Biomedical signal transmission \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0418/da1721a4a07d3c26ec27244b3cc3727f4dda90340a26ad01097a0f6cad8e9c03.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[112,747,882,809]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The figure1 represents the testbench setup for analog multiplexer. Alphabets A to H are considered as inputs and S0,S1,S2 are selection lines. All eight inputs are aranged with different analog signals with different voltages and also frequencies. Selectionlines are pulse waveforms which will generate the selection lines form 0 to 8. Supply voltage for this 8:1 analog multiplexer is $500\\\\mathrm{mV}$ or $0.5\\\\mathrm{V}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,65,226,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ICMAICT 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,880,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,373,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[457,81,882,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,939,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[149,140,796,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2: Schematic diagram of 8:1 Analog Multiplexer for Biomedical signal transmission \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0097/ce9bcb6b08d0314e7f7ec2f6281b3915e435e223af0907617f6f4c48fbbf66ef.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[164,507,835,767]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 2 is the schematic diagram of 8:1 multiplexer circuit. Here NMOS transistors are working as a switches to pass the Analog information from eight inputs. Three CMOS inverters are used in selection line system. \\\",\\\"Figure 3: Testbench of 16:1 Analog Multiplexer for Biomedical signal transmission \\\",\\\"The figure3 is the testbench of 16:1 analog multiplexer. In this testbench 16 different analog inputs are applied with varying frequencies. Four selection lines are used to select 16 different input lines. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0145/ef4bf5dcc5596b689957712c2662141acca5cf540d8b9b379e81121baa637862.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[114,65,226,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ICMAICT 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,882,80]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[457,81,882,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,939,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[203,130,845,394]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4: Schematic diagram of 16:1 Analog Multiplexer for Biomedical signal transmission \\\",\\\"Figure 4 is the schematic diagram of 16:1 multiplexer circuit. Here NMOS transistors are working as a switches to pass the Analog information from sixteen inputs. Four CMOS inverters are used in selection line system. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0805/0eb567c11888794501a5cfc7467c2d24b1f2f44cd77ceb93cf9ccbf25ab6f753.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[114,492,319,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3\\\\.Results and Discussions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[124,522,884,732]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 5: Output wave form of 8 to 1 mux at 1HZ frequency \\\",\\\"The figure 5 shows output waveform of one of the input signal which consist of $1\\\\\\\\mathrm{HZ}$ frequency with amplitude $2\\\\\\\\mathrm{mv}$ . By varying Selection line inputs from 0 to 8 are amplitude signalse are transferred to output V0. We also plotted current signals to measure the current and with this we measured power dissipation for 8:1 multiplexer. Figure 6 represents the 8:1 analog multiplexers at 500HZ, 200HZ, 100HZ and 50HZ. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0530/84a00a22f9b5e29e0360df505cd59f816eaf70270bad01767ac7c4972317a0bd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[114,65,226,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ICMAICT 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,882,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n 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\"ANALYSIS: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[290,415,707,595]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0451/58626b45d276ad4bb779272432d9f4a3ef9d10ca33d5a19fe59984c2c379561d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Switching frequencies</td><td>current</td><td>Power</td></tr><tr><td>1HZ</td><td>21.91PA</td><td>10.955 pW</td></tr><tr><td>50HZ</td><td>22.03PA</td><td>11.015 pW</td></tr><tr><td>100HZ</td><td>22.11PA</td><td>11.055 pW</td></tr><tr><td>500HZ</td><td>22.18PA</td><td>11.09pW</td></tr><tr><td>1KHZ</td><td>22.55PA</td><td>11.275 pW</td></tr><tr><td>10KHZ</td><td>33.79PA</td><td>16.895pW</td></tr></table>\",\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[287,663,709,864]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0548/f9b1373f2e15531f937b5878d3e80241812e51f663a72124ddf8bdbfc8d24dc5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Switching frequencies</td><td>current</td><td>Power</td></tr><tr><td>1HZ</td><td>24.71PA</td><td>12.55 pW</td></tr><tr><td>50HZ</td><td>26.13PA</td><td>14.15 pW</td></tr><tr><td>100HZ</td><td>26.11PA</td><td>14.03 pW</td></tr><tr><td>500HZ</td><td>26.81PA</td><td>15.9pW</td></tr><tr><td>1KHZ</td><td>26.75PA</td><td>15.275 pW</td></tr><tr><td>10KHZ</td><td>37.79PA</td><td>18.895pW</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1: 8:1 Analog multiplexer with Supply voltage ${0.5}\\\\\\\\mathrm{\\\\\\\\;V}{45}\\\\\\\\mathrm{\\\\\\\\;{nm}}$ Technology \\\",\\\"Table 2: 16:1 Analog multiplexer with Supply voltage ${0.5}\\\\\\\\mathrm{\\\\\\\\;V}{45}\\\\\\\\mathrm{\\\\\\\\;{nm}}$ Technology \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[114,65,226,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ICMAICT 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,880,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,373,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[457,81,882,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,940,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[112,134,878,180]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Table 1 and Table 2 represent the current and power results at various frequencies of 8:1 and 16:1 analog multiplexers. The average power of 8:1 analog multiplexer is $11.055\\\\mathrm{pW}$ and average power of 16:1 analog multiplexer is $14.15\\\\mathrm{pW}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,193,231,207]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4. Conclusion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[112,207,882,269]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This proposed 8:1 and 16:1 analog multiplexers are useful in biomedical transmission and these are designed to transmit mV volts of voltages and these circuits can transmit the signals with various frequencies like 1Hz to 10KHz signals without any distortion at the output. Power consumption of the Signal are attained in the result analysis. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,283,205,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,298,882,900]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[1] K Hari Kishore “Implementation of Low Power and Area Efficient 7-Bit Flash Analog to Digital Converter” Journal of Nanoscience and Nanotechnology, ISSN: 1546-1955, Volume-16, Issue No: (5-6), Page No: 22132217, June 2019. \\\",\\\"[2] K Hari Kishore “A Low Power 8-Bit Current-Steering DAC Using CMOS Technology” International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6, Page No: 137-140, April 2019. \\\",\\\"[3] Sheng-Cheng Lee; Tsan-Jieh Chen; HermingChiueh, \\\\\\\"A multichannel multi-mode physiological signals acquisition and analysis platform,\\\\\\\" Circuits and Systems (ISCAS), 2013 IEEE International Symposium on vol., no., pp.397,400, 19-23 May 2013. \\\",\\\"[4] Mahesh Madavath, K Hari Kishore \\\\\\\"Design and Analysis of Receiver Front-End of CMOS Cascode Common Source Stage with Inductive Degeneration Low Noise Amplifier on 65 nm Technology Process\\\\\\\" Journal of Nanoscience and Nanotechnology, ISSN: 1546-1955, Volume-16, Issue No: (5-6), Page No: 2628-2634, June 2019. \\\",\\\"[5] Mahesh Madavath, K Hari Kishore“Design and Analysis of Receiver Front-End of CMOS Cascode Common Source Stage with Inductive Degeneration Low Noise Amplifier on 65 nm Technology Process” Journal of Nanoscience and Nanotechnology, ISSN: 1546-1955, Volume-16, Issue No: (5-6), Page No: 2628-2634, June 2019. \\\",\\\"[6] Mahesh Madavath, K Hari Kishore “RF Front-End Design of Inductorless CMOS LNA Circuit with Noise Cancellation Method for IoT Applications” International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6, Page No: 176-183, April 2019. \\\",\\\"[7] Avinash Yadlapati, Hari Kishore Kakarla \\\\\\\"Low-power design-for-test implementation on phase-locked loop design\\\\\\\" Measurement and Control, ISSN: 0020-2940, Volume-52, Issue No: (7-8), Page No: 995-1001, June 2019. \\\",\\\"[8] Avinash Yadlapati, K Hari Kishore “Implementation of Asynchronous FIFO using Low Power DFT” International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6S, Page No: 152-156, April 2019. \\\",\\\"[9] Mahesh Madavath, Hari Kishore Kakarla, Azham Hussain, C.S. Boopathy “Design and Analysis of CMOS RF Receiver Front-End of LNA for Wireless Applications” Microprocessors and Microsystems, ISSN: 0141-9331, Volume-75, Article: 102999, June 2020. \\\",\\\"[10] K.Sarath Chandra, K Hari Kishore \\\\\\\"Electrical Characteristics of Double Gate FINFET under Different Modes of Operation\\\\\\\" International Journal of Innovative Technology and Exploring Engineering, ISSN: 2278-3075, Volume-8, Issue No: 6, Page No: 172-175, April 2019. \\\",\\\"[11] Liqiong Wei; Roy, K.; De, V.K., \\\\\\\"Low voltage low power CMOS design techniques for deep submicron ICs,\\\\\\\" VLSI Design, 2000. Thirteenth International Conference on, vol., no., pp.24,29, 2000. \\\",\\\"[12] Zimmermann, Reto; Fichtner, Wolfgang, \\\\\\\"Low-power logic styles: CMOS versus pass-transistor logic,\\\\\\\" SolidState Circuits, IEEE Journal of, vol.32, no.7, pp.1079,1090, Jul 1997. \\\",\\\"[13] K. Yano, Y. Sasaki, K. Rikino, and K. Seki, \\\\\\\"Top-down passtransistor logic design\\\\\\\", IEEE J. Solid-State Circuits, vol. 31, pp. 792-803, June1996. \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[114,65,226,78]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ICMAICT 2020 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[774,65,880,79]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOP Publishing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[112,81,373,96]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Journal of Physics: Conference Series \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[457,81,882,93]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1804 (2021) 012177 doi:10.1088/1742-6596/1804/1/012177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[497,939,507,948]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"7 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,134,882,210]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"[14] Galup-Montoro, C.; Schneider, M.C.; Coitinho, R.M., \\\\\\\"Resizing rules for MOS analog-design reuse,\\\\\\\" Design Test of Computers, IEEE, vol.19, no.2, pp.50,58, Mar-Apr 2002. \\\",\\\"[15] Galup-Montoro, C.; Schneider, M.C., \\\\\\\"Resizing rules for the reuse of MOS analog designs,\\\\\\\" Integrated Circuits and Systems Design, 2000. 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Imaging is critical for characterizing dynamic changes in tumors and metastases, the tumor microenvironment, tumor-stroma interactions, and drug targets, at multiscale levels. Magnetic resonance imaging (MRI) has emerged to be a primary imaging modality for both clinical and preclinical applications due to its advantages over other modalities, including sensitivity to soft tissues, nondepth limitations, and the use of nonionizing radiation. However, extending the application of MRI to achieve both qualitative and quantitative precise molecular imaging with the capability to quantify molecular biomarkers for early detection, staging, and monitoring therapeutic treatment requires the capacity to overcome several major challenges including the trade-off between metal-binding affinity and relaxivity, which is an issue frequently associated with small chelator contrast agents. In this review, we will introduce the criteria of ideal contrast agents for precision molecular imaging and discuss the relaxivity of current contrast agents with defined first shell coordination water molecules. We will then report our advances in creating a new class of protein-targeted MRI contrast agents (ProCAs) with contributions to relaxivity largely derived from the secondary sphere and correlation time. We will summarize our rationale, design strategy, and approaches to the development and optimization of our pioneering ProCAs with desired high relaxivity, metal stability, and molecular biomarker-targeting capability, for precision MRI. From first generation (ProCA1) to third generation (ProCA32), we have achieved dual high r1 and r2 values that are 6- to 10-fold higher than clinically approved contrast agents at magnetic fields of 1.5 T, and their relaxivity values at high field are also significantly higher, which enables high resolution during small animal imaging. Further engineering of multiple targeting moieties enables ProCA32 agents that have strong biomarker-binding affinity and specificity for an array of key molecular biomarkers associated with various chronic diseases, while maintaining relaxation and exceptional metal-binding and selectivity, serum stability, and resistance to transmetallation, which are critical in mitigating risks associated with metal toxicity. Our leading product ProCA32.collagen has enabled the first early detection of liver metastasis from multiple cancers at early stages by mapping the tumor environment and early stage of fibrosis from liver and lung in vivo, with strong translational potential to extend to precision MRI for preclinical and clinical applications for precision diagnosis and treatment."},"author":{"kind":"string","value":"Li, Dongjun|Kirberger, Michael|Qiao, Jingjuan|Gui, Zongxiang|Xue, Shenghui|Pu, Fan|Jiang, Jie|Xu, Yiting|Tan, Shanshan|Salarian, Mani|Ibhagui, Oluwatosin|Hekmatyar, Khan|Yang, Jenny J."},"content_list":{"kind":"list like","value":[{"bbox":"[43,89,100,104]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[102,113,894,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[53,178,942,228]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dongjun Li, MS, Michael Kirberger, PhD, Jingjuan Qiao, PhD, Zongxiang Gui, MS, Shenghui Xue, PhD, Fan Pu, PhD, Jie Jiang, PhD, Yiting Xu, MS, Shanshan Tan, PhD, Mani Salarian, PhD, Oluwatosin Ibhagui, PhD, Khan Hekmatyar, PhD, and Jenny J. Yang, PhD ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,265,482,652]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract: Cancer and other acute and chronic diseases are results of perturbations of common molecular determinants in key biological and signaling processes. Imaging is critical for characterizing dynamic changes in tumors and metastases, the mor microenvironment, tumor-stroma interactions, and drug targets, at multiscale levels. Magnetic resonance imaging (MRI) has emerged to be a primary imaging odality for both clinical and preclinical applications due to its advantages over their modalities, including sensitivity to soft tissues, nondepth limitations, and e use of nonionizing radiation. However, extending the application of MRI to chieve both qualitative and quantitative precise molecular imaging with the capability to quantify molecular biomarkers for early detection, staging, and monitoring erapeutic treatment requires the capacity to overcome several major challenges including the trade-off between metal-binding affinity and relaxivity, which is an issue frequently associated with small chelator contrast agents. In this review, we will introduce the criteria of ideal contrast agents for precision molecular imaging and discuss the relaxivity of current contrast agents with defined first shell coordination water olecules. We will then report our advances in creating a new class of protein-targeted RI contrast agents (ProCAs) with contributions to relaxivity largely derived from the secondary sphere and correlation time. We will summarize our rationale, design strategy, and approaches to the development and optimization of our pio-erering ProCAs with desired high relaxivity, metal stability, and molecular iomarker-targeting capability, for precision MRI. From first generation ProCA1) to third generation (ProCA32), we have achieved dual high $\\mathbf{r}_1$ and $\\mathbf{r}_2$ values that are 6- to 10-fold higher than clinically approved contrast agents at agnetic fields of $1.5\\mathrm{T}$ ,and their relaxivity values at high field are also significantly higher, which enables high resolution during small animal imaging. Further engineering of multiple targeting moieties enables ProCA32 agents that have strong biomarker-binding affinity and specificity for an array of key molecular biomarkers associated with various chronic diseases, while maintaining relaxation and exceptional metal-binding and selectivity, serum stability, and resistance to transmetallation, which are critical in mitigating risks associated with metal ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,667,482,710]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"From the Center for Diagnostics and Therapeutics, Advanced Translational Imaging Facility, Department of Chemistry, Georgia State University, Atlanta, GA (D.L., M.K., J.Q., Z.G., S.X., P.F., J.J., S.T., M.S., O.I., K.H., J.J.Y.); and InLighta BioSciences, LLC, Marietta, GA (Y.X., J.J.Y). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,710,482,783]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflicts of interest and sources of funding: J.J.Y. holds shares in the company InLighta Biosciences LLC, which licenses the rights to commercialize protein-targeted MRI contrast agents. J.J.Y. is a named inventor on issued or pending patents (US8173105 [EP1901659], US8367040 [EP3378496] contrast agents, US9339559 [EP1928507, CA 2621763], US 10525150 targeted contrast agents, US9956304 [EP2257316], US15/910893, US17/068215 contrast agents and imaging, US15/572,863 [WO16793465.2] targeted contrast agents). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,782,482,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This work was supported in part by NIH grants 33CA235319, R42AA112713, R42CA183376, 1R01EB007268, and S100D027045 to J.J.Y. Additional support for commercialization was provided to InLighta BioSciences by NIH (STTR and SBIR) through grants R42AA025863, R42CA183376, 1R44CA268403-01A1, NIDDK R01 DK126080-01A1, and UT2AA028659-01. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,834,482,865]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Correspondence to: Jenny J. Yang, PhD, Center for Diagnostics and Therapeutics, Advanced Translational Imaging Facility, Department of Chemistry, Georgia State University, Atlanta, GA 30303. E-mail: jenny@gsu.edu. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,865,482,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,906,213,915]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISSN: 0020-9996/24/5902-0170 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,915,245,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DOI: 10.1097/RLI.0000000000001057 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,258,956,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"toxicity. Our leading product ProCA32.collagen has enabled the first early detection of liver metastasis from multiple cancers at early stages by mapping the tumor environment and early stage of fibrosis from liver and lung in vivo, with strong translational potential to extend to precision MRI for preclinical and clinical applications for precision diagnosis and treatment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,327,937,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Key Words: MRI, contrast agent, protein-based, dual contrast, early detection ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,347,701,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Invest Radiol 2024;59:170-186 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,372,956,618]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chronic diseases including alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), and various types of cancers are results of perturbations of common molecular determinants in key biological and signaling processes. Noninvasive imaging is critical for characterizing dynamic changes of molecular disease biomarkers for disease progression and regression upon treatment or during therapy. Compared with x-rays and computed tomography, magnetic resonance imaging (MRI) provides improved imaging sensitivity of soft tissues, including nerves, muscles, ligaments, and tendons, without using ionizing radiation. Magnetic resonance imaging also provides better resolution, more comprehensive functional information, and better organ differentiation than ultrasound. In addition, it allows us to capture dynamic signal changes. Magnetic resonance imaging has emerged to be a primary imaging modality for both clinical and preclinical applications including but not limited to cardiac imaging for heart diseases; neuroimaging for Parkinson disease and epilepsy; and cancer imaging for primary and metastatic cancers, including brain tumors and hepatocellular carcinoma (HCC). This wide array of applications is largely due to the discovery and development of MRI contrast agents (CAs). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,618,956,836]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Magnetic resonance imaging CAs are molecular compounds designed to extend the known capabilities of MRI by altering the magnetic properties of nuclei, particularly protons, resulting in increasing contrast between different regions within an image, for example, distinguishing a tumor from the surrounding tissues. Gadolinium-based contrast agents (GBCAs) are the most widely used in preclinical and clinical practice because paramagnetic $\\mathrm{Gd(III)}$ has the highest number of unpaired electrons (7) with relatively slow electronic relaxation owing to its symmetric S electronic ground state, which necessitates strong nuclear relaxation. It often produces bright contrast enhancement in MR images by decreasing longitudinal relaxation $(\\mathrm{T}_{1})$ . This makes $\\mathrm{Gd(III)}$ a more desirable choice compared with other metal ions such as iron oxides, which primarily induce $\\mathrm{T}_{2}$ shortening and result in darkening contrast in $\\mathrm{T}_{2}$ images. Based on their size, contribution of water molecules, and structure, GBCAs can be divided into 3 classes: small molecule GBCAs (class I), large polymers including nanoparticle GBCAs (class II), and protein GBCAs (class III) (Fig. 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,836,956,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Class I includes the first developed Gd-chelator complexes. The major clinically available GBCAs include both macrocyclic/linear and ionic/nonionic chelators (Fig. 1A). The first GBCA, Gd-DTPA, was approved for clinical use by the Food and Drug Administration in 1988. These GBCAs coordinate Gd(III) through a nonadentate geometry, comprising 4 nitrogen and 4 oxygen ligands atoms from the chelator, and 1 available coordination site for an inner-sphere water ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[411,41,585,56]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REVIEW ARTICLE ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[41,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"170 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,312,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[513,946,956,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[102,89,464,344]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0579/ac56ea7007beae320b264d36a55f4db2dc9a56cbd89ff16efee6c843023965c4.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[466,90,691,336]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0230/279fc12e5065ce1b0ff6a400e52f332c59e83b48cd96065921ad633948302abe.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[709,94,888,338]","code_body":null,"code_caption":null,"image_caption":"[\"C \",\"IGURE 1. Three classes of GBCAs. A, Small molecule GBCA representatives Gd-BT-DO3A, Gd-HP-DO3A, Gd-DOTA, Gd-EOB-DTPA, MS-325, gadoquatane, nd gadopiclenol. B, Nanoparticle GBCA representatives. C, Protein GBCA representatives ProCA32s and ProCA1. \"]","image_footnote":"[]","img_path":"images/0059/f7ecf9fba9f6ccf92baaae454f68d4d8f4450cd46abb04f57689c717f5d16ec4.jpg","list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[37,397,486,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"olcule. Macrocyclic Gd-DOTA, $^{12,13}$ Gd-HP-DO3A, $^{14}$ and Gd-BT-DO3A $^{15}$ helate a Gd(III) in a rigid organized cavity whose size is preferable for d(III), $^{16,17}$ whereas linear Gd-DTPA, $^{11}$ Gd-DTPA-BMA, $^{18}$ Gd-BOPTA, $^{19}$ d-DTPA-BMEA, $^{20}$ and Gd-EOB-DTPA $^{21}$ have flexible open chains offering weaker protection of the Gd ion from endogenous metal ions. $^{22,23}$ adolinium-based contrast agents largely improve the sensitivity of MRI, and they also add functional information, such as perfusion $^{24}$ and cine $^{25,26}$ f heart, permeability of blood-brain barrier, $^{27}$ as well as perfusion and permeability in tumors $^{28,29}$ and inflammation. $^{30}$ Several significant GBCAs that ave been developed recently include the following: gadopliclenol, which as approved by the FDA in 2022 $^{31}$ ; gadoquatane (Bayer), a tetramer of OTA conjugates, $^{32}$ which is currently in phase 3 clinical trials $^{33,34}$ ; and OPO and PCTA, which coordinate 2 and 3 water molecules, respectively, but have yet to be FDA approved. $^{35}$ These structures have been substantially reviewed in the past. $^{35-43}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[35,592,486,901]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Today, more than one third of clinical MRIs are administered with these approved small, chelate-based MRI CAs. Projections suggest that the global MRI market size, valued at US $5.26 billion in 2022, will grow at a compound annual growth rate (CAGR) of $6.8\\%$ through 2030, based on anticipated increases in various diseases related to spine lesions, tumors, heart, and stroke impacting the area of blood vessels and brain, as well as advancements in diagnostic techniques such as open MRI, visualization software, and superconducting magnets, fueling MRI market growth.[44] This increase in market demand will also have a corresponding impact on contrast media. According to Contrast Media Market Outlook (2022-2032),[45] the global contrast media market should grow at a CAGR of $4.1\\%$ through the year 2032, with an increase in market value of US $5.67 billion from 2022 to US $8.45 billion in 2032. Despite the growth of MRI CA market and methodology, it represents only a small portion $(<18\\%)$ of the total diagnostic market (valued at US $32.3 billion in 2022 with a projected CAGR of $4.8\\%$ from 2023 to $2030^{[46]}$ ) and has not yet reached its potential in the field of molecular diagnostics, which is currently dominated by nuclear medicine. Although this clearly demonstrates a market-driven need for improved MRI CAs, future development must address several major limitations of current CAs, including the following: low biological specificity and sensitivity that impedes early detection, staging, and treatment monitoring; inability to quantify molecular biomarkers[7,47,48]; and importantly, potential issues with metal associated toxicity.[49] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[37,901,484,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One of the major limitations of approved clinical GBCAs is low relaxivity. Relaxivity is the degree to which a CA enhances the longi ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,398,958,630]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"tudinal and/or transverse water relaxation rate constants $(\\mathbb{R}_1$ and $\\mathbb{R}_2$ respectively), and thereby affects imaging. Relaxivity values $\\mathbf{r}_1$ (longitudinal) and $\\mathbf{r}_2$ (transverse) of clinical GBCAs are normally within the range of 3 to $5\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.4\\mathrm{T}$ (Fig. 2D), which is significantly smaller than the theoretical maximum value of $100\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ for $\\mathbf{r}_1^{48}$ with optimal parameters based on SBM theory (developed by Solomon, Bloembergen, and Morgan) $^{38}$ (Table 1). The small $\\mathbf{r}_2$ values of clinical GBCAs are not capable of generating significant contrast in vivo as seen in the simulated curve $^{50}$ (Fig. 3C). Heterogenous tissue backgrounds include cysts, lipids, fats, and other nonhomogeneous structures, all of which interfere with $\\mathbf{T}_1$ signal enhancement. Therefore, because of the associated small $\\mathbf{r}_1$ relaxivity with clinically approved current CAs, MRI cannot detect cancer and metastasis at early stage ( $<1-2\\mathrm{cm}$ ) with desired specificity and sensitivity. $^{51-53}$ Monitoring treatment effects and detecting subtle abnormal morphological changes associated with acute and chronic diseases, such as the tumor microenvironment and fibrosis, become even more challenging when there are no clearly defined nodule formations. $^{48,54-56}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,630,958,760]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The second limitation of most clinical CAs is the ability to achieve molecular imaging. Although several GBCAs can achieve limited molecular imaging (ie, Eovist and MultiHance), imaging at the molecular level is improved with higher $\\mathbf{r}_1$ values and, importantly, the ability to target a disease-specific biomarker.[35] Thus, the rationales behind combining a biomarker-targeting moiety with an MRI CA having a high $\\mathbf{r}_1$ relaxivity are to further enhance detection sensitivity and specificity to detect diseases at a very early stage, to improve tolerance through reduced dosage, to quantitatively stage diseases and monitor treatment response, and to investigate the biological foundation of the diseases.[35,54] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,760,958,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To provide robust contrast differences in tissue that corresponds to a relaxation rate change of approximately $0.5\\mathrm{s}^{-1}$ , approximately $100\\mu \\mathrm{M}$ of CA is needed for $\\mathbf{r}_1$ of $5\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.5\\mathrm{T}.^{35}$ The minimal local concentration of Gd(III) required for in vivo imaging is several orders of magnitude higher than the expression levels of relevant molecular biomarkers, such as receptors. For example, the receptor expression levels of HER2 (biomarker for breast cancer) and chemokine CXCR4 (for inflammation) are ${\\sim}10^{6}$ and $1.5\\times 10^{5}$ per cell, respectively, which is ${\\sim}0.03-0.17\\mathrm{nM}.$ [57,58] The overexpression of collagen at the extracellular matrix, as a biomarker for tumor microenvironment as well as liver and lung fibrosis, is usually in the concentration range of 1 to $20~\\mu \\mathrm{M}$ . It is speculated that relaxivity $\\mathbf{r}_1$ of at least $60\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ for a CA is required to detect $\\mu \\mathrm{M}$ biomarker expression levels.[59] Because high relaxivity of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,38,484,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[606,38,958,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[37,946,448,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,946,913,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[931,946,955,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"171 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[114,100,292,228]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0193/fdc278ce1044e6f253f529ab0f19764130845e7f298331047299f5f3ca5fa430.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[305,100,482,228]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0001/656b04fcc06c9f4aa7a2290dc2ea1365f425267ccc5b03bbe3dbf39a45f27f35.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[118,254,473,450]","code_body":null,"code_caption":null,"image_caption":"[\"A \",\"B \"]","image_footnote":"[]","img_path":"images/0920/bd902c7461a29fe726ac505cb5d6eccb78a22ebba854d4ce87c04cfdd9443437.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[506,113,637,227]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0054/2a385e13e6292851ed19c9282537b82a394c8382fb7ed6ea4139f8e27fc9f897.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[660,100,879,227]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0857/297197700a3e3a623aec81378e5c939e27aef5604bc95bad499646df76c9d4d3.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[518,266,838,428]","code_body":null,"code_caption":null,"image_caption":"[\"C \",\"r1 Simulation and NMRD of ProCA32s \",\"E \",\"IGURE 2. A, Coordination of second-sphere H-bond receptors for ProCA32s' 2 EF-hands. B, Schematic illustration of EF-hand 2 with 1 inner-sphere water oleule and 5 second-sphere water molecules, surrounded by bulk water. Bidentate carboxyl (#1); monodentate carboxyl (#2); main chain carbonyl #3); inner-sphere water (#4); hydrogen bonds (black dashed line); metallic bonds (red dashed line). C, Water number of Gd-DTPA, Eovist, ProCA30 $(n =)$ , ProCA32 $(n = 3)$ . Data are expressed as mean $\\\\pm$ SD. D, Relaxivity of ProCA32s and clinically available GBCAs at $1.4\\\\mathrm{T}$ in water. E, Inner-sphere plus econd-sphere relaxivities simulation of ProCA32s by SBM theory as a function of ${}^{1}\\\\mathsf{H}$ Larmor frequencies from $0.01 - 1000\\\\mathrm{MHz}$ (for ProCA32s' inner sphere, $\\\\tau_{R} = 3$ ns, $\\\\tau_{m} = 180$ ns, $q = 0.5$ , $\\\\mathrm{r}_{Gd-H} = 3\\\\AA$ ; for ProCA32s' second sphere, $\\\\tau_{R} = 3$ ns, $\\\\tau_{m} = 20$ ns, $q = 5$ , $\\\\mathrm{r}_{Gd-H} = 4.45\\\\AA$ ) overlaid with r1 NMRD profile f ProCA32s measured at $25^{\\\\circ}\\\\mathrm{C}$ as a function of ${}^{1}\\\\mathsf{H}$ Larmor frequencies from 0.01 to $40\\\\mathrm{MHz}$ . \"]","image_footnote":"[]","img_path":"images/0593/564c38cc43e8db26b741e55648f43748faeac26f34d2dba7f4fcc113468d2717.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[37,552,486,591]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"he GBCAs is a prerequisite for detection of low receptor concentration, it as previously assumed that it would not be possible to detect the receptor in vivo by approved Gd CAs without additional enrichment.[60] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,552,958,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To address this, extensive research has been directed toward molecular imaging,[54,61-65] including the following: the conjugation of targeting moieties to chelators capable of binding multiple Gd(III) ions, such as ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[35,628,958,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0001/0f6fc9e9b9fc9bbb07e529f233f87141595030ad6ad3d933a619b5f484225a98.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>Inner-Sphere Relaxation</td><td>Second-Sphere Relaxation</td></tr><tr><td>1/Ti,obs=1/Ti,d+1/Ti,p(1)</td><td></td></tr><tr><td>1/Ti,obs=1/Ti,d+ri[Gd](2)</td><td></td></tr><tr><td>(1/Ti,p)=(1/Ti,p)IS+(1/Ti,p)OS(3A)</td><td>(1/Ti,p)=(1/Ti,p)IS+(1/Ti,p)SS+(1/Ti,p)OS(3B)</td></tr><tr><td>(1/T1)IS=cq/55.5 1/T1m+τm=PM 1/T1m+τm(4A)</td><td>(1/T1)SS=cq'/55.5 1/T1m+τm=PM' 1/T1m+τm(4B)</td></tr><tr><td>(1/T2)IS=PM/τm T2m+τm-1T2m+Δωm2(5A)</td><td>(1/T2)SS=PM' T2m-2+τm-1T2m-1+Δωm2(5B)</td></tr><tr><td>1/Tim=1/TiDD+1/TiSC(6A)</td><td>1/Tim=1/TiDD+1/TiSC(6B)</td></tr><tr><td>1/T1DD=2/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(7τc2/1+ωS2τc2+3τc1/1+ωI2τc1)(7A)</td><td>1/T1DD=2/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(7γf2g2μB/6rGdH+3γf2g2μB/6rGdH)(7B)</td></tr><tr><td>1/T2DD=1/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(13τc2/1+ωS2τc2+3τc1/1+ωI2τc1+4τc1)(8A)</td><td>1/T2DD=1/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(13γf2g2μB/6rGdH+3γf2g2μB/6rGdH+4τc1)(8B)</td></tr><tr><td>1/τci=1/τR+1/τm+1/Tie(9A)</td><td>1/τci=1/τR+1/τm+1/Tie(9B)</td></tr><tr><td>1/Tie=2C(1/1+ωS2τv2+4/1+4ωS2τv2)(10)</td><td></td></tr><tr><td>1/T2e=C(5/1+ωS2τv2+2/1+4ωS2τv2+3)(11)</td><td></td></tr><tr><td>C=1/50 Δ2τv[4S(S+1)-3](12)</td><td></td></tr></table>","table_caption":"[\"TABLE 1. SBM Relaxation \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[39,40,89,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,38,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[39,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"172 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,314,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[545,946,956,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[57,94,355,280]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0735/22c969238856038f05bd290709df139e21616ecc16aa07cffcbde29fae7f212d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[360,95,658,280]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0438/cf683170e53bb6836fdbd0602a4ad9986b70ffb03cc8569f74709991f00beb78.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[680,94,915,276]","code_body":null,"code_caption":null,"image_caption":"[\"IGURE 3. Inner-sphere and second-sphere relaxivity simulations of ProCA32s and Gd-DOTA by SBM theory as a function of $^1\\\\mathsf{H}$ Larmor frequencies from .01-1000 MHz. A, $\\\\mathsf{r}_1$ relaxivity simulation. For ProCA32s' inner sphere, $\\\\tau_{R} = 3$ ns, $\\\\tau_{m} = 180$ ns, $q = 0.5$ , $\\\\mathsf{r}_{\\\\mathrm{Gd - H}} = 3\\\\AA$ . For ProCA32s' second sphere, $\\\\tau_{R} =$ ns, $\\\\tau_{m} = 20$ ns, $q = 5$ , $\\\\mathsf{r}_{\\\\mathrm{Gd - H}} = 4.45\\\\AA$ . For Gd-DTPA's inner sphere, $\\\\tau_{R} = 0.1$ ns, $\\\\tau_{m} = 240$ ns, $q = 1$ , $\\\\mathsf{r}_{\\\\mathrm{Gd - H}} = 3\\\\AA$ . B, $\\\\mathsf{r}_2$ relaxivity simulation. C, Simulation of liver RI signal change of ProCA32s and Gd-BT-DO3A at different Gd(III) concentration in T1-weighted (T1W) MRI and T2-weighted (T2W) MRI at 1.5 T. or ProCA32s, $\\\\mathsf{r}_1 = 34\\\\mathrm{mM}^{-1}s^{-1}$ , $\\\\mathsf{r}_2 = 50\\\\mathrm{mM}^{-1}s^{-1}$ . For Gd-BT-BO3A (Gadovist), $\\\\mathsf{r}_1 = 3.3\\\\mathrm{mM}^{-1}s^{-1}$ , $\\\\mathsf{r}_2 = 3.9\\\\mathrm{mM}^{-1}s^{-1}$ . Liver T1 is 547 milliseconds and T2 is 1 milliseconds at 1.5 T. For T1W image, TR = 400 milliseconds, TE = 11 milliseconds. For T2W image, TR = 5000 milliseconds, TE = 28 milliseconds. \"]","image_footnote":"[]","img_path":"images/0855/de13ae0013105001f911ffcba5b113098a2e5f4ff6ea5ccf5cf8fe9bc6156c6d.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[39,386,482,439]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ntibodies, $^{63}$ short peptides, $^{66,67}$ protein fragments; and nanoparticles/ubes, $^{68-72}$ liposomes, $^{73,74}$ and viruses $^{75}$ (Fig. 1B). Despite these efforts, o date, no biomarker-targeted CAs have been approved for MR molecular imaging of cancers or metastases in patients. $^{54,64-66,76}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,439,484,610]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The third limitation of clinical CAs is related to metal associated toxicity due to high GBCAs dosage required for imaging (Table 2).35 adolinium-based contrast agent administration is normally considered o be very safe because a retrospective analysis of over 158,000 GBCAs dministrations from 2000 to 2009 reported limited incidents of immedi- te adverse events (severe reaction occurred approximately 1 in 40,000 njections).77 However, nephrogenic systemic fibrosis (NSF) was identified in severe renal failure patients receiving GBCAs in 2006.78-80 his risk of NSF reportedly increased with the severity of impaired enal function, as most GBCAs are excreted almost exclusively by renal filtration, resulting in longer half-lives of GBCAs in renally impaired patients.81-84 The majority of reported cases of $\\mathrm{NSF^{85 - 89}}$ have been linked to 3 linear GBCAs, classified as group I by the American College ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,386,960,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of Radiology Committee on Drugs and Contrast Media, comprising Gd-DTPA-BMA (Omniscan; GE Healthcare), Gd-DTPA (Magnevist; Bayer HealthCare Pharmaceuticals), and Gd-DTPA-BMEA (OptiMARK; Guerbet).<sup>90</sup> The American College of Radiology group II and group III GBCAs associated with few or no instances of unconfounded cases of NSF (mostly macrocyclic molecules, except Gd-BOPTA, Gd-EOB-DTPA) include the following: Gd-BOPTA (MultiHance; Bracco Diagnostics), Gd-BT-DO3A (Gadavist; Bayer HealthCare Pharmaceuticals; Gadovist in many countries), Gd-DOTA (Dotarem; Guerbet, Clariscan-GE Healthcare), Gd-HP-DO3A (ProHance; Bracco Diagnostics), and Gd-EOB-DTPA (Eovist; Bayer HealthCare Pharmaceuticals; Primovist in many countries).<sup>90</sup> Current evidence suggests that, although all GBCAs have the potential to release Gd(III) in vivo, linear GBCAs are more prone to Gd(III) dissociation from the complex than macrocyclic GBCAs.<sup>9,49</sup> It is also important to note that NSF is rare (approximately 1000 cases in 200 million GBCA administrations),<sup>91</sup> and the occurrence of new NSF cases has dropped precipitously since 2010.<sup>92,93</sup> This is because routine ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[37,673,958,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0198/60f97b72d3cbc971649c284ff29e36f6192e057a0e9eee56339d4983436f6be8.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Trade Name</td><td>Chemical Code</td><td>Standard Dose, mmol/kg</td><td>Log (K*Tb)</td><td>Log (K*Gd)</td><td>Log (K*Ca)</td><td>Log (K*Zn)</td><td>Log (K*Gd/KCa)</td><td>Log (K*Gd/Zn)</td></tr><tr><td>hProCA32</td><td></td><td>0.0014*</td><td>22.5†</td><td>22.5†</td><td>8.7†</td><td>6.4†</td><td>14.7†</td><td>16.2†</td></tr><tr><td>hProCA32.collagen</td><td></td><td>0.0014*</td><td>22.0†</td><td>22.2†</td><td>8.1†</td><td>6.8†</td><td>14.1†</td><td>15.4†</td></tr><tr><td>Dotarem</td><td>Gd-DOTA</td><td>0.1</td><td>N/A</td><td>18.3‡</td><td>6.1‡</td><td>14.1‡</td><td>12.2‡</td><td>4.2‡</td></tr><tr><td>ProHance</td><td>Gd-HP-DO3A</td><td>0.1</td><td>N/A</td><td>17.2‡</td><td>8.2‡</td><td>12.8‡</td><td>9.0‡</td><td>4.4‡</td></tr><tr><td>Magnevist</td><td>Gd-DTPA</td><td>0.1</td><td>N/A</td><td>17.7‡</td><td>N/A‡</td><td>13.8‡</td><td>N/A</td><td>3.9‡</td></tr><tr><td>Omniscan</td><td>Gd-DTPA-BMA</td><td>0.1</td><td>N/A</td><td>14.9‡</td><td>5.0‡</td><td>10.1‡</td><td>9.9‡</td><td>4.8‡</td></tr><tr><td>MultiHance</td><td>Gd-BOPTA</td><td>0.1</td><td>N/A</td><td>18.4‡</td><td>N/A</td><td>13.9‡</td><td>N/A</td><td>4.5‡</td></tr><tr><td>Gadoquatrane</td><td>Gd-GlyMe-DOTA (tetramer)</td><td>N/A</td><td>N/A</td><td>19.3‡</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr><tr><td>Gadopiclenol</td><td>Gd-PCTA</td><td>0.05</td><td>N/A</td><td>15.5‡</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr></table>","table_caption":"[\"TABLE 2. Comparison of Conditional Thermodynamic Stability and Metal Selectivity of Commercially Available GBCAs With hProCA32 and hProCA32.Collagen at pH 7.2/7.4 at ${25}^{ \\\\circ }\\\\mathrm{C}$ \"]","table_footnote":"[\"$\\\\mathrm{K}^*$ indicates conditional thermodynamic stability. \",\"*Theoretical human dose by converting mouse dose. \",\"$\\\\dagger$ Stability constants measured by the fluorescence resonance transfer between tryptophan and metal in protein contrast agents. \",\"‡Stability constants of clinical contrast agents measured by pH potentiometric method. \",\"N/A, not available. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[39,38,486,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[606,38,958,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[37,945,450,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,945,913,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[929,946,956,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"173 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[41,90,482,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"screening for renal insufficiency and contraindicating the use of linear GBCAs Gd-DTPA, Gd-DTPA-BMA, and Gd-DTPA-BMEA have almost completely eliminated new cases of NSF.[94-97] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,129,482,296]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Another major concern regarding GBCAs, since 2014, is related to retention of Gd(III) in the central nervous system (CNS). $^{98-101}$ Similar to NSF risk, CNS Gd(III) accumulation has also been associated with over kinetic inertness of the GBCAs. $^{102-104}$ Although no evidence has yet indicated any harmful effects from the deposition of gadolinium, imaging methodologies and biopsy have confirmed deposition of Gd III) in CNS from both linear and macrocyclic CAs in patients with normal renal function. $^{98,105-107}$ Nevertheless, metal associated toxicity has raised major concerns and led to black box warnings for applications of RI CAs. Because of these cited concerns, very few new agents have been approved (Fig. 1A) for clinical imaging in the last 30 years, so there s now an important need to develop MRI CAs with new approaches to noble precision molecular imaging. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,296,482,592]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this review, we will introduce the requirements of an ideal CA or precision MRI. We will assess the challenges and limitations of classic SBM relaxation theory with defined first shell water, in current common approaches of CA development.[108-112] We will then report our development of our new class of protein-targeted MRI CAs (ProCAs) with additional significant contributions from the secondary shell water. His approach led to the development of our ProCA32 CA, which incorporates 2 Gd(III)-binding sites in a scaffold protein, resulting in a CA that exhibits $\\mathbf{r}_1$ and $\\mathbf{r}_2$ values that are 6- to 10-fold higher than clinically approved CAs at medical fields of 1.5 T or 3 T. We will then review important properties of the ProCA32 CAs, including exceptional metal-binding nd selectivity, serum stability, and resistance to transmetallation, which re critical to mitigating risks associated with metal toxicity. This platform CA ProCA32 was then further engineered with multiple targeting oieties directed toward specific biomarkers, including collagen, PSMA, XCR4, HER2, and others. Combining these new molecular-targeted As with an advanced new precision MRI method has enabled sensitive nd selective imaging of tissue abnormalities that has not previously been ossible with current clinical MRI CAs. The safety profile of ProCA32 gents and MRI relaxation properties indicate strong translational potential for preclinical and clinical applications of ProCA32 MRI CAs. The review will then conclude with future perspectives for development of new CAs, improved imaging, and perspectives on precision MRI. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,613,443,640]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CRITERIA OF IDEAL MRI CONTRAST AGENTS FOR PRECISION MRI ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[41,644,482,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An ideal precision molecular imaging CA with significantly improved sensitivity and specificity should exhibit the following properties summarized later. First, high relaxivity per Gd(III) improves the sensitivity of the MRI scan to both focal and diffusive diseases by providing greater contrast enhancement between lesions or disease changes and healthy tissue to detect smaller lesions and fibrosis. It also improves safety by reducing the injection dose to achieve comparable contrast enhancement. Second is the high safety profile including high in vivo stability, thermodynamic stability, and kinetic inertness. Gd(III) released or displaced by transmetallation from the chelator poses potential risks for health, particularly with respect to NSF and CNS. High in vivo stability and kinetic inertness will ensure that Gd remains chelated before excretion from the body. In addition, an agent should produce no short-term or long-term adverse effects. The agent cannot trigger any downstream biological pathways and should have minimal or no immunogenicity response. Third is the biomarker-targeting capability; MRI CAs with targeting capability for biomarkers for molecular imaging will enable early detection and subtyping of disease states.[35,54] First, high relaxivity is required to ensure sufficient contrast at the local environment to detect low expression molecular biomarkers such as receptors located at the desired lesions or with diffusive diseases such as fibrosis. Based on Sherry et al, a relaxivity of $100\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ for the detection limit of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,90,956,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\sim 0.69~\\mu \\mathrm{M}$ is required at $9.4~\\mathrm{T}.$ [13] Second, strong target-binding affinity and specificity is required to reduce off-target effect. Third, the image enhancement must be sufficient to quantify molecular biomarker changes during disease progression and regression. This capability will enable accurate staging with molecular subtyping and report treatment effectiveness. It would be extremely beneficial to have enhancement for both $\\mathrm{T}_{1}$ and $\\mathrm{T}_{2}$ (dual contrast with ratiometric changes), which can reduce heterogeneous background noise, including noise from lipids and cysts. Fourth is the high tissue penetration for quantification and dynamic contrast. To achieve tempospatial mapping of heterogenous expression of molecular biomarkers during disease progression and regression, it is important that the CA is small enough to reach all or most overexpressed biomarkers, while avoiding problems such as enhanced permeability and retention (EPR) of tumor effects, as occurs with nanoparticles and antibodies. This capability will take advantage of MRI's capacity for temporal and spatial resolution during imaging, and thereby increase the potential to detect, stratify, and stage diseases; monitor treatment response; and study the biology of diseases at the molecular level in vivo, as well as correlate imaging results with histological analysis. Although dynamic contrast enhancement with dynamic changes of CAs has been approved for clinical applications,[28,29,114] it has low sensitivity due to arterial input function kinetic properties that interfere with quantification and low relaxivity. It is also important for the agent to reach the molecular biomarkers quickly to facilitate temporal imaging of dynamic molecular contrast enhancement that can provide important data related to disease vessel structure and subtle structural changes.[52,115,116] Fifth, rapid, quick, and complete clearance of the CA can reduce any potential toxicity. The agent should accumulate quickly in the organ/tissue of interest to reduce the waiting period for MRI scanning, followed by fast washout of unbound agent to improve targeted imaging. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,496,947,523]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CLASSICAL MRI CONTRAST AGENTS WITH DEFINED FIRST SHELL WATER RELAXATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[513,527,956,681]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The general theory of solvent nuclear relaxation in the presence of paramagnetic substances is summarized[108-112,117,118] (Table 1). In the presence of the MRI CA, the observed solvent relaxation rate, $1 / T_{i,obs}$ , is defined by Equations 1 and 2, where $1 / T_{i,d}$ is the diamagnetic relaxation rate, that is, the relaxation rate of the solvent (water) nuclei in the absence of $\\mathrm{Gd(III)}$ complex, and $1 / T_{i,p}$ is the paramagnetic relaxation rate, that is, the relaxation rate enhancement caused by $\\mathrm{Gd(III)}$ complex, which is linearly proportional to the concentration of the $\\mathrm{Gd(III)}$ complex; $r_i$ is the relaxivity of the complexed $\\mathrm{Gd(III)}$ ; and [Gd] is the $\\mathrm{Gd(III)}$ concentration of complexed $\\mathrm{Gd(III)}$ . It is worth noting that Equations 1 and 2 only apply to dilute paramagnetic solutions where the paramagnetic ions or molecules are randomly distributed and do not strongly interact with each other. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,683,956,811]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The paramagnetic relaxation of the water protons originates from the dipole-dipole (DD) interactions between the nuclear spins and the fluctuating local magnetic field caused by the unpaired electron spins. This interaction can be achieved either by water molecules binding directly with $\\mathrm{Gd(III)}$ (inner-sphere relaxation) or water molecules diffusing in the surroundings of the $\\mathrm{Gd(III)}$ (outer-sphere relaxation). These water molecules carrying the paramagnetic effect with shorter relaxation time will exchange with bulk water to propagate the paramagnetic influence. This interaction is described in Equation 3 where \"IS\" and \"OS\" refer to inner and outer spheres, $^{119,120}$ respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,811,956,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The longitudinal and transverse inner-sphere relaxation rates are given by Equations 4A and 5A, where $c$ is the molar concentration of the Gd(III) complex (relaxivity is calculated when $c = 1\\mathrm{mM}$ ); $q$ is the number of bound water molecules per Gd in the inner sphere; $P_{m}$ is the mole fraction of bound water molecules in the inner sphere; $\\tau_{m}$ is the water residency time in the inner sphere of the complex (equal to the reciprocal water exchange rate $1 / k_{ex}$ ); and $1 / T_{1m}$ and $1 / T_{2m}$ are, respectively, the longitudinal and transverse proton relaxation rates in the bound water in the inner sphere. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,41,87,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,40,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[41,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"174 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,314,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[547,946,955,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[35,90,484,232]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The relaxation of the bound water protons $(T_{im})$ is determined by DD and scalar (SC) (or contact) mechanisms as seen in Equation 6A by Solomon, Bloembergen, and Morgan (SBM Equation). Because the contribution from DD is much greater than SC for GBCAs, only the DD mechanism will be discussed to define $T_{im}$ as seen in Equations 7A, and 8A. The local magnetic fluctuations are defined by Equations 9A and 9B, where $\\tau_{R}$ is the rotational correlation time of the Gd III), and $T_{ie}$ is the electron spin relaxation time of the Gd(III). The longitudinal and transverse electron spin relaxation times $T_{1e}$ and $T_{2e}$ are defined by Equations 10 and 11, respectively. The relaxation theory as been extensively explained by others.38,121-123 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[46,232,482,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Optimal relaxivity can be achieved by modifying any of the major ater factors $q$ , $\\tau_{R}$ , and $\\tau_{m}$ . From Equation 4A, we can reason that increasing the $q$ can improve inner-sphere relaxivity. All clinical GBCAs are 1 bound water molecule per Gd in the inner sphere, except adopiclenol, which has 2. In the case of most small chelators (class I, ig. 1A) and large molecules (class II, Fig. 2B), the outer sphere contribution is not defined and negligible because water in the outer spheres is not constrained as reviewed by Aime et al. The commercial CAs and their functionalized derivatives based on the DTPA and DOTA basic tructures have a molecular weight of $\\sim 600 - 800\\mathrm{Da}$ . That corresponds to ontational correlation times of approximately 60 to 80 ps. Their water residence lifetime is typically in the range of 50 to 500 ns and $\\mathrm{T}_{1\\mathrm{e}}\\sim 1$ ns at .5 T. The inner-sphere relaxivity is largely dominated by the overall correlation time $\\tau_{R}$ that is roughly proportional to the \"effective\" molecular radius (Debye-Stokes equation), which exhibits a reasonable linear correlation to the molecular weight. The outer sphere contribution is nearly identical for the various complexes. The second shell contribution, which rgely depends on structural features, is likely negligible for clinical GBCAs, due to lack of defined water molecules in close proximity to Gd(III). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,477,484,695]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Higher relaxivity can be achieved when $q$ is increased to 2-3 by lowering the denticity of the multidentate ligand (Fig. 1A). [125-129] However, increasing $q$ to 2 usually decreases the thermodynamic stability nd/or kinetic inertness of the Gd(III) complex and increases the risk f Gd(III) transmetallation. Increasing $q$ also invites the possibility of nion binding and displacement of coordinated water ligands, [130] which, n turn, decreases the relaxivity in vivo. Efforts to develop GBCAs with slow transmetallation rates, by modifying macrocyclic chelators such as PCTA that has $q = 2$ , have also resulted in low conditional $K_{d}$ values, as reported for gadopiclenol $(K_{d} = 15.5)^{125 - 129}$ (Fig. 1A, Table 2). Caravan et al [131] reported the use of an EF-hand calcium-binding peptide and derivatives to form complexes with Gd (III) with high relaxivity $(\\mathrm{r}_1 = 21.2\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.5~\\mathrm{T}$ ). However, their agent exhibited low Gd-binding affinity $(K_{d} = \\sim 100\\mu \\mathrm{M})$ . Although both inner sphere and outer sphere can contribute to the overall proton relaxivity, inner-sphere relaxation is only well defined by Equations 4A-9A, whereas outer sphere water is largely underestimated due to lack of structural information. [132,133] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,695,484,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tuning rotational correlation time $\\tau_{R}$ and the water residency time $\\tau_{m}$ may also improve relaxivity.134 It is noteworthy that the optimal $\\tau_{R}$ and $\\tau_{m}$ needed to attain the theoretical relaxivity maximum depend on the magnetic fields, and higher magnetic fields have lower maximum theoretical relaxivity values. Unfortunately, clinical CAs have values $\\tau_{R} = \\sim 100$ ps, which limit the agents to low relaxivity. A linear dependence was observed by correlating the molecular weights of Gd-DOTA, Gd-DTPA, and their derivatives, with their relaxivities,43 which was also indicative of rotational correlation.135,136 Efforts to improve relaxivity and increase Gd number have also explored development of Gd liposomes, dendrimers,137 and biopolymers74 (Fig. 1B), or structural modifications involving PEGylation and glycosylation.138,139 However, these attempts have not resulted in the expected high relaxivity based on the increase in molecular weight because Gd(III) is subject to internal local motion.135 Internal motion was successfully eliminated in the blood pool agent P792 by placing a metal ion at the molecular barycenter,140 which increased the relaxivity to $29\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.4\\mathrm{T}$ . The conjugation of 4 GdGlyMe-DOTA molecules (gadoquatrane) to form a rigid complex by ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,89,956,206]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Lohrke et al $^{34}$ resulted in relaxivity to $11.8~\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ per Gd in human plasma at $1.4\\mathrm{T}$ , although it was still constrained by the fast correlation time. In another example, MS-325, a blood pool agent used for MR angiography, was found to exhibit reduced internal flexibility resulting in increased relaxivity due to nonspecific binding with serum protein albumin (BSA, HSA). $^{141}$ However, this agent was characterized by having an undefined loading number of the small chelator to HSA ( $>65\\mathrm{kDa}$ ) and a long excretion time and was later removed from the clinical market for in vivo applications. $^{142}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,206,956,360]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The addition of targeting moieties such as small molecules, peptides, or antibodies, through conjugation or engineering, clearly increases specificity of small chelator-based CAs such as DTPA or ProHance to tumors and biomarkers of other chronic diseases.[63,66] However, it remains to be demonstrated whether metal-binding affinity and specificity remain unaltered by the modification when compared with the unmodified parent compound. Studies have indicated that the incorporation of targeting moieties into small chelator PET tracers frequently leads to a reduction in metal-binding affinity.[143] In summary, attempts to enhance relaxivity by primarily concentrating on the utilization of inner-sphere water coordination, while avoiding compromises in metal-binding affinity, specificity, and potential safety concerns, have proven to be a complex challenge. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,381,951,408]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"FIXING WATER FOR SECOND SHELL CONTRIBUTION FOR HIGH RELAXIVITY","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,411,958,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Metalloproteins typically exhibit a well-defined second shell of water molecules, fixed by hydrogen bonding acceptor or donor residues, particularly in the vicinity of the metal-binding sites.[144-147] We hypothesized that relaxivity, metal binding, and targeting capability could be simultaneously optimized if we took advantage of the presence of second shell water by the protein environment around the Gd(III) coordination center[148] (Table 1). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,501,956,655]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This interaction is described in Equation 3B where \"IS,\" \"SS\" and \"OS\" refer to inner, second, and outer spheres. Inner-sphere water molecules can interact directly with $\\mathrm{Gd(III)}$ in the range of 3.0 to $3.2\\AA$ ,[35,121,149] whereas multiple second-sphere water molecules can interact with hydrogen donors or acceptors of liganding atoms in residues surrounding the Gd site, in the range of 3.5 to $4.5\\AA$ in proteins.[43,150] These contributions from the second spheres to overall proton relaxivity can also be quantitatively estimated (Fig. 2A, B). Second-sphere relaxation is defined by Equations 4B-9B (a prime symbol is used to denote second-sphere relaxivity in the equations). Inner- and second-sphere relaxation values are derived from the same formulas, but some parameters have varied values between inner and second spheres. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,657,956,772]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Longitudinal and transverse second-sphere relaxation rates are given by Equations 4B and 5B, where $q'$ is the number of bound water molecules in the second sphere per Gd; $\\tau_{m}$ and $\\tau_{m}'$ are the water residency times in the inner sphere and second sphere of the complex (equal to the reciprocal water exchange rate, $1 / k_{ex}$ or $1 / k_{ex}'$ ); and $1 / T_{1m}'$ and $1 / T_{2m}'$ are the longitudinal and transverse proton relaxation rates in the bound water in the second sphere. The relaxation of the bound water protons of second sphere $(T_{im}')$ is determined by DD as seen in Equation 6B, which is identical to the inner-sphere mechanism. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,772,956,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Simulations indicate that second shell water contribution for relaxivity can be calculated if we have defined number of water positioning around the paramagnetic metal ions. In addition, both relaxivity values can be further significantly increased by tuning correlation time to ns regime instead of ps for small molecules. This can be done by fixing the metal-water proton vector to rotate isotropically with the entire molecule at a desired correlation time such as ns, so that Gd(III) will have the same $\\tau_{R}$ as the whole rigid structure. This is well demonstrated in the excellent agreement of our experimental nuclear magnetic relaxation dispersion (NMRD) data (Fig. 2E) with simulated relaxivity.[50] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,902,956,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To demonstrate the effect of second-sphere water molecules on relaxivity of our pioneered ProCA32 CAs, relaxivity simulations were ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,38,482,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[606,38,958,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[39,946,448,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,946,910,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[931,946,956,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"175 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[41,89,482,179]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"conducted as a function of ${}^{1}\\mathrm{H}$ Larmor frequencies from 0.01 to $1000\\mathrm{MHz}$ for ProCA32 inner and second spheres for $\\mathbf{r}_1$ and $\\mathbf{r}_2$ . Results suggested that second-sphere contributions to relaxivity can be higher than contributions from the inner sphere for both $\\mathbf{r}_1$ (Fig. 3A) and $\\mathbf{r}_2$ (Fig. 3B), and that the combined contributions from the inner and second sphere produce a significant increase in relaxivity, with a peak maximum that is consistent with experimental NMRD data (Fig. 2E). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[52,195,479,280]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ATIONAL DESIGN AND OPTIMIZATION OF PROTEIN MRI CONTRAST AGENTS TO SIMULTANEOUSLY IMPROVE MULTIPLE KEY FACTORS CONTRIBUTING TO RELAXIVITY, METAL BINDING STABILITY, AND MOLECULAR TARGETING OF CONTRAST AGENTS FOR PRECISION MRI ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[46,283,482,527]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Building on extensive efforts directed toward the rational design of calcium-binding proteins $^{146,151-158}$ with controlled metal-binding affinity, metal selectivity, and relaxation properties, $^{147}$ we have created a new class of ProCAs $^{50,62,148,159-162}$ based on the following rationales. First, slow the rotational correlation time to 1-10 ns range either by the e novo design of a Gd(III)-binding pocket or shaping an existing Ca(II)-inding pocket in a protein. $^{47,146}$ Either approach results in the Gd-water proton vector synchronizing with the entire protein structure. Second, increase the water molecule number of the second/outer sphere of Gd(III) enter by surface modification such as PEGylation to define water at the econd shell of the protein frame. $^{132,148}$ Third is the shorter water residency me due to the oxygen ligand atom and steric crowding nature of the rotein-binding pocket coupled with favorable arrangement of water molecules in a second coordination sphere. Our hypothesis, which is dramatically different from previously reported studies, $^{125,131,138,163-167}$ involved simultaneously increasing both $\\mathbf{r}_1$ and $\\mathbf{r}_2$ relaxivities without trading off etal-binding stability, and doing so by tuning structural arrangement, otational correlation time, and water exchange rate, at the inner shell end second/outer sphere. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,529,482,811]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ProCA1 was first designed by de novo design, creating a Gd(III)-inding site on domain 1 of cell adhesion protein (CA1.CD2) followed by surface PEGylation (Fig. 1C). The created metal-binding site has 6 potential oxygen ligands from the carboxyl side chains of E15, D56, D58, D62, and D64. By \"embedding\" a Gd(III)-binding site into CA1. CD2, the bound Gd(III) is free from internal tumbling, with rotational correlation time at approximately 10 ns (~12 kDa), corresponding to optimal relaxivity for the current clinically allowed magnetic field strength. To further improve the relaxivity by increasing q number, 1 position of the metal-binding geometry was left open in the design, and terbium lifetime luminescence indicated that the bound Gd(III) in ProCA1 was coordinated with 2 water molecules. In addition, we further demonstrated that PEGylation increased water number in the second coordination shell. Correlation time, q of 2 in first shell, and second shell coordination water all contributed to the dramatically increased relaxivity value of ProCA1 $(\\mathrm{r}_1 = 117~\\mathrm{mM}^{-1}\\mathrm{s}^{-1},$ $\\mathrm{r}_2 = 129~\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.5\\mathrm{T})$ . ProCA1 had the highest $\\mathbf{r}_1$ and $\\mathbf{r}_2$ values that were 10- to 20-fold greater than those of the currently used clinical CAs. Using $\\mathrm{O^{17}}$ NMR and various biophysical methods, we have also shown that water is at the fast exchange region and $\\tau_{m}$ is not rate limited. This high relaxivity enabled molecular imaging for early detection of HER2 and GRPR in ovarian cancer, breast cancer, and prostate cancer, in several animal models (Fig. 5). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,811,484,875]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Besides high relaxivity, ProCA1 also had a significantly greater Gd(III) selectivity over Zn(II) compared with DTPA-BMA (log $[K_{Gdt} / K_{GdZn}]$ of 5.3 vs 4.8, respectively) and endogenous calcium and magnesium. However, further improvement was needed for thermodynamic stability of Gd-ProCA1, as its log $K_{cond}$ was 12.06. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,875,482,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To further improve metal selectivity and Gd-binding affinity and increase relaxivity using second water shell contribution, we created ProCA32 with 2 Gd(III)-binding sites (Fig. 1C). Unlike small chelators, ProCA32 was rationally designed from reshaping $2\\mathrm{Ca(II)}$ -binding sites ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,90,956,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in parvalbumin, followed by surface PEGylation. A rat/human $\\alpha$ -parvalbumin ( $\\sim 12$ kDa) has 2 coupled calcium-binding EF-hand motifs (helix-loop-helix domains). To achieve much stronger Gd(III)-binding affinity and selectivity and high relaxivity[50,169] (Fig. 1C), Gd(III) in EF-hand motif 1 was coordinated by 5 existing negatively charged carboxylate oxygen ligands (D52, D54, E60, and bidentate E63) and a sixth charged oxygen ligand from substitution S56D, as well as a carbonyl oxygen ligand from F58 (Fig. 1C).[116] The EF-hand 2 Gd(III)-binding site was composed of 5 negatively charged oxygen ligands from carboxy groups of D91, D93, D95, and bidentate E102, as well as carbonyl of K97. A single water molecule bridges the gap between the Gd(III) ion and the oxygen atom from G99 and is shared between the 2 coupled Gd EF-hand-binding sites in each first shell (0.5 each), as determined by Tb(III) luminescence lifetime decay.[50,170] Importantly, there are approximately 10 water molecules that are well defined by protein ligand H-bond receptor groups, with an average of 5 molecules per Gd(III) in the second sphere with an average distance of $4.45\\AA$ (Figs. 2A, B). A significant number of H-bond acceptors on the chelating ligands, including carbonyl groups from the peptide bonds and carboxyl groups from side chains, play a crucial role in stabilizing 2 coupled EF-hand metal-binding sites. These H-bond acceptors directly capture several water molecules entering the second or outer spheres around the Gd(III) center to contribute high relaxivity. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,372,956,501]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We have shown that ProCA32 agents exhibit both high $\\mathrm{r_1}$ ( $30\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.4\\mathrm{T}$ ) and $\\mathbf{r}_2$ ( $42\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.4\\mathrm{T}$ ) values that were 6- to 10-fold higher than clinically approved CAs at medical field strengths $1.5\\mathrm{T}^{50,52,59,116}$ (Fig. 2D). In addition, their $\\mathbf{r}_1$ relaxivity values are $\\sim 18\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at high field, which is important for small animal imaging, due to the corresponding smaller organ size (mice are $\\sim 1000$ -fold smaller than humans), because higher-resolution imaging can be achieved under higher magnetic field. We demonstrate that second-sphere contributions to relaxivity are even higher than that from the inner sphere for both $\\mathbf{r}_1$ and $\\mathbf{r}_2$ across all field strength. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,503,956,642]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The high relaxivity of ProCA32 has been the result of designed second shell contributions from large fixed hydration numbers resulting from trapping water in the rigid protein environment, slower rotational correlation time $\\tau_{R}$ , and faster water residency time $\\tau_{m}$ . The 2 coupled metal-binding pockets in the scaffold protein have the same $\\tau_{R}$ as the whole rigid structure, with a slow tumbling rate of the Gd(III) protein complex in the $\\sim 3 - 10$ ns range.[147,171,172] Slow rotation of ProCA32 plus fixed water orientation also significantly contributes to high second-sphere relaxation, coupled with a much greater $q$ number in the second sphere, resulting in much more pronounced second and outer sphere relaxivity effects of ProCA32. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,644,956,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To demonstrate the effect of first- and second-sphere water molecules on relaxivity of ProCA32, we performed simulations of $\\mathbf{r}_1$ and $\\mathbf{r}_2$ as functions of ${}^{1}\\mathrm{H}$ Larmor frequencies from 0.01 to $1000\\mathrm{MHz}$ . For inner-sphere relaxivity simulations (Figs. 3A, B), values used were $q = 0.5$ (Fig. 2C), ${}^{50}\\tau_{m} = 180$ ns, ${}^{50}r_{GdH} = 3\\AA$ , ${}^{149}$ and $\\tau_{R} = 3$ ns. For second-sphere relaxivity simulations (Figs. 3A, B), values used were $q = 5$ , $\\tau_{m} = 20$ ns, ${}^{134,173,174}r_{GdH} = 4.45\\AA$ , ${}^{43,134,150,175,176}$ and $\\tau_{R} = 3$ ns. Simulation results suggested that second-sphere contributions to relaxivity were higher than contributions from the inner sphere for both $\\mathbf{r}_1$ (Fig. 3A) and $\\mathbf{r}_2$ (Fig. 3B), and that the combined contributions from the inner and second sphere produce a significant increase in relaxivity, with a peak maximum that was consistent with experimental NMRD data of ProCA32 (Xue et al $^{50}$ ) (Fig. 2E). At $1.5\\mathrm{T}$ , second-sphere relaxivity from the simulation contributed almost $60\\%$ of the overall relaxivity for both $\\mathbf{r}_1$ and $\\mathbf{r}_2$ , which was significantly greater than all reported agents (including clinical) that are characterized by modest contributions from the second and outer spheres. $^{36}$ Thus, the well-defined large second shell water contribution of ProCA32 (Figs. 2A, B) is drastically different from all other CAs reported to date. Moreover, methoxy PEG succinimidyl carboxymethyl ester (M-SCM-2000), which reacts with the amine group of lysine(s), can be used to modify the protein surface, which provides additional carbonyl groups that in the second and outer sphere of the Gd(III) center further increase ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,41,87,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,40,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[41,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"176 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,314,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[547,946,955,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[35,90,484,128]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the second/outer sphere $q$ number. This surface modification also increases the molecular weight of ProCA32 by 2 kDa, resulting in further slowdown of the rotational correlation time, $\\tau_{R}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,129,484,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The shorter water residency time $\\tau_{m}$ of ProCA32 is achieved by utilization of oxygen ligand atoms rather than nitrogen,[125,177-180] configured in a sterically crowded volume, and coupled with favorable arrangement of water molecules in a second coordination sphere. The F-hand carboxyl atoms in metal-binding pocket are innately more sterically crowded than what is observed with clinical GBCAs[181] (Fig. 1C), hereas the water exchange rate can be accelerated by increasing the steric compression around the water-binding site.[35,41,182] In contrast, for d-DTPA derivatives, the water exchange rate enhancement is usually attained by loss of thermodynamic stability.[183-185] This significantly higher $\\mathbf{r}_1$ ( $30\\mathrm{mM}^{-1}\\mathrm{s}^{-1}$ at $1.4\\mathrm{T}$ ) of ProCA32 provides much greater sensitivity during MRI scanning. Only $\\sim 9~\\mu \\mathrm{M}$ local concentration of ProCA32 is required to provide robust contrast differences in tissue corresponding to a relaxation rate change of approximately $0.5\\mathrm{s}^{-1}$ . This s 10 times lower than the concentration requirement for clinical GBCAs.[35] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[43,322,486,439]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"oreover, clinical GBCAs, due to their low $\\mathbf{r}_2$ values, cannot produce significant change in vivo using $\\mathrm{T}_{2}$ -weighted imaging and $\\mathrm{T}_{2}$ map imaging. Onversely, ProCA32 possesses both high $\\mathbf{r}_1$ and $\\mathbf{r}_2$ values at both low and high magnetic field. This means that ProCA32 can function as a dual $\\mathrm{T}_{1}$ and $\\mathrm{T}_{2}$ CA that can overcome heterogeneous tissue background and provide even higher contrast enhancement by $\\mathrm{T}_{2}$ -weighted MRI, as well as the capability to capture molecular biomarker changes (see Bioarter Targeting for Precision Molecular Imaging and Preclinical Applications) (52,59,115,116,162). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,457,482,514]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"TRATEGIES USED FOR ACHIEVING UNPRECEDENTED METAL BINDING SELECTIVITY AND STABILITY OF PROCA32 THAT ARE CRITICAL IN PREVENTING RISKS ASSOCIATED WITH METAL TOXICITY ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[37,518,486,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"High thermodynamic stability is of great importance for GBCAs, it ensures the equilibrium lies heavily on the side of the intact complex dL and $\\mathrm{Gd}_2\\mathrm{L}$ , leaving little free $\\mathrm{Gd(III)}$ after equilibrium. The thermodynamic stability constant $\\mathrm{K}_{\\mathrm{therm}}$ provides the affinity of $\\mathrm{Gd(III)}$ for a given ligand. This stability is defined by Equation 13 if the ligand chelates a single $\\mathrm{Gd(III)}$ ion (eg, all the clinical GBCAs) and Equation 14 if the ligand chelates 2 $\\mathrm{Gd(III)}$ ions (eg, ProCA32 agents). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[168,611,482,639]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\nG d + L \\Leftarrow G d L K _ {\\text {t h e r m}} = \\frac {[ G d L ]}{[ G d ] [ L ]} \\tag {13}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[159,655,482,686]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$$\n2 G d + L \\rightleftharpoons G d _ {2} L K _ {\\text {t h e r m}} = \\frac {[ G d _ {2} L ]}{[ G d ] ^ {2} [ L ]} \\tag {14}\n$$","text_format":"latex","text_level":null,"type":"equation"},{"bbox":"[35,694,486,811]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Thermodynamic stability is measured under very basic conditions (pH $\\sim 11$ ), because at this pH, there are no competing protons for the chelate and a theoretical maximum stability is obtained. For in vivo applications, it is more important to attain thermodynamic stability at physiological pH 7.4 (ie, conditional stability).<sup>37</sup> As there is significant proton competition at pH 7.4, depending on the basicity of the ligand, $K_{\\mathrm{cond}}$ is always substantially lower than $K_{\\mathrm{therm}}$ (Table 2). Thermodynamic and conditional thermodynamic stability constants have been previously determined by pH potentiometric methods for clinical GBCAs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[35,811,486,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$\\mathrm{K}_{\\mathrm{therm}}$ and $\\mathrm{K}_{\\mathrm{cond}}$ cannot predicate in vivo stability of Gd(III) complex alone. For example, Gd-DTPA has both higher $\\mathrm{K}_{\\mathrm{therm}}$ and $\\mathrm{K}_{\\mathrm{cond}}$ ( $\\mathrm{K}_{\\mathrm{cond}}$ is 3 orders of magnitude higher) than Gd-BT-DO3A, yet Gd-DTPA is believed to have caused NSF in renal impaired patients, whereas Gd-BT-DO3A was not.[85,94] Attempts have been made to explain acute toxicity results ( $\\mathrm{LD}_{50}$ ) and in vivo stability of GBCAs by calculating overall selectivity of Gd(III), taking into account cations of H, Ca, Cu, and Zn.[186,187] A more straightforward way to look at metal selectivity is to directly compare the Gd(III)-binding affinity with other endogenous ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,90,958,489]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"metal ions by the ratio of the conditional thermodynamic stabilities between the 2 ions (Table 2).[9,38,116,187,188] The dissociation rates of the Gd(III) complex at pH 1.0, which are referred as kinetic stability, reveal the kinetic inertness of the Gd(III) complex during competition with hydrogen ions, and this measurement agrees with in vivo stabilities reported for clinical GBCAs.[9,189-191] In addition, transmetallation also reflects kinetic inertness. In vitro transmetallation assessment is determined by monitoring relaxivity changes in the presence of Zn(II) following challenge with phosphate because the thermodynamic stability constant of clinical GBCAs for Zn(II) is only approximately 4 orders of magnitude lower than for $\\mathrm{Gd(III)}^{23}$ (Table 2).[186,192,193] R1 relaxivity will drop if Gd(III) is replaced by Zn(II). The order of kinetic inertness of macrocyclic GBCAs such as Gd-DOTA and Gd-HP-DO3A[52,59,116] is higher than linear GBCAs such as Gd-EOB-DTPA and Gd-DTPA-BMA. In addition, ionic linear CAs Gd-EOB-DTPA, Gd-DTPA, and Gd-Gd-BOPTA performed better than nonionic linear CA Gd-DTPA-BMA. Frenzel et al[194] reported an ex vivo method to evaluate kinetic inertness of GBCAs in human serum under realistic physiological conditions. Human serum from healthy volunteers was incubated with $1\\mathrm{mM}$ CA at $37^{\\circ}\\mathrm{C}$ , mimicking in vivo stability in healthy patients, and then the same samples were prepared with the addition of $10\\mathrm{mM}$ phosphate, thereby mimicking end-stage renal disease patients. Free Gd(III) is separated and determined by an HPLC system with a chelating Sepharose column connected to an inductively coupled plasma mass spectrometry. Following the same trends of kinetic inertness, macrocyclic GBCAs are stable in human serum for 15 days, but linear GBCAs will release $2\\% -30\\%$ of total Gd(III), and nonionic linear GBCAs will release approximately 10 times more Gd than ionic GBCAs. In summary, multiple ex vivo methods confirmed the in vivo stability data of GBCAs, wherein macrocyclic GBCAs with a preorganized cavity optimized for chelating Gd(III) have much greater kinetic stability than the more flexible linear GBCAs,[9,35,38,195,196] which makes them safer for clinical use. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,489,958,694]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In addition to significantly improved relaxivity, the next generation of MRI CAs should be equivalent to, or better than, macrocyclic GBCAs with respect to thermodynamic stability, kinetic inertness, and, importantly, metal selectivity against endogenous metal ions such as $\\mathrm{Mg(II)}$ , $\\mathrm{Ca(II)}$ , and $\\mathrm{Zn(II)}$ . Because of the presence of multiple protonation sites in proteins, the pH potentiometric method commonly used for small chelators to determinate Gd stability and metal selectivity is not applicable to proteins. Yang et al[148] developed 2 different approaches to determine the conditional thermodynamic stability/binding affinity and metal specificity of ProCAs by a competition titration with Fluo-5N (a metal ion indicator) for ProCA1 and a luminescence resonance energy transfer for ProCA32 with F103W mutation in a metal-Gd(III) buffer system.[50] A luminescence resonance energy transfer competition method was applied to measure the Gd (III)-, $\\mathrm{Ca(II)}$ -, $\\mathrm{Mg(II)}$ -, and $\\mathrm{Zn(II)}$ -binding affinity for ProCA32 and metal selectivity, and the resulting conditional thermodynamic stability data are summarized in Table 2.[50,52,59,116] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,695,958,888]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Strikingly, ProCA32 exhibited a Gd(III) thermodynamic stability comparable to that of DTPA of 21, whereas wild-type parvalbumin was reported to have a Gd(III) thermodynamic stability of 11.[197] Grum et al[198] also reported design of MRI CA from $\\alpha$ -parvalbumin ( $\\mathrm{r}_1 = 51 \\mathrm{mM}^{-1} \\mathrm{s}^{-1}$ at $1.5 \\mathrm{T}$ ) but exhibited low Gd(III)-binding affinity. ProCA32 achieved the greatest metal selectivity for Gd(III) over Ca(II), Mg(II), Zn(II), and other physiological metal ions, with selectivity values that were $>100-$ to $10^{11}$ -folds higher than DTPA. Conditional thermodynamic stability of Gd-ProCA32 has a log constant of 22, which outperformed both macrocyclic and linear GBCAs, such as Gd-DOTA and Gd-DTPA (Log Kcond $\\sim 17-18$ ) (Table 2). Most importantly, ProCA32 had much lower conditional thermodynamic stability for Zn(II) than the clinical GBCAs ( $\\sim 6-7$ orders of magnitude lower). These indicated that the selectivity of ProCA32 for Gd(III) over Zn(II) was more than 10- to $10^{14}$ -fold higher compared with both macrocyclic and linear clinical GBCAs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,888,958,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The highly selective nature of ProCA32 provides strong foundation for higher kinetic inertness and in vivo stability of ProCA32 compared with clinical GBCAs. Transmetallation studies (Fig. 4A) demonstrated that ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,38,482,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[606,38,958,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[37,946,448,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,945,913,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[929,946,956,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"177 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[80,97,348,249]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0959/388692a365d8c9695eceb1fce12f97826e8e713d82b73522b8c61bdbbc400a51.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[360,122,646,177]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0705/5be933d029e75477e06ec8e25d2912b0946c8976150bad465fc5f5aef2f077bc.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[653,91,919,247]","code_body":null,"code_caption":null,"image_caption":"[\"IGURE 4. A, The relaxation rates change of clinical contrast agents (black diamond Eovist; black circle Magnevist; white square MultiHance; white triangle Omniscan; blue square ProHance; yellow circle Dotarem) and red lozenge ProCA32.collagen1 in the presence of $\\\\mathrm{ZnCl}_2$ at different time points p to 4 days. B, Serum stability test of hProCA32.collagen shows that hProCA32.collagen remained intact in serum for up to 14 days (M, protein marker; P, ProCA32.collagen only; S, serum only). C, Size of ProCA32.collagen. Yellow color denotes ProCA32's scaffold. Red color denotes collagen-targeting moiety. Green color denotes the flexible linker. Cyan color denotes coordination amino acids. Blue circles denote Gd(III). \"]","image_footnote":"[]","img_path":"images/0785/774a850f4ed8a9d27625026dc6451f50ba5ec7534a5b733563751b348b736dce.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[43,333,482,412]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"roCA32 exhibited strong kinetic inertness comparable to macrocyclic BCAs, such as Gd-DOTA and Gd-HP-DO3A, and significantly greater inetic inertness than linear GBCAs, and also that ionic linear CAs have higher kinetic inertness than the nonionic ones including Eovist and ultiHance[52,59,116] (Fig. 4A). In addition, ProCA32 exhibited strong serum stability and remains intact for $>12$ days (Fig. 4B).[50] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[41,412,484,542]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The exceptional kinetic stability and metal selectivity of Gd-ProCA32 ver clinical GBCAs can be attributed to several key determinants used in the design strategy for metal-binding proteins. $^{146,155,156}$ First, ProCA32 as 7 coordinating atoms, almost exclusively from oxygen atoms with stronger affinity. Oxygen ligand atoms have greater water off rates than nitrogen ligand atoms that are related to $\\tau_{m}$ . In contrast, although clinical GBCAs have 8 total coordinating atoms for Gd(III), they are a mixture of oxygen and nitrogen, with lower affinity and slower off rates. $^{181}$ Second, metal-binding affinity is largely determined by fullness of the 1st coordination shell. The 2 metal-binding sites of ProCA32 are strongly ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,333,958,542]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"coupled and share a single water ( $q$ number of 0.5 per $\\mathrm{Gd(III)}$ ). In contrast, all approved GBCAs have $q$ values of 1. Third, ProCA32 agents have 5 negatively charged carboxylate oxygens tuned by S56D in EF-hand 1 and 4 negatively charged carboxylate oxygens in EF-hand 2 (Fig. 1B) $^{116}$ that are well balanced for electrostatic interaction. The preorganized metal-binding pockets of ProCA32 not only have optimal conformation and coordination for $\\mathrm{Gd(III)}$ but also have flexibility to enable sidechain rotation in the absence of $\\mathrm{Gd(III)}$ to reduce electrostatic repulsion. $^{146,158}$ Thus ProCA32 exhibited the strongest affinity to $\\mathrm{Gd(III)}$ . The designed pair of coupled Gd-binding sites in ProCA32 have significantly greater metal selectivity primarily due to protein sidechain flexibility that enables adaptations for metal coordination, $^{148,199-202}$ and metal selectivity for $\\mathrm{Gd}$ (III) over divalent metal ions including $\\mathrm{Ca(II)}$ , $\\mathrm{Mg(II)}$ , and $\\mathrm{Zn(II)}$ . In contrast, although macrocyclic chelators have strong Gd affinity with preformed coordination, they do not have the flexibility required to adapt to metal ions with smaller radii, which is essential for metal selectivity. $^{148,199-202}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[208,558,788,897]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 5. Applications of ProCA32s to detect different diseases by targeting different biomarkers. All the protein-based MRI contrast agents are injected via tail vein at a dosage of $0.02 - 0.03\\\\mathrm{mmol / kg}$ \"]","image_footnote":"[]","img_path":"images/0565/578f1c6870c9a00408748d0521e64824aecc0c861057c66ef1fa3694d8d92ff0.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[39,40,89,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,38,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[39,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"178 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,315,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[545,946,956,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[48,95,423,309]","code_body":null,"code_caption":null,"image_caption":"[\"B \"]","image_footnote":"[]","img_path":"images/0155/be43e3d0dc16c8cf4cc7bfa82fe7edd25c4ea4ee9168f7cb25eb8f102348464c.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[443,94,951,296]","code_body":null,"code_caption":null,"image_caption":"[\"IGURE 6. A, Estimation of the collagen-binding affinity of hProCA32.collagen to collagen type I, type III, and type IV using modified indirect zyme-linked immunosorbent assay. B, Two hepatocellular carcinoma (HCC) and normal human liver tissue microarray stained with Sirius red (red) nd ProCA32.collagen1 (brown) exhibiting the strong binding of the contrast agent to collagen human patient tissue (all scale bars, $100\\\\mu \\\\mathrm{m}$ ). \"]","image_footnote":"[]","img_path":"images/0333/aed27a352ebdbaad978401eacf8b1860246418aac7200e66899695c74f1cac18.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[48,372,482,399]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"IOMARKER TARGETING FOR PRECISION MOLECULAR IMAGING AND PRECLINICAL APPLICATIONS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[39,403,486,605]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Having established the third generation of MRI CAs (ProCA32) ith strong affinity and selectivity for Gd(III) and improved relaxivity o achieve improved contrast, we next considered how to further refine he efficacy and precision of our MRI CAs for improved early detection of disease and disease specificity based on our established riteria. Several important guidances were established for the selection and design of molecular biomarkers for precision MRI. First, we elected several key molecular biomarkers that are common across multiple chronic diseases and are expressed in the extracellular environment. These biomarkers should be readily accessible by ProCAs hen they are activated during disease stage. To date, we have successfully developed biomarker-targeted ProCA32 MRI CAs for collagen, HER2, EGFR, PMSA, GLPR, and CXCR4, and various other targets[47,48,50,52,57,62,76,115,159-162] (Fig. 5); however, for the purpose of brevity in this review and to demonstrate our rationale and success ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,372,956,399]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"in achieving precision MRI, we will only present as an exemplary case ProCA32.collagen, which specifically targets type I collagen. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,399,958,579]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Type I collagen is an extracellular matrix protein that is overexpressed (10- to 20-fold $\\mu$ M) and deposited during progression of a number of diseases, leading to pathological changes and remodeling of the tissues in the tumor microenvironment, fibrosis progression of liver, lung, and kidney, and cardiovascular fibrosis.[203] Fibrosis occurs in a number of major diseases such as myocardial infarction, NASH, cirrhosis, liver fibrosis, pulmonary fibrosis, and various cancers.[204-206] More importantly, overexpressed collagen can be crosslinked by LoX or degraded by MMPs with expression of pathologic patterns that depend on the stage and tissue/organ environment, as revealed by second-harmonic generation imaging.[207,208] The expression of collagen also plays an important role in nodule formation, permeability of cancer, and metastasis migration. Recent studies have also reported that collagen formation is an indication for therapeutic responses.[56] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,579,956,606]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Second, we designed a targeting moiety with a defined tertiary structure to have strong biomarker-binding affinity and wherein the ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[62,630,944,875]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 7. A, Magnetic resonance imaging of liver before and 24 hours postinjection of ProCA32.collagen1 at a dosage of $0.02\\\\mathrm{mmol / kg}$ in UM hepatic metastasis mouse model. B, Hemotoxylin-eosin staining of 6 UM metastasis tumors and its corresponding Sirius red staining, which shows the expression of collagen (red) and their corresponding locations in MRI. Tumor 2 exhibited an infiltrative pattern (green circle), whereas the other tumors exhibited a nodular pattern. \"]","image_footnote":"[]","img_path":"images/0428/9ae8f67408855f47c97a94f2d6aea59e92a18246555fb509e8a04da485e61914.jpg","list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[39,38,486,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[606,38,958,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[37,946,450,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,945,913,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[931,946,956,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"179 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[41,89,482,399]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"addition to the ProCAs would not result in alteration of biomarker-binding affinity or reduction of metal-binding affinity and relaxivity properties of ProCAs. This is achieved by ensuring the targeting moiety for collagen type I maintains an intradisulfide bond and that the key lysine residues are well positioned to interact with collagen. A flexible hinge is used to connect the targeting moiety and the roCA scaffold, without imposing conformational constraints. With this esign, ProCA32.collagen has a strong collagen type I-binding affinity $\\mathrm{K_d} = 1.0~\\mu \\mathrm{M})$ as determined by enzyme-linked immunosorbent assay[16] Fig. 6A). The created ProCA32.collagen also exhibits strong binding specificity over other collagen types, including collagens III and IV. As seen in Figure 6B, it has strong patient tissue specificity for fibrotic stroma f HCC and exhibits the same pathological pattern observed with Sirius ed, suggesting its strong translational potential.[52] Importantly, the 2 etal-binding sites of ProCA32.collagen retain the same relaxation properties of high $\\mathbf{r}_1$ and $\\mathbf{r}_2$ relaxivity, thermodynamic stability, and metal-binding finity and stability as the parent protein ProCA32 without a targeting moiety.[116] This represents a significant milestone for ProCAs, as it addresses the challenges faced by short peptide targeting moieties with conormational variations that can lead to substantial changes in affinity nd specificity upon conjugation. Furthermore, it underscores the effectiveness of the approach to developing ProCAs, as small chelator-based As frequently experience decreased metal binding and relaxivity hen incorporating targeting moieties.[143] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[43,399,482,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Third, to ensure the quantitative capability in mapping biomarker empox spatial expression levels in the disease states, a developed CA is required to have strong tissue penetration to reach all of the overexpressed biomarkers, and this may be constrained by the size of the olecule. Figure 4C shows that, like other ProCAs developed against ER2 and CXCR4, ProCA32.collagen is $\\sim 2 - 3\\mathrm{nm}$ in diameter with a ocular weight of $14\\mathrm{kDa}$ , which makes it small enough to access verexpressed collagen in tumor microenvironment and fibrosis tissues. In contrast, much larger ( $\\sim 150\\mathrm{kDa}$ ) antibodies are more likely to locate lose to the blood vessels and less likely to reach the overexpressed iomarkers.[59,62] Thus, a smaller CA is not only important for high tumor/isease targeting ratio, but also because it can be more easily excreted from the kidneys and therefore poses fewer toxicity concerns related to metal deposition. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[511,90,956,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As an example, the detection of uveal melanoma (UM) lesions was demonstrated by ProCA32.collagen in a UM hepatic metastasis mouse model.115 Uveal melanoma hepatic metastatic lesions overexpress type I collagen. By $\\mathrm{T}_{1}$ inversion recovery pulse sequence, lesions as small as $0.250\\mathrm{mm}^2$ could be detected after injecting ProCA32.collagen, whereas the tumors were not detected either by the clinical CA Eovist or our nontargeted blood pool agent ProCA32 (Fig. 7A). Both hemotoxylineosin and corresponding Sirius red staining of these UM tumors confirmed the overexpression of collagen (red) in liver lesions detected by MRI with ProCA32.collagen (Fig. 7B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,219,956,309]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ProCA32-enabled MRI has been investigated for detection and staging of liver fibrosis, liver metastasis, and lung fibrosis, in different mouse models. As previously discussed, ProCA32 agents are both $\\mathrm{T}_{1}$ and $\\mathrm{T}_{2}$ CAs. Both $\\mathrm{T}_{1}$ and $\\mathrm{T}_{2}$ properties $(\\mathrm{T}_{2} / \\mathrm{T}_{1}$ ratio imaging) have been leveraged to detect liver tumors and metastatic UM in liver.[50] Similarly, we have also been able to successfully detect liver metastasis from ovarian cancer,[59] pancreatic cancer, and colon cancer (manuscript in preparation). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[513,309,956,580]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fibrosis occurs in a number of major diseases such as NASH, cirrhosis, liver fibrosis, pulmonary fibrosis, and myocardial infarction. There is a pressing need for noninvasive detection of fibrosis at early stage and the capacity to stage fibrosis for treatment, because the current criterion standard, biopsy, can produce large errors $(>33\\%)$ for detection of early-stage lesions, when tissues exhibit high heterogeneity. There is also an additional need to develop noninvasive imaging methods to evaluate drug responses and for drug discovery. We have achieved success in early detection of liver fibrosis from several origins including alcohol (ASH), fat (NASH), and carcinogens (DEN).7,52 A bolus of ProCA32.collagen in both TAA/alcohol-induced and NASH-induced liver fibrosis mouse models produced stage-dependent $\\mathbb{R}_1$ and $\\mathbb{R}_2$ changes verified by histological and inductively coupled plasma optical emission spectroscopy of Gd(III) analyses (Fig. 8A).52 Meanwhile, ProCA32.collagen produced no enhancement in normal liver at 24 hours postinjection. Consistent with the $\\mathbb{R}_1$ map, the $\\mathrm{T}_{2}$ map results also exhibited the same pattern at 24 hours for both early and late stages of fibrosis, with more significant changes observed in late-stage fibrotic liver (Fig. 8B). More importantly, using ProCA32.collagen with our developed imaging methodology, we can achieve the detection of early- and late-stage fibrosis with good sensitivity and specificity (Fig. 8C), as our work addresses ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[52,605,452,874]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0098/4a93432a3386d723e2e34aa769f66159541f89f864e6fc048b39423a63c5ca39.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[479,604,660,745]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0512/f800ba047cc4b996de6e7e689ce52471c47914ed80dac296c199494482c070c0.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[698,614,937,741]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0037/74b57bf4fb904ae15d2c3f1cd4f4b9f1bfb5f0fcba69937f2ae57bbd488cc5ff.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[479,747,680,874]","code_body":null,"code_caption":null,"image_caption":"[\"FIGURE 8. Early-stage detection of liver fibrosis in TAA/alcohol mouse model. A, R1 maps and $\\\\Delta R1$ values of normal, early-stage, and late-stage liver fibrosis before and 24 hours after injection of ProCA32.collagen1 with a dosage of $0.02\\\\mathrm{mmol / kg}$ . B, $\\\\Delta R2$ values derived from T2 maps demonstrating the highest enhancement for late-stage liver fibrosis at 24 hours postinjection. C, ProCA32.collagen1 can distinguish early-stage liver fibrosis from normal and late-stage fibrotic liver with $\\\\Delta R1$ derived from an R1 map at 24-hour time point. \"]","image_footnote":"[]","img_path":"images/0367/e2436311ed689658bc885d76760528ea583c33321181a731b6642240b0794168.jpg","list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[39,41,87,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,38,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[41,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"180 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,314,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[545,946,956,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[53,91,942,359]","code_body":null,"code_caption":null,"image_caption":"[\"IGURE 9. Detection of early- and late-stage idiopathic pulmonary fibrosis (IPF) by a bolus of $0.02\\\\mathrm{mmol / kg}$ hProCA32.collagen. UTE-MRI of the lungs of ormal (A), early-stage IPF (B), and late-stage IPF (C) hProCA32.collagen-enabled detection of heterogeneous enhancement of collagenous oneycombing at the subpleural and paraseptal areas of the lung at early stage (B) and late stage (C), highlighted by orange arrows. Magnetic resonance age changes were not observed in late-stage IPF mice at before and 3 hours after injection of Gadovist (D). E, Comparison of ProCA32.collagen attain uptake (red) in BM-induced IPF at alveolar (top) and E-cigarette-induced lung fibrosis in COPD mouse models at the bronchial airways in 3D UTE RI correlated with Sirius red staining. F, Lung signal enhancement $(\\\\%)$ of normal, nicotine-induced lung fibrosis model for COPD, and BM-induced ice (LS, late stage; $\\\\ast \\\\ast \\\\ast \\\\ast P < 0.001$ one-way analysis of variance). \"]","image_footnote":"[]","img_path":"images/0541/5662b96d430b1d01793018e758f5e8c8ebedc77e36d77bb80d753403d0f9f6bf.jpg","list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[39,463,482,514]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"he additional diffusive diseases of fibrosis without defined boundary f nodules and heterogeneity. Moreover, based on our results to date, his methodology will also enable us to follow drug treatment responses y MRI in vivo. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[35,514,486,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Recently, we have made another major leap in application of roCA32.collagen and MRI for detection and staging of lung fibrosis in vivo, originating from both IPF and electronic cigarette smoke inhalation, in animal models. Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we reported the development of human collagen-targeted protein MRI CA (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. We have demonstrated the robust detection of early- and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio increase and with good sensitivity and specificity using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, was noninvasively detected by multiple MRI techniques and verified by histological correlation. By using a $\\mathrm{T}_{1}$ -weighted ultrashort echo time (UTE) pulse sequence in a bleomycin (BM)-induced IPF mouse model, injection of hProCA32.collagen resulted in $60\\%$ and $80.5\\%$ enhancement at a 3-hour time point compared with preinjection for the early and late stage of IPF mice, respectively, whereas injection of hProCA32.collagen into healthy normal mice did not result in any noticeable MRI enhancement (Figs. 9A-C, and F). In contrast, injection of gadobutrol (GdBT-DO3A) into late-stage IPF mice did not result in significant enhancement (Fig. 9D). Both examples demonstrated the capability of ProCA32. collagen to detect and stage fibrosis in liver and lung with histological correlation. Moreover, we extended our demonstration to include ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,463,958,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the detection of fibrosis in the lung airways of a mouse model with electronic cigarette-induced COPD, using hProCA32.collagen-enabled precision MRI. Notably, the uptake of ProCA32.collagen is distinct between IPF and COPD mouse models, as depicted in Figure 9E. Magnetic resonance imaging results were validated by histological analysis. $^{116}$ The developed hProCA32. collagen is expected to have strong translational potential in the noninvasive detection and staging of lung diseases and facilitating effective treatment to halt further chronic lung disease progression. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[529,587,938,615]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PHARMACOKINETICS AND BIODISTRIBUTION OF PROCA32 CONTRAST AGENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[508,617,958,760]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Several key physicochemical properties of ProCA32.collagen have been determined for preclinical and clinical application. Because of the high relaxivity of ProCA32.collagen $(30/42, \\mathrm{r}_1 / \\mathrm{r}_2, \\mathrm{mM}^{-1} \\mathrm{s}^{-1}$ at $1.4 \\mathrm{T}$ ), ProCA32. collagen is formulated at $5 \\mathrm{mM}$ , which is 50- to 200-fold lower in concentration than clinical GBCAs $(0.25 - 1 \\mathrm{M})$ . For related studies in our laboratory, the required dose of ProCA32.collagen was calculated to be $0.017 \\mathrm{mmol} / \\mathrm{kg}$ . By using a body surface area normalization method,[209] the converted theoretical human dose was calculated to be $0.0014 \\mathrm{mmol} / \\mathrm{kg}$ . This is a 71-fold lower dose than Gd-DOTA, Gd-HP-DO3A, and Gd-DTPA $(0.1 \\mathrm{mmol} / \\mathrm{kg}$ standard dose) and 18-fold lower than Gd-EOB-DTPA $(0.025 \\mathrm{mmol} / \\mathrm{kg}$ standard dose) (Table 2). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,760,958,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pharmacokinetics of ProCA32.collagen (PEGylated and non-PEGylated) was studied in mice in our laboratory after a single intravenous injection of $0.017\\mathrm{mmol / kg}$ ProCA32.collagen. PEGylated ProCA32.collagen was cleared from circulation in mice with a mean plasma elimination half-life $(t_{1 / 2\\beta})$ of 9.93 hours,52 because PEGylation significantly increases blood retention time of the protein.132 ProCA32.collagen without PEGylation exhibited a shorter terminal half-life of $\\sim 4$ hours (unpublished data). PEGylated ProCA32.collagen had higher exposure time with volume of distribution $(V_{ss})$ of $1.77~\\mathrm{L / kg}$ (2-fold higher than that of ProCA32), indicating the contribution of the targeting ability of ProCA32.collagen and its distribution and penetration into tissues.52 The biodistribution of Gd(III) at 14 days postinjection of PEGylated ProCA32.collagen $(0.017\\mathrm{mmol / kg}$ dose) was measured with inductively ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,38,484,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[606,38,958,53]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Protein MRI Contrast Agents as an Effective Approach ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[37,946,450,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,946,913,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[929,946,956,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"181 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[35,90,486,192]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"coupled plasma optical emission spectroscopy using harvested organs in normal mice. Lower than $0.002\\mu \\mathrm{mol}$ Gd(III) per gram of organ was detected in the liver, skin, kidney, heart, lung, muscle, bone, and brain, whereas Gd-EOB-DTPA had more than 3-folds higher residual Gd(III) in the skin, kidney, and bone compared with PEGylated ProCA32.collagen.[52] Moreover, there was only $0.0002\\mu \\mathrm{mol}$ Gd(III) per gram of organ in the brain for PEGylated ProCA32.collagen. This is more than 10-folds over residual Gd(III) than Gd-EOB-DTPA.[52,116] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,210,439,223]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CONCLUSIONS AND FUTURE PERSPECTIVE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[46,226,484,483]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In summary, we have created a platform technology for the rational design of a novel class of ProCAs that incorporate Gd(III)-binding site(s) and a isase molecular biomarker-targeting moiety such as collagen,[52,115,116] ER2,[62] PSMA,[162] GRPR,[159] CXCR4,[59] and VEGFR, into a stable scaffold protein (Fig. 1C) to detect and image several types of cancers in animal odels. Our leading CA (ProCA32.collagen) specifically targets type I collagen and exhibits significant increases in both $\\mathbf{r}_1$ and $\\mathbf{r}_2$ relaxivities compared with clinically approved $\\mathrm{Gd}^{3+}$ CAs, resulting in exceptional imaging apability, especially when combined with precision MRI, for noninvasive end quantitative mapping of tempospatial changes of collagen expression using progression and regression of diseases. The results of preclinical studies in the Yang laboratory suggest that ProCA32.collagen can detect lesions 100 times smaller than the detection limits of current clinical CAs and an also detects early-stage liver fibrosis in animal models.[52] ProCA32.collagen enables early-stage detection of hepatic liver cancer and metastasis $0.2 - 20 \\mathrm{~mm}$ , with fibrosis and steatosis in mouse models, with a 4-fold increase in contrast-to-noise ratio.[50,52] ProCA32.collagen also itigates metal toxicity due to its lower dosage, strong resistance to transmetallation, and exceptional metal selectivity for $\\mathrm{Gd}^{3+}$ over physiological metal ions, with strong translational potential. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,485,484,587]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The successful development of a protein-based MRI CA ProCA32 ith improved contrast capabilities has validated the rationale and strategy ehind its design. Coupled with a targeting moiety, ProCA32.collagen hasemonstrated its capability to achieve qualitative and quantitative precision ocular imaging of several key molecular disease biomarkers in various chronic diseases (fibrosis, metastatic cancer, etc) in multiple animal odels. The safety profile and MRI properties indicate strong potential for preclinical and clinical application of ProCA32. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,587,484,664]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The base scaffold of ProCA32 can be used to detect variable chronic diseases by combining with different biomarker-targeting moieties. Meanwhile, it can advance drug discoveries via noninvasively monitoring disease progression. ProCA32 CAs are also expected to translate into clinical practice in the near future after scale-up production. The manufacturing and large-scale production of ProCA32.collagen is currently underway. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[39,664,484,858]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Advancement of pulse sequences such as multitasking will further address respiratory and cardiac motion effects. Histological correlation with MR images will be further improved by 3D imaging processing and registration. CEST properties and multicolor molecular MRI will be explored using ProCA32. In addition, this same principle can be applied to design of Gd(III) free Mn(II)-based and biomarker-targeted CAs.[210-213] With this development of a protein CA platform having high $\\mathbf{r}_1$ and $\\mathbf{r}_2$ relaxivity values, metal-binding stability, and significantly reducing dosage, we are also moving forward to develop responsive CAs (SMART), as pioneered by Meade et al, which are able to respond to changes in biological processes such as calcium or proteases.[52,66,67,116,214,215] Despite these advances, future development of new CAs will continue to be driven by strong commitment to patient need and market demand for improved medical diagnostic imaging of the CNS, cancerous soft tissues, vasculature, and internal organs, including the liver, heart, and lungs.[7] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[175,875,346,887]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[37,888,486,928]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The authors thank Chunqi Qian for critically reviewing this article. They also thank James Prestegard, Michael Tweedle, past Yang members, important collaborators, and dedicated colleagues for the helpful ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[508,90,958,452]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"discussion and contribution. They thank the NIH Shared Instrument Grant S10OD027045 and funding support from Georgia States University to establish the Advanced Translational Imaging Facility. D.L., M.S., and S.X. were sponsored by GSU MBD fellowships, whereas Z.G. and O.I. were sponsored by GSU CDT fellowships; S.T. was sponsored by a BB fellowship. Importantly, this work is also dedicated to William Thomas (Tom) Dixon, who was a true inspiration for Jenny Yang's career development and relaxation theory. Tom graduated from the University of Minnesota with a bachelor's degree in mechanical engineering in 1967. He later attended medical school at Stanford University but moved back to Minnesota in 1969 to work at the Control Data Corporation developing new supercomputers. Tom then moved to UC San Diego where he graduated in 1980 with a degree in physics. Tom met his wife, Dabney Katherine White, while in San Diego. They were married in St Louis in 1982. In 1986, Tom moved to Atlanta to lead the Frits Philips Center for Magnetic Resonance Imaging at Emory University. Tom then worked in the private sector from 2000 to 2012, before returning to Emory and retiring in 2017. Tom was well known to his peers for his sense of humor, humility, and compassion. He was also well known for his important contributions to MRI contrast imaging, including development of new pulse sequences to enhance MR CA utility, particularly his development of a method to create images that show water only, fat only, and the difference between water and fat intensity, known as the Dixon Method (see Radiology. 1984;153:189-194). As of August 2022, the article had been cited more than 2700 times. His many contributions to science will continue to inspire the next generation of researchers and challenge us all to strive for excellence. The authors appreciate Tom's detailed discussions about relaxation theory and properties of ProCAs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[685,465,782,478]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[520,485,956,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Taylor AJ, Salerno M, Dharmakumar R, et al. T1 mapping: basic techniques and clinical applications. JACC Cardiovasc Imaging. 2016;9:67-81. \",\"2. Meijer FJ, Goraj B. Brain MRI in Parkinson's disease. Front Biosci (Elite Ed). 2014;6:360-369. \",\"3. Lapalme-Remis S, Nguyen DK. Neuroimaging of epilepsy. Continuum (Minneap Minn). 2022;28:306-338. \",\"4. Lother D, Robert M, Elwood E, et al. Imaging in metastatic breast cancer, CT, PET/CT, MRI, WB-DWI, CCA: review and new perspectives. Cancer Imaging. 2023;23:53. \",\"5. Villanueva-Meyer JE, Mabray MC, Cha S. Current clinical brain tumor imaging. Neurosurgery. 2017;81:397-415. \",\"6. Vietti Violi N, Taouli B. Abbreviated MRI for HCC surveillance: is it ready for clinical use? Eur Radiol. 2020;30:4147-4149. \",\"7. Kennedy P, Taouli B. Collagen-targeted MRI contrast agent for liver fibrosis detection. Nat Rev Gastroenterol Hepatol. 2020;17:201-202. \",\"8. Alzola-Aldamizetxebarria S, Fernandez-Mendez L, Pedro D, et al. A comprehensive introduction to magnetic resonance imaging relaxometry and contrast agents. ACS Omega. 2022;7:36905-36917. \",\"9. Port M, Idee J-M, Medina C, et al. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals. 2008;21:469-490. \",\"10. Laniado M, Weinmann HJ, Schorner W, et al. First use of GdDTPA/dimeglumine in man. Physiol Chem Phys Med NMR. 1984;16:157-165. \",\"11. Weinmann HJ, Brasch RC, Press WR, et al. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol. 1984;142:619-624. \",\"12. Bousquet J-C, Saini S, Stark DD, et al. Gd-DOTA: characterization of a new paramagnetic complex. Radiology. 1988;166:693-698. \",\"13. Magerstadt M, Gansow OA, Brechbiel MW, et al. Gd(DOTA): an alternative to Gd(DTPA) as a T1,2 relaxation agent for NMR imaging or spectroscopy. Magn Reson Med. 1986;3:808-812. \",\"14. Runge VM, Bradley WG, Brant-Zawadzki MN, et al. Clinical safety and efficacy of gadoteridol: a study in 411 patients with suspected intracranial and spinal disease. Radiology. 1991;181:701-709. \",\"15. Vogler H, Platzek J, Schuhmann-Giampieri G, et al. Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging. Eur J Radiol. 1995;21:1-10. \",\"16. Kubicek, V., É. Toth. In: R. van Eldik and C.D. Hubbard, Editors. Design and Function of Metal Complexes as Contrast Agents in MRI, in Advances in Inorganic Chemistry. Cambridge, MA: Academic Press. 2009:63-129. \"]","page_idx":"12","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[39,41,87,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,38,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[41,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"182 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,314,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[545,946,956,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). 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Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[682,946,910,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[931,946,956,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"183 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[41,91,482,926]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"73. Briley-Saebo KC, Geninatti-Crich S, Cormode DP, et al. 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Published by Wolters Kluwer Health, Inc. ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[41,91,484,927]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"128. Aime S, Calabi L, Cavallotti C, et al. [Gd-AAZTA]: a new structural entry for an improved generation of MRI contrast agents. Inorg Chem. 2004;43:7588-7590. \",\"129. Fries P, Müller A, Seidel R, et al. P03277—a new approach to achieve high-contrast enhancement: initial results of an experimental extracellular gadolinium-based magnetic resonance contrast agent. Invest Radiol. 2015;50:835–842. \",\"130. Supkowski RM, Horrocks WD. Displacement of inner-sphere water molecules from Eu3+ analogues of $\\\\mathrm{Gd}3+$ MRI contrast agents by carbonate and phosphate anions: dissociation constants from luminescence data in the rapid-exchange limit. Inorg Chem. 1999;38:5616-5619. \",\"31. Caravan P, Greenwood JM, Welch JT, et al. 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Published by Wolters Kluwer Health, Inc. 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Contrast Media Mol Imaging. 2015;10:245-265. \"]","page_idx":"16","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[39,41,87,51]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Li et al ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[513,40,956,54]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Investigative Radiology Volume 59, Number 2, February 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[41,946,66,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"186 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[84,946,314,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"www.investigativeradiology.com ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[547,946,956,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"© 2023 The Author(s). 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","text_format":null,"text_level":null,"type":"footer"}],"string":"[\n {\n \"bbox\": \"[43,89,100,104]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OPEN \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[102,113,894,165]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[53,178,942,228]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dongjun Li, MS, Michael Kirberger, PhD, Jingjuan Qiao, PhD, Zongxiang Gui, MS, Shenghui Xue, PhD, Fan Pu, PhD, Jie Jiang, PhD, Yiting Xu, MS, Shanshan Tan, PhD, Mani Salarian, PhD, Oluwatosin Ibhagui, PhD, Khan Hekmatyar, PhD, and Jenny J. Yang, PhD \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,265,482,652]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract: Cancer and other acute and chronic diseases are results of perturbations of common molecular determinants in key biological and signaling processes. Imaging is critical for characterizing dynamic changes in tumors and metastases, the mor microenvironment, tumor-stroma interactions, and drug targets, at multiscale levels. Magnetic resonance imaging (MRI) has emerged to be a primary imaging odality for both clinical and preclinical applications due to its advantages over their modalities, including sensitivity to soft tissues, nondepth limitations, and e use of nonionizing radiation. However, extending the application of MRI to chieve both qualitative and quantitative precise molecular imaging with the capability to quantify molecular biomarkers for early detection, staging, and monitoring erapeutic treatment requires the capacity to overcome several major challenges including the trade-off between metal-binding affinity and relaxivity, which is an issue frequently associated with small chelator contrast agents. In this review, we will introduce the criteria of ideal contrast agents for precision molecular imaging and discuss the relaxivity of current contrast agents with defined first shell coordination water olecules. We will then report our advances in creating a new class of protein-targeted RI contrast agents (ProCAs) with contributions to relaxivity largely derived from the secondary sphere and correlation time. We will summarize our rationale, design strategy, and approaches to the development and optimization of our pio-erering ProCAs with desired high relaxivity, metal stability, and molecular iomarker-targeting capability, for precision MRI. From first generation ProCA1) to third generation (ProCA32), we have achieved dual high $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ values that are 6- to 10-fold higher than clinically approved contrast agents at agnetic fields of $1.5\\\\mathrm{T}$ ,and their relaxivity values at high field are also significantly higher, which enables high resolution during small animal imaging. Further engineering of multiple targeting moieties enables ProCA32 agents that have strong biomarker-binding affinity and specificity for an array of key molecular biomarkers associated with various chronic diseases, while maintaining relaxation and exceptional metal-binding and selectivity, serum stability, and resistance to transmetallation, which are critical in mitigating risks associated with metal \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,667,482,710]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"From the Center for Diagnostics and Therapeutics, Advanced Translational Imaging Facility, Department of Chemistry, Georgia State University, Atlanta, GA (D.L., M.K., J.Q., Z.G., S.X., P.F., J.J., S.T., M.S., O.I., K.H., J.J.Y.); and InLighta BioSciences, LLC, Marietta, GA (Y.X., J.J.Y). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,710,482,783]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Conflicts of interest and sources of funding: J.J.Y. holds shares in the company InLighta Biosciences LLC, which licenses the rights to commercialize protein-targeted MRI contrast agents. J.J.Y. is a named inventor on issued or pending patents (US8173105 [EP1901659], US8367040 [EP3378496] contrast agents, US9339559 [EP1928507, CA 2621763], US 10525150 targeted contrast agents, US9956304 [EP2257316], US15/910893, US17/068215 contrast agents and imaging, US15/572,863 [WO16793465.2] targeted contrast agents). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,782,482,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This work was supported in part by NIH grants 33CA235319, R42AA112713, R42CA183376, 1R01EB007268, and S100D027045 to J.J.Y. Additional support for commercialization was provided to InLighta BioSciences by NIH (STTR and SBIR) through grants R42AA025863, R42CA183376, 1R44CA268403-01A1, NIDDK R01 DK126080-01A1, and UT2AA028659-01. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,834,482,865]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Correspondence to: Jenny J. Yang, PhD, Center for Diagnostics and Therapeutics, Advanced Translational Imaging Facility, Department of Chemistry, Georgia State University, Atlanta, GA 30303. E-mail: jenny@gsu.edu. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,865,482,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,906,213,915]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN: 0020-9996/24/5902-0170 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,915,245,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DOI: 10.1097/RLI.0000000000001057 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,258,956,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"toxicity. Our leading product ProCA32.collagen has enabled the first early detection of liver metastasis from multiple cancers at early stages by mapping the tumor environment and early stage of fibrosis from liver and lung in vivo, with strong translational potential to extend to precision MRI for preclinical and clinical applications for precision diagnosis and treatment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,327,937,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Key Words: MRI, contrast agent, protein-based, dual contrast, early detection \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,347,701,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Invest Radiol 2024;59:170-186 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,372,956,618]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Chronic diseases including alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), and various types of cancers are results of perturbations of common molecular determinants in key biological and signaling processes. Noninvasive imaging is critical for characterizing dynamic changes of molecular disease biomarkers for disease progression and regression upon treatment or during therapy. Compared with x-rays and computed tomography, magnetic resonance imaging (MRI) provides improved imaging sensitivity of soft tissues, including nerves, muscles, ligaments, and tendons, without using ionizing radiation. Magnetic resonance imaging also provides better resolution, more comprehensive functional information, and better organ differentiation than ultrasound. In addition, it allows us to capture dynamic signal changes. Magnetic resonance imaging has emerged to be a primary imaging modality for both clinical and preclinical applications including but not limited to cardiac imaging for heart diseases; neuroimaging for Parkinson disease and epilepsy; and cancer imaging for primary and metastatic cancers, including brain tumors and hepatocellular carcinoma (HCC). This wide array of applications is largely due to the discovery and development of MRI contrast agents (CAs). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,618,956,836]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Magnetic resonance imaging CAs are molecular compounds designed to extend the known capabilities of MRI by altering the magnetic properties of nuclei, particularly protons, resulting in increasing contrast between different regions within an image, for example, distinguishing a tumor from the surrounding tissues. Gadolinium-based contrast agents (GBCAs) are the most widely used in preclinical and clinical practice because paramagnetic $\\\\mathrm{Gd(III)}$ has the highest number of unpaired electrons (7) with relatively slow electronic relaxation owing to its symmetric S electronic ground state, which necessitates strong nuclear relaxation. It often produces bright contrast enhancement in MR images by decreasing longitudinal relaxation $(\\\\mathrm{T}_{1})$ . This makes $\\\\mathrm{Gd(III)}$ a more desirable choice compared with other metal ions such as iron oxides, which primarily induce $\\\\mathrm{T}_{2}$ shortening and result in darkening contrast in $\\\\mathrm{T}_{2}$ images. Based on their size, contribution of water molecules, and structure, GBCAs can be divided into 3 classes: small molecule GBCAs (class I), large polymers including nanoparticle GBCAs (class II), and protein GBCAs (class III) (Fig. 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,836,956,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Class I includes the first developed Gd-chelator complexes. The major clinically available GBCAs include both macrocyclic/linear and ionic/nonionic chelators (Fig. 1A). The first GBCA, Gd-DTPA, was approved for clinical use by the Food and Drug Administration in 1988. These GBCAs coordinate Gd(III) through a nonadentate geometry, comprising 4 nitrogen and 4 oxygen ligands atoms from the chelator, and 1 available coordination site for an inner-sphere water \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[411,41,585,56]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REVIEW ARTICLE \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[41,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"170 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,312,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[513,946,956,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[102,89,464,344]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0579/ac56ea7007beae320b264d36a55f4db2dc9a56cbd89ff16efee6c843023965c4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[466,90,691,336]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0230/279fc12e5065ce1b0ff6a400e52f332c59e83b48cd96065921ad633948302abe.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[709,94,888,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"C \\\",\\\"IGURE 1. Three classes of GBCAs. A, Small molecule GBCA representatives Gd-BT-DO3A, Gd-HP-DO3A, Gd-DOTA, Gd-EOB-DTPA, MS-325, gadoquatane, nd gadopiclenol. B, Nanoparticle GBCA representatives. C, Protein GBCA representatives ProCA32s and ProCA1. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0059/f7ecf9fba9f6ccf92baaae454f68d4d8f4450cd46abb04f57689c717f5d16ec4.jpg\",\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[37,397,486,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"olcule. Macrocyclic Gd-DOTA, $^{12,13}$ Gd-HP-DO3A, $^{14}$ and Gd-BT-DO3A $^{15}$ helate a Gd(III) in a rigid organized cavity whose size is preferable for d(III), $^{16,17}$ whereas linear Gd-DTPA, $^{11}$ Gd-DTPA-BMA, $^{18}$ Gd-BOPTA, $^{19}$ d-DTPA-BMEA, $^{20}$ and Gd-EOB-DTPA $^{21}$ have flexible open chains offering weaker protection of the Gd ion from endogenous metal ions. $^{22,23}$ adolinium-based contrast agents largely improve the sensitivity of MRI, and they also add functional information, such as perfusion $^{24}$ and cine $^{25,26}$ f heart, permeability of blood-brain barrier, $^{27}$ as well as perfusion and permeability in tumors $^{28,29}$ and inflammation. $^{30}$ Several significant GBCAs that ave been developed recently include the following: gadopliclenol, which as approved by the FDA in 2022 $^{31}$ ; gadoquatane (Bayer), a tetramer of OTA conjugates, $^{32}$ which is currently in phase 3 clinical trials $^{33,34}$ ; and OPO and PCTA, which coordinate 2 and 3 water molecules, respectively, but have yet to be FDA approved. $^{35}$ These structures have been substantially reviewed in the past. $^{35-43}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[35,592,486,901]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Today, more than one third of clinical MRIs are administered with these approved small, chelate-based MRI CAs. Projections suggest that the global MRI market size, valued at US $5.26 billion in 2022, will grow at a compound annual growth rate (CAGR) of $6.8\\\\%$ through 2030, based on anticipated increases in various diseases related to spine lesions, tumors, heart, and stroke impacting the area of blood vessels and brain, as well as advancements in diagnostic techniques such as open MRI, visualization software, and superconducting magnets, fueling MRI market growth.[44] This increase in market demand will also have a corresponding impact on contrast media. According to Contrast Media Market Outlook (2022-2032),[45] the global contrast media market should grow at a CAGR of $4.1\\\\%$ through the year 2032, with an increase in market value of US $5.67 billion from 2022 to US $8.45 billion in 2032. Despite the growth of MRI CA market and methodology, it represents only a small portion $(<18\\\\%)$ of the total diagnostic market (valued at US $32.3 billion in 2022 with a projected CAGR of $4.8\\\\%$ from 2023 to $2030^{[46]}$ ) and has not yet reached its potential in the field of molecular diagnostics, which is currently dominated by nuclear medicine. Although this clearly demonstrates a market-driven need for improved MRI CAs, future development must address several major limitations of current CAs, including the following: low biological specificity and sensitivity that impedes early detection, staging, and treatment monitoring; inability to quantify molecular biomarkers[7,47,48]; and importantly, potential issues with metal associated toxicity.[49] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[37,901,484,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One of the major limitations of approved clinical GBCAs is low relaxivity. Relaxivity is the degree to which a CA enhances the longi \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,398,958,630]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"tudinal and/or transverse water relaxation rate constants $(\\\\mathbb{R}_1$ and $\\\\mathbb{R}_2$ respectively), and thereby affects imaging. Relaxivity values $\\\\mathbf{r}_1$ (longitudinal) and $\\\\mathbf{r}_2$ (transverse) of clinical GBCAs are normally within the range of 3 to $5\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.4\\\\mathrm{T}$ (Fig. 2D), which is significantly smaller than the theoretical maximum value of $100\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ for $\\\\mathbf{r}_1^{48}$ with optimal parameters based on SBM theory (developed by Solomon, Bloembergen, and Morgan) $^{38}$ (Table 1). The small $\\\\mathbf{r}_2$ values of clinical GBCAs are not capable of generating significant contrast in vivo as seen in the simulated curve $^{50}$ (Fig. 3C). Heterogenous tissue backgrounds include cysts, lipids, fats, and other nonhomogeneous structures, all of which interfere with $\\\\mathbf{T}_1$ signal enhancement. Therefore, because of the associated small $\\\\mathbf{r}_1$ relaxivity with clinically approved current CAs, MRI cannot detect cancer and metastasis at early stage ( $<1-2\\\\mathrm{cm}$ ) with desired specificity and sensitivity. $^{51-53}$ Monitoring treatment effects and detecting subtle abnormal morphological changes associated with acute and chronic diseases, such as the tumor microenvironment and fibrosis, become even more challenging when there are no clearly defined nodule formations. $^{48,54-56}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,630,958,760]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The second limitation of most clinical CAs is the ability to achieve molecular imaging. Although several GBCAs can achieve limited molecular imaging (ie, Eovist and MultiHance), imaging at the molecular level is improved with higher $\\\\mathbf{r}_1$ values and, importantly, the ability to target a disease-specific biomarker.[35] Thus, the rationales behind combining a biomarker-targeting moiety with an MRI CA having a high $\\\\mathbf{r}_1$ relaxivity are to further enhance detection sensitivity and specificity to detect diseases at a very early stage, to improve tolerance through reduced dosage, to quantitatively stage diseases and monitor treatment response, and to investigate the biological foundation of the diseases.[35,54] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,760,958,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To provide robust contrast differences in tissue that corresponds to a relaxation rate change of approximately $0.5\\\\mathrm{s}^{-1}$ , approximately $100\\\\mu \\\\mathrm{M}$ of CA is needed for $\\\\mathbf{r}_1$ of $5\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.5\\\\mathrm{T}.^{35}$ The minimal local concentration of Gd(III) required for in vivo imaging is several orders of magnitude higher than the expression levels of relevant molecular biomarkers, such as receptors. For example, the receptor expression levels of HER2 (biomarker for breast cancer) and chemokine CXCR4 (for inflammation) are ${\\\\sim}10^{6}$ and $1.5\\\\times 10^{5}$ per cell, respectively, which is ${\\\\sim}0.03-0.17\\\\mathrm{nM}.$ [57,58] The overexpression of collagen at the extracellular matrix, as a biomarker for tumor microenvironment as well as liver and lung fibrosis, is usually in the concentration range of 1 to $20~\\\\mu \\\\mathrm{M}$ . It is speculated that relaxivity $\\\\mathbf{r}_1$ of at least $60\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ for a CA is required to detect $\\\\mu \\\\mathrm{M}$ biomarker expression levels.[59] Because high relaxivity of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,38,484,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[37,946,448,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,946,913,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[931,946,955,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"171 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[114,100,292,228]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0193/fdc278ce1044e6f253f529ab0f19764130845e7f298331047299f5f3ca5fa430.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[305,100,482,228]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0001/656b04fcc06c9f4aa7a2290dc2ea1365f425267ccc5b03bbe3dbf39a45f27f35.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[118,254,473,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"A \\\",\\\"B \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0920/bd902c7461a29fe726ac505cb5d6eccb78a22ebba854d4ce87c04cfdd9443437.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[506,113,637,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0054/2a385e13e6292851ed19c9282537b82a394c8382fb7ed6ea4139f8e27fc9f897.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[660,100,879,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0857/297197700a3e3a623aec81378e5c939e27aef5604bc95bad499646df76c9d4d3.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[518,266,838,428]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"C \\\",\\\"r1 Simulation and NMRD of ProCA32s \\\",\\\"E \\\",\\\"IGURE 2. A, Coordination of second-sphere H-bond receptors for ProCA32s' 2 EF-hands. B, Schematic illustration of EF-hand 2 with 1 inner-sphere water oleule and 5 second-sphere water molecules, surrounded by bulk water. Bidentate carboxyl (#1); monodentate carboxyl (#2); main chain carbonyl #3); inner-sphere water (#4); hydrogen bonds (black dashed line); metallic bonds (red dashed line). C, Water number of Gd-DTPA, Eovist, ProCA30 $(n =)$ , ProCA32 $(n = 3)$ . Data are expressed as mean $\\\\\\\\pm$ SD. D, Relaxivity of ProCA32s and clinically available GBCAs at $1.4\\\\\\\\mathrm{T}$ in water. E, Inner-sphere plus econd-sphere relaxivities simulation of ProCA32s by SBM theory as a function of ${}^{1}\\\\\\\\mathsf{H}$ Larmor frequencies from $0.01 - 1000\\\\\\\\mathrm{MHz}$ (for ProCA32s' inner sphere, $\\\\\\\\tau_{R} = 3$ ns, $\\\\\\\\tau_{m} = 180$ ns, $q = 0.5$ , $\\\\\\\\mathrm{r}_{Gd-H} = 3\\\\\\\\AA$ ; for ProCA32s' second sphere, $\\\\\\\\tau_{R} = 3$ ns, $\\\\\\\\tau_{m} = 20$ ns, $q = 5$ , $\\\\\\\\mathrm{r}_{Gd-H} = 4.45\\\\\\\\AA$ ) overlaid with r1 NMRD profile f ProCA32s measured at $25^{\\\\\\\\circ}\\\\\\\\mathrm{C}$ as a function of ${}^{1}\\\\\\\\mathsf{H}$ Larmor frequencies from 0.01 to $40\\\\\\\\mathrm{MHz}$ . \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0593/564c38cc43e8db26b741e55648f43748faeac26f34d2dba7f4fcc113468d2717.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[37,552,486,591]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"he GBCAs is a prerequisite for detection of low receptor concentration, it as previously assumed that it would not be possible to detect the receptor in vivo by approved Gd CAs without additional enrichment.[60] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,552,958,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To address this, extensive research has been directed toward molecular imaging,[54,61-65] including the following: the conjugation of targeting moieties to chelators capable of binding multiple Gd(III) ions, such as \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[35,628,958,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0001/0f6fc9e9b9fc9bbb07e529f233f87141595030ad6ad3d933a619b5f484225a98.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Inner-Sphere Relaxation</td><td>Second-Sphere Relaxation</td></tr><tr><td>1/Ti,obs=1/Ti,d+1/Ti,p(1)</td><td></td></tr><tr><td>1/Ti,obs=1/Ti,d+ri[Gd](2)</td><td></td></tr><tr><td>(1/Ti,p)=(1/Ti,p)IS+(1/Ti,p)OS(3A)</td><td>(1/Ti,p)=(1/Ti,p)IS+(1/Ti,p)SS+(1/Ti,p)OS(3B)</td></tr><tr><td>(1/T1)IS=cq/55.5 1/T1m+τm=PM 1/T1m+τm(4A)</td><td>(1/T1)SS=cq'/55.5 1/T1m+τm=PM' 1/T1m+τm(4B)</td></tr><tr><td>(1/T2)IS=PM/τm T2m+τm-1T2m+Δωm2(5A)</td><td>(1/T2)SS=PM' T2m-2+τm-1T2m-1+Δωm2(5B)</td></tr><tr><td>1/Tim=1/TiDD+1/TiSC(6A)</td><td>1/Tim=1/TiDD+1/TiSC(6B)</td></tr><tr><td>1/T1DD=2/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(7τc2/1+ωS2τc2+3τc1/1+ωI2τc1)(7A)</td><td>1/T1DD=2/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(7γf2g2μB/6rGdH+3γf2g2μB/6rGdH)(7B)</td></tr><tr><td>1/T2DD=1/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(13τc2/1+ωS2τc2+3τc1/1+ωI2τc1+4τc1)(8A)</td><td>1/T2DD=1/15 γf2g2μB/6rGdH S(S+1)(μ0/4π)2(13γf2g2μB/6rGdH+3γf2g2μB/6rGdH+4τc1)(8B)</td></tr><tr><td>1/τci=1/τR+1/τm+1/Tie(9A)</td><td>1/τci=1/τR+1/τm+1/Tie(9B)</td></tr><tr><td>1/Tie=2C(1/1+ωS2τv2+4/1+4ωS2τv2)(10)</td><td></td></tr><tr><td>1/T2e=C(5/1+ωS2τv2+2/1+4ωS2τv2+3)(11)</td><td></td></tr><tr><td>C=1/50 Δ2τv[4S(S+1)-3](12)</td><td></td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 1. SBM Relaxation \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[39,40,89,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,38,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[39,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"172 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,314,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[545,946,956,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[57,94,355,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0735/22c969238856038f05bd290709df139e21616ecc16aa07cffcbde29fae7f212d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[360,95,658,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0438/cf683170e53bb6836fdbd0602a4ad9986b70ffb03cc8569f74709991f00beb78.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[680,94,915,276]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"IGURE 3. Inner-sphere and second-sphere relaxivity simulations of ProCA32s and Gd-DOTA by SBM theory as a function of $^1\\\\\\\\mathsf{H}$ Larmor frequencies from .01-1000 MHz. A, $\\\\\\\\mathsf{r}_1$ relaxivity simulation. For ProCA32s' inner sphere, $\\\\\\\\tau_{R} = 3$ ns, $\\\\\\\\tau_{m} = 180$ ns, $q = 0.5$ , $\\\\\\\\mathsf{r}_{\\\\\\\\mathrm{Gd - H}} = 3\\\\\\\\AA$ . For ProCA32s' second sphere, $\\\\\\\\tau_{R} =$ ns, $\\\\\\\\tau_{m} = 20$ ns, $q = 5$ , $\\\\\\\\mathsf{r}_{\\\\\\\\mathrm{Gd - H}} = 4.45\\\\\\\\AA$ . For Gd-DTPA's inner sphere, $\\\\\\\\tau_{R} = 0.1$ ns, $\\\\\\\\tau_{m} = 240$ ns, $q = 1$ , $\\\\\\\\mathsf{r}_{\\\\\\\\mathrm{Gd - H}} = 3\\\\\\\\AA$ . B, $\\\\\\\\mathsf{r}_2$ relaxivity simulation. C, Simulation of liver RI signal change of ProCA32s and Gd-BT-DO3A at different Gd(III) concentration in T1-weighted (T1W) MRI and T2-weighted (T2W) MRI at 1.5 T. or ProCA32s, $\\\\\\\\mathsf{r}_1 = 34\\\\\\\\mathrm{mM}^{-1}s^{-1}$ , $\\\\\\\\mathsf{r}_2 = 50\\\\\\\\mathrm{mM}^{-1}s^{-1}$ . For Gd-BT-BO3A (Gadovist), $\\\\\\\\mathsf{r}_1 = 3.3\\\\\\\\mathrm{mM}^{-1}s^{-1}$ , $\\\\\\\\mathsf{r}_2 = 3.9\\\\\\\\mathrm{mM}^{-1}s^{-1}$ . Liver T1 is 547 milliseconds and T2 is 1 milliseconds at 1.5 T. For T1W image, TR = 400 milliseconds, TE = 11 milliseconds. For T2W image, TR = 5000 milliseconds, TE = 28 milliseconds. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0855/de13ae0013105001f911ffcba5b113098a2e5f4ff6ea5ccf5cf8fe9bc6156c6d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[39,386,482,439]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ntibodies, $^{63}$ short peptides, $^{66,67}$ protein fragments; and nanoparticles/ubes, $^{68-72}$ liposomes, $^{73,74}$ and viruses $^{75}$ (Fig. 1B). Despite these efforts, o date, no biomarker-targeted CAs have been approved for MR molecular imaging of cancers or metastases in patients. $^{54,64-66,76}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,439,484,610]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The third limitation of clinical CAs is related to metal associated toxicity due to high GBCAs dosage required for imaging (Table 2).35 adolinium-based contrast agent administration is normally considered o be very safe because a retrospective analysis of over 158,000 GBCAs dministrations from 2000 to 2009 reported limited incidents of immedi- te adverse events (severe reaction occurred approximately 1 in 40,000 njections).77 However, nephrogenic systemic fibrosis (NSF) was identified in severe renal failure patients receiving GBCAs in 2006.78-80 his risk of NSF reportedly increased with the severity of impaired enal function, as most GBCAs are excreted almost exclusively by renal filtration, resulting in longer half-lives of GBCAs in renally impaired patients.81-84 The majority of reported cases of $\\\\mathrm{NSF^{85 - 89}}$ have been linked to 3 linear GBCAs, classified as group I by the American College \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,386,960,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of Radiology Committee on Drugs and Contrast Media, comprising Gd-DTPA-BMA (Omniscan; GE Healthcare), Gd-DTPA (Magnevist; Bayer HealthCare Pharmaceuticals), and Gd-DTPA-BMEA (OptiMARK; Guerbet).<sup>90</sup> The American College of Radiology group II and group III GBCAs associated with few or no instances of unconfounded cases of NSF (mostly macrocyclic molecules, except Gd-BOPTA, Gd-EOB-DTPA) include the following: Gd-BOPTA (MultiHance; Bracco Diagnostics), Gd-BT-DO3A (Gadavist; Bayer HealthCare Pharmaceuticals; Gadovist in many countries), Gd-DOTA (Dotarem; Guerbet, Clariscan-GE Healthcare), Gd-HP-DO3A (ProHance; Bracco Diagnostics), and Gd-EOB-DTPA (Eovist; Bayer HealthCare Pharmaceuticals; Primovist in many countries).<sup>90</sup> Current evidence suggests that, although all GBCAs have the potential to release Gd(III) in vivo, linear GBCAs are more prone to Gd(III) dissociation from the complex than macrocyclic GBCAs.<sup>9,49</sup> It is also important to note that NSF is rare (approximately 1000 cases in 200 million GBCA administrations),<sup>91</sup> and the occurrence of new NSF cases has dropped precipitously since 2010.<sup>92,93</sup> This is because routine \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[37,673,958,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0198/60f97b72d3cbc971649c284ff29e36f6192e057a0e9eee56339d4983436f6be8.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Trade Name</td><td>Chemical Code</td><td>Standard Dose, mmol/kg</td><td>Log (K*Tb)</td><td>Log (K*Gd)</td><td>Log (K*Ca)</td><td>Log (K*Zn)</td><td>Log (K*Gd/KCa)</td><td>Log (K*Gd/Zn)</td></tr><tr><td>hProCA32</td><td></td><td>0.0014*</td><td>22.5†</td><td>22.5†</td><td>8.7†</td><td>6.4†</td><td>14.7†</td><td>16.2†</td></tr><tr><td>hProCA32.collagen</td><td></td><td>0.0014*</td><td>22.0†</td><td>22.2†</td><td>8.1†</td><td>6.8†</td><td>14.1†</td><td>15.4†</td></tr><tr><td>Dotarem</td><td>Gd-DOTA</td><td>0.1</td><td>N/A</td><td>18.3‡</td><td>6.1‡</td><td>14.1‡</td><td>12.2‡</td><td>4.2‡</td></tr><tr><td>ProHance</td><td>Gd-HP-DO3A</td><td>0.1</td><td>N/A</td><td>17.2‡</td><td>8.2‡</td><td>12.8‡</td><td>9.0‡</td><td>4.4‡</td></tr><tr><td>Magnevist</td><td>Gd-DTPA</td><td>0.1</td><td>N/A</td><td>17.7‡</td><td>N/A‡</td><td>13.8‡</td><td>N/A</td><td>3.9‡</td></tr><tr><td>Omniscan</td><td>Gd-DTPA-BMA</td><td>0.1</td><td>N/A</td><td>14.9‡</td><td>5.0‡</td><td>10.1‡</td><td>9.9‡</td><td>4.8‡</td></tr><tr><td>MultiHance</td><td>Gd-BOPTA</td><td>0.1</td><td>N/A</td><td>18.4‡</td><td>N/A</td><td>13.9‡</td><td>N/A</td><td>4.5‡</td></tr><tr><td>Gadoquatrane</td><td>Gd-GlyMe-DOTA (tetramer)</td><td>N/A</td><td>N/A</td><td>19.3‡</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr><tr><td>Gadopiclenol</td><td>Gd-PCTA</td><td>0.05</td><td>N/A</td><td>15.5‡</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 2. Comparison of Conditional Thermodynamic Stability and Metal Selectivity of Commercially Available GBCAs With hProCA32 and hProCA32.Collagen at pH 7.2/7.4 at ${25}^{ \\\\\\\\circ }\\\\\\\\mathrm{C}$ \\\"]\",\n \"table_footnote\": \"[\\\"$\\\\\\\\mathrm{K}^*$ indicates conditional thermodynamic stability. \\\",\\\"*Theoretical human dose by converting mouse dose. \\\",\\\"$\\\\\\\\dagger$ Stability constants measured by the fluorescence resonance transfer between tryptophan and metal in protein contrast agents. \\\",\\\"‡Stability constants of clinical contrast agents measured by pH potentiometric method. \\\",\\\"N/A, not available. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[39,38,486,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[37,945,450,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,945,913,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[929,946,956,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"173 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[41,90,482,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"screening for renal insufficiency and contraindicating the use of linear GBCAs Gd-DTPA, Gd-DTPA-BMA, and Gd-DTPA-BMEA have almost completely eliminated new cases of NSF.[94-97] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,129,482,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Another major concern regarding GBCAs, since 2014, is related to retention of Gd(III) in the central nervous system (CNS). $^{98-101}$ Similar to NSF risk, CNS Gd(III) accumulation has also been associated with over kinetic inertness of the GBCAs. $^{102-104}$ Although no evidence has yet indicated any harmful effects from the deposition of gadolinium, imaging methodologies and biopsy have confirmed deposition of Gd III) in CNS from both linear and macrocyclic CAs in patients with normal renal function. $^{98,105-107}$ Nevertheless, metal associated toxicity has raised major concerns and led to black box warnings for applications of RI CAs. Because of these cited concerns, very few new agents have been approved (Fig. 1A) for clinical imaging in the last 30 years, so there s now an important need to develop MRI CAs with new approaches to noble precision molecular imaging. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,296,482,592]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this review, we will introduce the requirements of an ideal CA or precision MRI. We will assess the challenges and limitations of classic SBM relaxation theory with defined first shell water, in current common approaches of CA development.[108-112] We will then report our development of our new class of protein-targeted MRI CAs (ProCAs) with additional significant contributions from the secondary shell water. His approach led to the development of our ProCA32 CA, which incorporates 2 Gd(III)-binding sites in a scaffold protein, resulting in a CA that exhibits $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ values that are 6- to 10-fold higher than clinically approved CAs at medical fields of 1.5 T or 3 T. We will then review important properties of the ProCA32 CAs, including exceptional metal-binding nd selectivity, serum stability, and resistance to transmetallation, which re critical to mitigating risks associated with metal toxicity. This platform CA ProCA32 was then further engineered with multiple targeting oieties directed toward specific biomarkers, including collagen, PSMA, XCR4, HER2, and others. Combining these new molecular-targeted As with an advanced new precision MRI method has enabled sensitive nd selective imaging of tissue abnormalities that has not previously been ossible with current clinical MRI CAs. The safety profile of ProCA32 gents and MRI relaxation properties indicate strong translational potential for preclinical and clinical applications of ProCA32 MRI CAs. The review will then conclude with future perspectives for development of new CAs, improved imaging, and perspectives on precision MRI. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,613,443,640]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CRITERIA OF IDEAL MRI CONTRAST AGENTS FOR PRECISION MRI \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,644,482,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"An ideal precision molecular imaging CA with significantly improved sensitivity and specificity should exhibit the following properties summarized later. First, high relaxivity per Gd(III) improves the sensitivity of the MRI scan to both focal and diffusive diseases by providing greater contrast enhancement between lesions or disease changes and healthy tissue to detect smaller lesions and fibrosis. It also improves safety by reducing the injection dose to achieve comparable contrast enhancement. Second is the high safety profile including high in vivo stability, thermodynamic stability, and kinetic inertness. Gd(III) released or displaced by transmetallation from the chelator poses potential risks for health, particularly with respect to NSF and CNS. High in vivo stability and kinetic inertness will ensure that Gd remains chelated before excretion from the body. In addition, an agent should produce no short-term or long-term adverse effects. The agent cannot trigger any downstream biological pathways and should have minimal or no immunogenicity response. Third is the biomarker-targeting capability; MRI CAs with targeting capability for biomarkers for molecular imaging will enable early detection and subtyping of disease states.[35,54] First, high relaxivity is required to ensure sufficient contrast at the local environment to detect low expression molecular biomarkers such as receptors located at the desired lesions or with diffusive diseases such as fibrosis. Based on Sherry et al, a relaxivity of $100\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ for the detection limit of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,90,956,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\sim 0.69~\\\\mu \\\\mathrm{M}$ is required at $9.4~\\\\mathrm{T}.$ [13] Second, strong target-binding affinity and specificity is required to reduce off-target effect. Third, the image enhancement must be sufficient to quantify molecular biomarker changes during disease progression and regression. This capability will enable accurate staging with molecular subtyping and report treatment effectiveness. It would be extremely beneficial to have enhancement for both $\\\\mathrm{T}_{1}$ and $\\\\mathrm{T}_{2}$ (dual contrast with ratiometric changes), which can reduce heterogeneous background noise, including noise from lipids and cysts. Fourth is the high tissue penetration for quantification and dynamic contrast. To achieve tempospatial mapping of heterogenous expression of molecular biomarkers during disease progression and regression, it is important that the CA is small enough to reach all or most overexpressed biomarkers, while avoiding problems such as enhanced permeability and retention (EPR) of tumor effects, as occurs with nanoparticles and antibodies. This capability will take advantage of MRI's capacity for temporal and spatial resolution during imaging, and thereby increase the potential to detect, stratify, and stage diseases; monitor treatment response; and study the biology of diseases at the molecular level in vivo, as well as correlate imaging results with histological analysis. Although dynamic contrast enhancement with dynamic changes of CAs has been approved for clinical applications,[28,29,114] it has low sensitivity due to arterial input function kinetic properties that interfere with quantification and low relaxivity. It is also important for the agent to reach the molecular biomarkers quickly to facilitate temporal imaging of dynamic molecular contrast enhancement that can provide important data related to disease vessel structure and subtle structural changes.[52,115,116] Fifth, rapid, quick, and complete clearance of the CA can reduce any potential toxicity. The agent should accumulate quickly in the organ/tissue of interest to reduce the waiting period for MRI scanning, followed by fast washout of unbound agent to improve targeted imaging. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,496,947,523]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CLASSICAL MRI CONTRAST AGENTS WITH DEFINED FIRST SHELL WATER RELAXATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,527,956,681]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The general theory of solvent nuclear relaxation in the presence of paramagnetic substances is summarized[108-112,117,118] (Table 1). In the presence of the MRI CA, the observed solvent relaxation rate, $1 / T_{i,obs}$ , is defined by Equations 1 and 2, where $1 / T_{i,d}$ is the diamagnetic relaxation rate, that is, the relaxation rate of the solvent (water) nuclei in the absence of $\\\\mathrm{Gd(III)}$ complex, and $1 / T_{i,p}$ is the paramagnetic relaxation rate, that is, the relaxation rate enhancement caused by $\\\\mathrm{Gd(III)}$ complex, which is linearly proportional to the concentration of the $\\\\mathrm{Gd(III)}$ complex; $r_i$ is the relaxivity of the complexed $\\\\mathrm{Gd(III)}$ ; and [Gd] is the $\\\\mathrm{Gd(III)}$ concentration of complexed $\\\\mathrm{Gd(III)}$ . It is worth noting that Equations 1 and 2 only apply to dilute paramagnetic solutions where the paramagnetic ions or molecules are randomly distributed and do not strongly interact with each other. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,683,956,811]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The paramagnetic relaxation of the water protons originates from the dipole-dipole (DD) interactions between the nuclear spins and the fluctuating local magnetic field caused by the unpaired electron spins. This interaction can be achieved either by water molecules binding directly with $\\\\mathrm{Gd(III)}$ (inner-sphere relaxation) or water molecules diffusing in the surroundings of the $\\\\mathrm{Gd(III)}$ (outer-sphere relaxation). These water molecules carrying the paramagnetic effect with shorter relaxation time will exchange with bulk water to propagate the paramagnetic influence. This interaction is described in Equation 3 where \\\"IS\\\" and \\\"OS\\\" refer to inner and outer spheres, $^{119,120}$ respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,811,956,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The longitudinal and transverse inner-sphere relaxation rates are given by Equations 4A and 5A, where $c$ is the molar concentration of the Gd(III) complex (relaxivity is calculated when $c = 1\\\\mathrm{mM}$ ); $q$ is the number of bound water molecules per Gd in the inner sphere; $P_{m}$ is the mole fraction of bound water molecules in the inner sphere; $\\\\tau_{m}$ is the water residency time in the inner sphere of the complex (equal to the reciprocal water exchange rate $1 / k_{ex}$ ); and $1 / T_{1m}$ and $1 / T_{2m}$ are, respectively, the longitudinal and transverse proton relaxation rates in the bound water in the inner sphere. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,41,87,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,40,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[41,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"174 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,314,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[547,946,955,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[35,90,484,232]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The relaxation of the bound water protons $(T_{im})$ is determined by DD and scalar (SC) (or contact) mechanisms as seen in Equation 6A by Solomon, Bloembergen, and Morgan (SBM Equation). Because the contribution from DD is much greater than SC for GBCAs, only the DD mechanism will be discussed to define $T_{im}$ as seen in Equations 7A, and 8A. The local magnetic fluctuations are defined by Equations 9A and 9B, where $\\\\tau_{R}$ is the rotational correlation time of the Gd III), and $T_{ie}$ is the electron spin relaxation time of the Gd(III). The longitudinal and transverse electron spin relaxation times $T_{1e}$ and $T_{2e}$ are defined by Equations 10 and 11, respectively. The relaxation theory as been extensively explained by others.38,121-123 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[46,232,482,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Optimal relaxivity can be achieved by modifying any of the major ater factors $q$ , $\\\\tau_{R}$ , and $\\\\tau_{m}$ . From Equation 4A, we can reason that increasing the $q$ can improve inner-sphere relaxivity. All clinical GBCAs are 1 bound water molecule per Gd in the inner sphere, except adopiclenol, which has 2. In the case of most small chelators (class I, ig. 1A) and large molecules (class II, Fig. 2B), the outer sphere contribution is not defined and negligible because water in the outer spheres is not constrained as reviewed by Aime et al. The commercial CAs and their functionalized derivatives based on the DTPA and DOTA basic tructures have a molecular weight of $\\\\sim 600 - 800\\\\mathrm{Da}$ . That corresponds to ontational correlation times of approximately 60 to 80 ps. Their water residence lifetime is typically in the range of 50 to 500 ns and $\\\\mathrm{T}_{1\\\\mathrm{e}}\\\\sim 1$ ns at .5 T. The inner-sphere relaxivity is largely dominated by the overall correlation time $\\\\tau_{R}$ that is roughly proportional to the \\\"effective\\\" molecular radius (Debye-Stokes equation), which exhibits a reasonable linear correlation to the molecular weight. The outer sphere contribution is nearly identical for the various complexes. The second shell contribution, which rgely depends on structural features, is likely negligible for clinical GBCAs, due to lack of defined water molecules in close proximity to Gd(III). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,477,484,695]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Higher relaxivity can be achieved when $q$ is increased to 2-3 by lowering the denticity of the multidentate ligand (Fig. 1A). [125-129] However, increasing $q$ to 2 usually decreases the thermodynamic stability nd/or kinetic inertness of the Gd(III) complex and increases the risk f Gd(III) transmetallation. Increasing $q$ also invites the possibility of nion binding and displacement of coordinated water ligands, [130] which, n turn, decreases the relaxivity in vivo. Efforts to develop GBCAs with slow transmetallation rates, by modifying macrocyclic chelators such as PCTA that has $q = 2$ , have also resulted in low conditional $K_{d}$ values, as reported for gadopiclenol $(K_{d} = 15.5)^{125 - 129}$ (Fig. 1A, Table 2). Caravan et al [131] reported the use of an EF-hand calcium-binding peptide and derivatives to form complexes with Gd (III) with high relaxivity $(\\\\mathrm{r}_1 = 21.2\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.5~\\\\mathrm{T}$ ). However, their agent exhibited low Gd-binding affinity $(K_{d} = \\\\sim 100\\\\mu \\\\mathrm{M})$ . Although both inner sphere and outer sphere can contribute to the overall proton relaxivity, inner-sphere relaxation is only well defined by Equations 4A-9A, whereas outer sphere water is largely underestimated due to lack of structural information. [132,133] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,695,484,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tuning rotational correlation time $\\\\tau_{R}$ and the water residency time $\\\\tau_{m}$ may also improve relaxivity.134 It is noteworthy that the optimal $\\\\tau_{R}$ and $\\\\tau_{m}$ needed to attain the theoretical relaxivity maximum depend on the magnetic fields, and higher magnetic fields have lower maximum theoretical relaxivity values. Unfortunately, clinical CAs have values $\\\\tau_{R} = \\\\sim 100$ ps, which limit the agents to low relaxivity. A linear dependence was observed by correlating the molecular weights of Gd-DOTA, Gd-DTPA, and their derivatives, with their relaxivities,43 which was also indicative of rotational correlation.135,136 Efforts to improve relaxivity and increase Gd number have also explored development of Gd liposomes, dendrimers,137 and biopolymers74 (Fig. 1B), or structural modifications involving PEGylation and glycosylation.138,139 However, these attempts have not resulted in the expected high relaxivity based on the increase in molecular weight because Gd(III) is subject to internal local motion.135 Internal motion was successfully eliminated in the blood pool agent P792 by placing a metal ion at the molecular barycenter,140 which increased the relaxivity to $29\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.4\\\\mathrm{T}$ . The conjugation of 4 GdGlyMe-DOTA molecules (gadoquatrane) to form a rigid complex by \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,89,956,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Lohrke et al $^{34}$ resulted in relaxivity to $11.8~\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ per Gd in human plasma at $1.4\\\\mathrm{T}$ , although it was still constrained by the fast correlation time. In another example, MS-325, a blood pool agent used for MR angiography, was found to exhibit reduced internal flexibility resulting in increased relaxivity due to nonspecific binding with serum protein albumin (BSA, HSA). $^{141}$ However, this agent was characterized by having an undefined loading number of the small chelator to HSA ( $>65\\\\mathrm{kDa}$ ) and a long excretion time and was later removed from the clinical market for in vivo applications. $^{142}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,206,956,360]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The addition of targeting moieties such as small molecules, peptides, or antibodies, through conjugation or engineering, clearly increases specificity of small chelator-based CAs such as DTPA or ProHance to tumors and biomarkers of other chronic diseases.[63,66] However, it remains to be demonstrated whether metal-binding affinity and specificity remain unaltered by the modification when compared with the unmodified parent compound. Studies have indicated that the incorporation of targeting moieties into small chelator PET tracers frequently leads to a reduction in metal-binding affinity.[143] In summary, attempts to enhance relaxivity by primarily concentrating on the utilization of inner-sphere water coordination, while avoiding compromises in metal-binding affinity, specificity, and potential safety concerns, have proven to be a complex challenge. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,381,951,408]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"FIXING WATER FOR SECOND SHELL CONTRIBUTION FOR HIGH RELAXIVITY\",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,411,958,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Metalloproteins typically exhibit a well-defined second shell of water molecules, fixed by hydrogen bonding acceptor or donor residues, particularly in the vicinity of the metal-binding sites.[144-147] We hypothesized that relaxivity, metal binding, and targeting capability could be simultaneously optimized if we took advantage of the presence of second shell water by the protein environment around the Gd(III) coordination center[148] (Table 1). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,501,956,655]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This interaction is described in Equation 3B where \\\"IS,\\\" \\\"SS\\\" and \\\"OS\\\" refer to inner, second, and outer spheres. Inner-sphere water molecules can interact directly with $\\\\mathrm{Gd(III)}$ in the range of 3.0 to $3.2\\\\AA$ ,[35,121,149] whereas multiple second-sphere water molecules can interact with hydrogen donors or acceptors of liganding atoms in residues surrounding the Gd site, in the range of 3.5 to $4.5\\\\AA$ in proteins.[43,150] These contributions from the second spheres to overall proton relaxivity can also be quantitatively estimated (Fig. 2A, B). Second-sphere relaxation is defined by Equations 4B-9B (a prime symbol is used to denote second-sphere relaxivity in the equations). Inner- and second-sphere relaxation values are derived from the same formulas, but some parameters have varied values between inner and second spheres. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,657,956,772]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Longitudinal and transverse second-sphere relaxation rates are given by Equations 4B and 5B, where $q'$ is the number of bound water molecules in the second sphere per Gd; $\\\\tau_{m}$ and $\\\\tau_{m}'$ are the water residency times in the inner sphere and second sphere of the complex (equal to the reciprocal water exchange rate, $1 / k_{ex}$ or $1 / k_{ex}'$ ); and $1 / T_{1m}'$ and $1 / T_{2m}'$ are the longitudinal and transverse proton relaxation rates in the bound water in the second sphere. The relaxation of the bound water protons of second sphere $(T_{im}')$ is determined by DD as seen in Equation 6B, which is identical to the inner-sphere mechanism. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,772,956,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Simulations indicate that second shell water contribution for relaxivity can be calculated if we have defined number of water positioning around the paramagnetic metal ions. In addition, both relaxivity values can be further significantly increased by tuning correlation time to ns regime instead of ps for small molecules. This can be done by fixing the metal-water proton vector to rotate isotropically with the entire molecule at a desired correlation time such as ns, so that Gd(III) will have the same $\\\\tau_{R}$ as the whole rigid structure. This is well demonstrated in the excellent agreement of our experimental nuclear magnetic relaxation dispersion (NMRD) data (Fig. 2E) with simulated relaxivity.[50] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,902,956,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To demonstrate the effect of second-sphere water molecules on relaxivity of our pioneered ProCA32 CAs, relaxivity simulations were \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,38,482,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[39,946,448,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,946,910,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[931,946,956,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"175 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[41,89,482,179]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"conducted as a function of ${}^{1}\\\\mathrm{H}$ Larmor frequencies from 0.01 to $1000\\\\mathrm{MHz}$ for ProCA32 inner and second spheres for $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ . Results suggested that second-sphere contributions to relaxivity can be higher than contributions from the inner sphere for both $\\\\mathbf{r}_1$ (Fig. 3A) and $\\\\mathbf{r}_2$ (Fig. 3B), and that the combined contributions from the inner and second sphere produce a significant increase in relaxivity, with a peak maximum that is consistent with experimental NMRD data (Fig. 2E). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[52,195,479,280]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ATIONAL DESIGN AND OPTIMIZATION OF PROTEIN MRI CONTRAST AGENTS TO SIMULTANEOUSLY IMPROVE MULTIPLE KEY FACTORS CONTRIBUTING TO RELAXIVITY, METAL BINDING STABILITY, AND MOLECULAR TARGETING OF CONTRAST AGENTS FOR PRECISION MRI \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[46,283,482,527]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Building on extensive efforts directed toward the rational design of calcium-binding proteins $^{146,151-158}$ with controlled metal-binding affinity, metal selectivity, and relaxation properties, $^{147}$ we have created a new class of ProCAs $^{50,62,148,159-162}$ based on the following rationales. First, slow the rotational correlation time to 1-10 ns range either by the e novo design of a Gd(III)-binding pocket or shaping an existing Ca(II)-inding pocket in a protein. $^{47,146}$ Either approach results in the Gd-water proton vector synchronizing with the entire protein structure. Second, increase the water molecule number of the second/outer sphere of Gd(III) enter by surface modification such as PEGylation to define water at the econd shell of the protein frame. $^{132,148}$ Third is the shorter water residency me due to the oxygen ligand atom and steric crowding nature of the rotein-binding pocket coupled with favorable arrangement of water molecules in a second coordination sphere. Our hypothesis, which is dramatically different from previously reported studies, $^{125,131,138,163-167}$ involved simultaneously increasing both $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ relaxivities without trading off etal-binding stability, and doing so by tuning structural arrangement, otational correlation time, and water exchange rate, at the inner shell end second/outer sphere. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,529,482,811]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ProCA1 was first designed by de novo design, creating a Gd(III)-inding site on domain 1 of cell adhesion protein (CA1.CD2) followed by surface PEGylation (Fig. 1C). The created metal-binding site has 6 potential oxygen ligands from the carboxyl side chains of E15, D56, D58, D62, and D64. By \\\"embedding\\\" a Gd(III)-binding site into CA1. CD2, the bound Gd(III) is free from internal tumbling, with rotational correlation time at approximately 10 ns (~12 kDa), corresponding to optimal relaxivity for the current clinically allowed magnetic field strength. To further improve the relaxivity by increasing q number, 1 position of the metal-binding geometry was left open in the design, and terbium lifetime luminescence indicated that the bound Gd(III) in ProCA1 was coordinated with 2 water molecules. In addition, we further demonstrated that PEGylation increased water number in the second coordination shell. Correlation time, q of 2 in first shell, and second shell coordination water all contributed to the dramatically increased relaxivity value of ProCA1 $(\\\\mathrm{r}_1 = 117~\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1},$ $\\\\mathrm{r}_2 = 129~\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.5\\\\mathrm{T})$ . ProCA1 had the highest $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ values that were 10- to 20-fold greater than those of the currently used clinical CAs. Using $\\\\mathrm{O^{17}}$ NMR and various biophysical methods, we have also shown that water is at the fast exchange region and $\\\\tau_{m}$ is not rate limited. This high relaxivity enabled molecular imaging for early detection of HER2 and GRPR in ovarian cancer, breast cancer, and prostate cancer, in several animal models (Fig. 5). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,811,484,875]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Besides high relaxivity, ProCA1 also had a significantly greater Gd(III) selectivity over Zn(II) compared with DTPA-BMA (log $[K_{Gdt} / K_{GdZn}]$ of 5.3 vs 4.8, respectively) and endogenous calcium and magnesium. However, further improvement was needed for thermodynamic stability of Gd-ProCA1, as its log $K_{cond}$ was 12.06. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,875,482,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To further improve metal selectivity and Gd-binding affinity and increase relaxivity using second water shell contribution, we created ProCA32 with 2 Gd(III)-binding sites (Fig. 1C). Unlike small chelators, ProCA32 was rationally designed from reshaping $2\\\\mathrm{Ca(II)}$ -binding sites \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,90,956,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in parvalbumin, followed by surface PEGylation. A rat/human $\\\\alpha$ -parvalbumin ( $\\\\sim 12$ kDa) has 2 coupled calcium-binding EF-hand motifs (helix-loop-helix domains). To achieve much stronger Gd(III)-binding affinity and selectivity and high relaxivity[50,169] (Fig. 1C), Gd(III) in EF-hand motif 1 was coordinated by 5 existing negatively charged carboxylate oxygen ligands (D52, D54, E60, and bidentate E63) and a sixth charged oxygen ligand from substitution S56D, as well as a carbonyl oxygen ligand from F58 (Fig. 1C).[116] The EF-hand 2 Gd(III)-binding site was composed of 5 negatively charged oxygen ligands from carboxy groups of D91, D93, D95, and bidentate E102, as well as carbonyl of K97. A single water molecule bridges the gap between the Gd(III) ion and the oxygen atom from G99 and is shared between the 2 coupled Gd EF-hand-binding sites in each first shell (0.5 each), as determined by Tb(III) luminescence lifetime decay.[50,170] Importantly, there are approximately 10 water molecules that are well defined by protein ligand H-bond receptor groups, with an average of 5 molecules per Gd(III) in the second sphere with an average distance of $4.45\\\\AA$ (Figs. 2A, B). A significant number of H-bond acceptors on the chelating ligands, including carbonyl groups from the peptide bonds and carboxyl groups from side chains, play a crucial role in stabilizing 2 coupled EF-hand metal-binding sites. These H-bond acceptors directly capture several water molecules entering the second or outer spheres around the Gd(III) center to contribute high relaxivity. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,372,956,501]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We have shown that ProCA32 agents exhibit both high $\\\\mathrm{r_1}$ ( $30\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.4\\\\mathrm{T}$ ) and $\\\\mathbf{r}_2$ ( $42\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.4\\\\mathrm{T}$ ) values that were 6- to 10-fold higher than clinically approved CAs at medical field strengths $1.5\\\\mathrm{T}^{50,52,59,116}$ (Fig. 2D). In addition, their $\\\\mathbf{r}_1$ relaxivity values are $\\\\sim 18\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at high field, which is important for small animal imaging, due to the corresponding smaller organ size (mice are $\\\\sim 1000$ -fold smaller than humans), because higher-resolution imaging can be achieved under higher magnetic field. We demonstrate that second-sphere contributions to relaxivity are even higher than that from the inner sphere for both $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ across all field strength. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,503,956,642]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The high relaxivity of ProCA32 has been the result of designed second shell contributions from large fixed hydration numbers resulting from trapping water in the rigid protein environment, slower rotational correlation time $\\\\tau_{R}$ , and faster water residency time $\\\\tau_{m}$ . The 2 coupled metal-binding pockets in the scaffold protein have the same $\\\\tau_{R}$ as the whole rigid structure, with a slow tumbling rate of the Gd(III) protein complex in the $\\\\sim 3 - 10$ ns range.[147,171,172] Slow rotation of ProCA32 plus fixed water orientation also significantly contributes to high second-sphere relaxation, coupled with a much greater $q$ number in the second sphere, resulting in much more pronounced second and outer sphere relaxivity effects of ProCA32. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,644,956,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To demonstrate the effect of first- and second-sphere water molecules on relaxivity of ProCA32, we performed simulations of $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ as functions of ${}^{1}\\\\mathrm{H}$ Larmor frequencies from 0.01 to $1000\\\\mathrm{MHz}$ . For inner-sphere relaxivity simulations (Figs. 3A, B), values used were $q = 0.5$ (Fig. 2C), ${}^{50}\\\\tau_{m} = 180$ ns, ${}^{50}r_{GdH} = 3\\\\AA$ , ${}^{149}$ and $\\\\tau_{R} = 3$ ns. For second-sphere relaxivity simulations (Figs. 3A, B), values used were $q = 5$ , $\\\\tau_{m} = 20$ ns, ${}^{134,173,174}r_{GdH} = 4.45\\\\AA$ , ${}^{43,134,150,175,176}$ and $\\\\tau_{R} = 3$ ns. Simulation results suggested that second-sphere contributions to relaxivity were higher than contributions from the inner sphere for both $\\\\mathbf{r}_1$ (Fig. 3A) and $\\\\mathbf{r}_2$ (Fig. 3B), and that the combined contributions from the inner and second sphere produce a significant increase in relaxivity, with a peak maximum that was consistent with experimental NMRD data of ProCA32 (Xue et al $^{50}$ ) (Fig. 2E). At $1.5\\\\mathrm{T}$ , second-sphere relaxivity from the simulation contributed almost $60\\\\%$ of the overall relaxivity for both $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ , which was significantly greater than all reported agents (including clinical) that are characterized by modest contributions from the second and outer spheres. $^{36}$ Thus, the well-defined large second shell water contribution of ProCA32 (Figs. 2A, B) is drastically different from all other CAs reported to date. Moreover, methoxy PEG succinimidyl carboxymethyl ester (M-SCM-2000), which reacts with the amine group of lysine(s), can be used to modify the protein surface, which provides additional carbonyl groups that in the second and outer sphere of the Gd(III) center further increase \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,41,87,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,40,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[41,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"176 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,314,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[547,946,955,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[35,90,484,128]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the second/outer sphere $q$ number. This surface modification also increases the molecular weight of ProCA32 by 2 kDa, resulting in further slowdown of the rotational correlation time, $\\\\tau_{R}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,129,484,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The shorter water residency time $\\\\tau_{m}$ of ProCA32 is achieved by utilization of oxygen ligand atoms rather than nitrogen,[125,177-180] configured in a sterically crowded volume, and coupled with favorable arrangement of water molecules in a second coordination sphere. The F-hand carboxyl atoms in metal-binding pocket are innately more sterically crowded than what is observed with clinical GBCAs[181] (Fig. 1C), hereas the water exchange rate can be accelerated by increasing the steric compression around the water-binding site.[35,41,182] In contrast, for d-DTPA derivatives, the water exchange rate enhancement is usually attained by loss of thermodynamic stability.[183-185] This significantly higher $\\\\mathbf{r}_1$ ( $30\\\\mathrm{mM}^{-1}\\\\mathrm{s}^{-1}$ at $1.4\\\\mathrm{T}$ ) of ProCA32 provides much greater sensitivity during MRI scanning. Only $\\\\sim 9~\\\\mu \\\\mathrm{M}$ local concentration of ProCA32 is required to provide robust contrast differences in tissue corresponding to a relaxation rate change of approximately $0.5\\\\mathrm{s}^{-1}$ . This s 10 times lower than the concentration requirement for clinical GBCAs.[35] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[43,322,486,439]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"oreover, clinical GBCAs, due to their low $\\\\mathbf{r}_2$ values, cannot produce significant change in vivo using $\\\\mathrm{T}_{2}$ -weighted imaging and $\\\\mathrm{T}_{2}$ map imaging. Onversely, ProCA32 possesses both high $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ values at both low and high magnetic field. This means that ProCA32 can function as a dual $\\\\mathrm{T}_{1}$ and $\\\\mathrm{T}_{2}$ CA that can overcome heterogeneous tissue background and provide even higher contrast enhancement by $\\\\mathrm{T}_{2}$ -weighted MRI, as well as the capability to capture molecular biomarker changes (see Bioarter Targeting for Precision Molecular Imaging and Preclinical Applications) (52,59,115,116,162). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,457,482,514]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"TRATEGIES USED FOR ACHIEVING UNPRECEDENTED METAL BINDING SELECTIVITY AND STABILITY OF PROCA32 THAT ARE CRITICAL IN PREVENTING RISKS ASSOCIATED WITH METAL TOXICITY \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[37,518,486,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"High thermodynamic stability is of great importance for GBCAs, it ensures the equilibrium lies heavily on the side of the intact complex dL and $\\\\mathrm{Gd}_2\\\\mathrm{L}$ , leaving little free $\\\\mathrm{Gd(III)}$ after equilibrium. The thermodynamic stability constant $\\\\mathrm{K}_{\\\\mathrm{therm}}$ provides the affinity of $\\\\mathrm{Gd(III)}$ for a given ligand. This stability is defined by Equation 13 if the ligand chelates a single $\\\\mathrm{Gd(III)}$ ion (eg, all the clinical GBCAs) and Equation 14 if the ligand chelates 2 $\\\\mathrm{Gd(III)}$ ions (eg, ProCA32 agents). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[168,611,482,639]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\nG d + L \\\\Leftarrow G d L K _ {\\\\text {t h e r m}} = \\\\frac {[ G d L ]}{[ G d ] [ L ]} \\\\tag {13}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[159,655,482,686]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$$\\n2 G d + L \\\\rightleftharpoons G d _ {2} L K _ {\\\\text {t h e r m}} = \\\\frac {[ G d _ {2} L ]}{[ G d ] ^ {2} [ L ]} \\\\tag {14}\\n$$\",\n \"text_format\": \"latex\",\n \"text_level\": null,\n \"type\": \"equation\"\n },\n {\n \"bbox\": \"[35,694,486,811]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Thermodynamic stability is measured under very basic conditions (pH $\\\\sim 11$ ), because at this pH, there are no competing protons for the chelate and a theoretical maximum stability is obtained. For in vivo applications, it is more important to attain thermodynamic stability at physiological pH 7.4 (ie, conditional stability).<sup>37</sup> As there is significant proton competition at pH 7.4, depending on the basicity of the ligand, $K_{\\\\mathrm{cond}}$ is always substantially lower than $K_{\\\\mathrm{therm}}$ (Table 2). Thermodynamic and conditional thermodynamic stability constants have been previously determined by pH potentiometric methods for clinical GBCAs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[35,811,486,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$\\\\mathrm{K}_{\\\\mathrm{therm}}$ and $\\\\mathrm{K}_{\\\\mathrm{cond}}$ cannot predicate in vivo stability of Gd(III) complex alone. For example, Gd-DTPA has both higher $\\\\mathrm{K}_{\\\\mathrm{therm}}$ and $\\\\mathrm{K}_{\\\\mathrm{cond}}$ ( $\\\\mathrm{K}_{\\\\mathrm{cond}}$ is 3 orders of magnitude higher) than Gd-BT-DO3A, yet Gd-DTPA is believed to have caused NSF in renal impaired patients, whereas Gd-BT-DO3A was not.[85,94] Attempts have been made to explain acute toxicity results ( $\\\\mathrm{LD}_{50}$ ) and in vivo stability of GBCAs by calculating overall selectivity of Gd(III), taking into account cations of H, Ca, Cu, and Zn.[186,187] A more straightforward way to look at metal selectivity is to directly compare the Gd(III)-binding affinity with other endogenous \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,90,958,489]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"metal ions by the ratio of the conditional thermodynamic stabilities between the 2 ions (Table 2).[9,38,116,187,188] The dissociation rates of the Gd(III) complex at pH 1.0, which are referred as kinetic stability, reveal the kinetic inertness of the Gd(III) complex during competition with hydrogen ions, and this measurement agrees with in vivo stabilities reported for clinical GBCAs.[9,189-191] In addition, transmetallation also reflects kinetic inertness. In vitro transmetallation assessment is determined by monitoring relaxivity changes in the presence of Zn(II) following challenge with phosphate because the thermodynamic stability constant of clinical GBCAs for Zn(II) is only approximately 4 orders of magnitude lower than for $\\\\mathrm{Gd(III)}^{23}$ (Table 2).[186,192,193] R1 relaxivity will drop if Gd(III) is replaced by Zn(II). The order of kinetic inertness of macrocyclic GBCAs such as Gd-DOTA and Gd-HP-DO3A[52,59,116] is higher than linear GBCAs such as Gd-EOB-DTPA and Gd-DTPA-BMA. In addition, ionic linear CAs Gd-EOB-DTPA, Gd-DTPA, and Gd-Gd-BOPTA performed better than nonionic linear CA Gd-DTPA-BMA. Frenzel et al[194] reported an ex vivo method to evaluate kinetic inertness of GBCAs in human serum under realistic physiological conditions. Human serum from healthy volunteers was incubated with $1\\\\mathrm{mM}$ CA at $37^{\\\\circ}\\\\mathrm{C}$ , mimicking in vivo stability in healthy patients, and then the same samples were prepared with the addition of $10\\\\mathrm{mM}$ phosphate, thereby mimicking end-stage renal disease patients. Free Gd(III) is separated and determined by an HPLC system with a chelating Sepharose column connected to an inductively coupled plasma mass spectrometry. Following the same trends of kinetic inertness, macrocyclic GBCAs are stable in human serum for 15 days, but linear GBCAs will release $2\\\\% -30\\\\%$ of total Gd(III), and nonionic linear GBCAs will release approximately 10 times more Gd than ionic GBCAs. In summary, multiple ex vivo methods confirmed the in vivo stability data of GBCAs, wherein macrocyclic GBCAs with a preorganized cavity optimized for chelating Gd(III) have much greater kinetic stability than the more flexible linear GBCAs,[9,35,38,195,196] which makes them safer for clinical use. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,489,958,694]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In addition to significantly improved relaxivity, the next generation of MRI CAs should be equivalent to, or better than, macrocyclic GBCAs with respect to thermodynamic stability, kinetic inertness, and, importantly, metal selectivity against endogenous metal ions such as $\\\\mathrm{Mg(II)}$ , $\\\\mathrm{Ca(II)}$ , and $\\\\mathrm{Zn(II)}$ . Because of the presence of multiple protonation sites in proteins, the pH potentiometric method commonly used for small chelators to determinate Gd stability and metal selectivity is not applicable to proteins. Yang et al[148] developed 2 different approaches to determine the conditional thermodynamic stability/binding affinity and metal specificity of ProCAs by a competition titration with Fluo-5N (a metal ion indicator) for ProCA1 and a luminescence resonance energy transfer for ProCA32 with F103W mutation in a metal-Gd(III) buffer system.[50] A luminescence resonance energy transfer competition method was applied to measure the Gd (III)-, $\\\\mathrm{Ca(II)}$ -, $\\\\mathrm{Mg(II)}$ -, and $\\\\mathrm{Zn(II)}$ -binding affinity for ProCA32 and metal selectivity, and the resulting conditional thermodynamic stability data are summarized in Table 2.[50,52,59,116] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,695,958,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Strikingly, ProCA32 exhibited a Gd(III) thermodynamic stability comparable to that of DTPA of 21, whereas wild-type parvalbumin was reported to have a Gd(III) thermodynamic stability of 11.[197] Grum et al[198] also reported design of MRI CA from $\\\\alpha$ -parvalbumin ( $\\\\mathrm{r}_1 = 51 \\\\mathrm{mM}^{-1} \\\\mathrm{s}^{-1}$ at $1.5 \\\\mathrm{T}$ ) but exhibited low Gd(III)-binding affinity. ProCA32 achieved the greatest metal selectivity for Gd(III) over Ca(II), Mg(II), Zn(II), and other physiological metal ions, with selectivity values that were $>100-$ to $10^{11}$ -folds higher than DTPA. Conditional thermodynamic stability of Gd-ProCA32 has a log constant of 22, which outperformed both macrocyclic and linear GBCAs, such as Gd-DOTA and Gd-DTPA (Log Kcond $\\\\sim 17-18$ ) (Table 2). Most importantly, ProCA32 had much lower conditional thermodynamic stability for Zn(II) than the clinical GBCAs ( $\\\\sim 6-7$ orders of magnitude lower). These indicated that the selectivity of ProCA32 for Gd(III) over Zn(II) was more than 10- to $10^{14}$ -fold higher compared with both macrocyclic and linear clinical GBCAs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,888,958,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The highly selective nature of ProCA32 provides strong foundation for higher kinetic inertness and in vivo stability of ProCA32 compared with clinical GBCAs. Transmetallation studies (Fig. 4A) demonstrated that \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,38,482,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[37,946,448,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,945,913,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[929,946,956,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"177 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[80,97,348,249]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0959/388692a365d8c9695eceb1fce12f97826e8e713d82b73522b8c61bdbbc400a51.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[360,122,646,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0705/5be933d029e75477e06ec8e25d2912b0946c8976150bad465fc5f5aef2f077bc.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[653,91,919,247]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"IGURE 4. A, The relaxation rates change of clinical contrast agents (black diamond Eovist; black circle Magnevist; white square MultiHance; white triangle Omniscan; blue square ProHance; yellow circle Dotarem) and red lozenge ProCA32.collagen1 in the presence of $\\\\\\\\mathrm{ZnCl}_2$ at different time points p to 4 days. B, Serum stability test of hProCA32.collagen shows that hProCA32.collagen remained intact in serum for up to 14 days (M, protein marker; P, ProCA32.collagen only; S, serum only). C, Size of ProCA32.collagen. Yellow color denotes ProCA32's scaffold. Red color denotes collagen-targeting moiety. Green color denotes the flexible linker. Cyan color denotes coordination amino acids. Blue circles denote Gd(III). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0785/774a850f4ed8a9d27625026dc6451f50ba5ec7534a5b733563751b348b736dce.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[43,333,482,412]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"roCA32 exhibited strong kinetic inertness comparable to macrocyclic BCAs, such as Gd-DOTA and Gd-HP-DO3A, and significantly greater inetic inertness than linear GBCAs, and also that ionic linear CAs have higher kinetic inertness than the nonionic ones including Eovist and ultiHance[52,59,116] (Fig. 4A). In addition, ProCA32 exhibited strong serum stability and remains intact for $>12$ days (Fig. 4B).[50] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[41,412,484,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The exceptional kinetic stability and metal selectivity of Gd-ProCA32 ver clinical GBCAs can be attributed to several key determinants used in the design strategy for metal-binding proteins. $^{146,155,156}$ First, ProCA32 as 7 coordinating atoms, almost exclusively from oxygen atoms with stronger affinity. Oxygen ligand atoms have greater water off rates than nitrogen ligand atoms that are related to $\\\\tau_{m}$ . In contrast, although clinical GBCAs have 8 total coordinating atoms for Gd(III), they are a mixture of oxygen and nitrogen, with lower affinity and slower off rates. $^{181}$ Second, metal-binding affinity is largely determined by fullness of the 1st coordination shell. The 2 metal-binding sites of ProCA32 are strongly \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,333,958,542]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"coupled and share a single water ( $q$ number of 0.5 per $\\\\mathrm{Gd(III)}$ ). In contrast, all approved GBCAs have $q$ values of 1. Third, ProCA32 agents have 5 negatively charged carboxylate oxygens tuned by S56D in EF-hand 1 and 4 negatively charged carboxylate oxygens in EF-hand 2 (Fig. 1B) $^{116}$ that are well balanced for electrostatic interaction. The preorganized metal-binding pockets of ProCA32 not only have optimal conformation and coordination for $\\\\mathrm{Gd(III)}$ but also have flexibility to enable sidechain rotation in the absence of $\\\\mathrm{Gd(III)}$ to reduce electrostatic repulsion. $^{146,158}$ Thus ProCA32 exhibited the strongest affinity to $\\\\mathrm{Gd(III)}$ . The designed pair of coupled Gd-binding sites in ProCA32 have significantly greater metal selectivity primarily due to protein sidechain flexibility that enables adaptations for metal coordination, $^{148,199-202}$ and metal selectivity for $\\\\mathrm{Gd}$ (III) over divalent metal ions including $\\\\mathrm{Ca(II)}$ , $\\\\mathrm{Mg(II)}$ , and $\\\\mathrm{Zn(II)}$ . In contrast, although macrocyclic chelators have strong Gd affinity with preformed coordination, they do not have the flexibility required to adapt to metal ions with smaller radii, which is essential for metal selectivity. $^{148,199-202}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[208,558,788,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 5. Applications of ProCA32s to detect different diseases by targeting different biomarkers. All the protein-based MRI contrast agents are injected via tail vein at a dosage of $0.02 - 0.03\\\\\\\\mathrm{mmol / kg}$ \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0565/578f1c6870c9a00408748d0521e64824aecc0c861057c66ef1fa3694d8d92ff0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[39,40,89,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,38,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[39,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"178 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,315,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[545,946,956,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[48,95,423,309]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"B \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0155/be43e3d0dc16c8cf4cc7bfa82fe7edd25c4ea4ee9168f7cb25eb8f102348464c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[443,94,951,296]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"IGURE 6. A, Estimation of the collagen-binding affinity of hProCA32.collagen to collagen type I, type III, and type IV using modified indirect zyme-linked immunosorbent assay. B, Two hepatocellular carcinoma (HCC) and normal human liver tissue microarray stained with Sirius red (red) nd ProCA32.collagen1 (brown) exhibiting the strong binding of the contrast agent to collagen human patient tissue (all scale bars, $100\\\\\\\\mu \\\\\\\\mathrm{m}$ ). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0333/aed27a352ebdbaad978401eacf8b1860246418aac7200e66899695c74f1cac18.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[48,372,482,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"IOMARKER TARGETING FOR PRECISION MOLECULAR IMAGING AND PRECLINICAL APPLICATIONS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,403,486,605]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Having established the third generation of MRI CAs (ProCA32) ith strong affinity and selectivity for Gd(III) and improved relaxivity o achieve improved contrast, we next considered how to further refine he efficacy and precision of our MRI CAs for improved early detection of disease and disease specificity based on our established riteria. Several important guidances were established for the selection and design of molecular biomarkers for precision MRI. First, we elected several key molecular biomarkers that are common across multiple chronic diseases and are expressed in the extracellular environment. These biomarkers should be readily accessible by ProCAs hen they are activated during disease stage. To date, we have successfully developed biomarker-targeted ProCA32 MRI CAs for collagen, HER2, EGFR, PMSA, GLPR, and CXCR4, and various other targets[47,48,50,52,57,62,76,115,159-162] (Fig. 5); however, for the purpose of brevity in this review and to demonstrate our rationale and success \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,372,956,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"in achieving precision MRI, we will only present as an exemplary case ProCA32.collagen, which specifically targets type I collagen. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,399,958,579]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Type I collagen is an extracellular matrix protein that is overexpressed (10- to 20-fold $\\\\mu$ M) and deposited during progression of a number of diseases, leading to pathological changes and remodeling of the tissues in the tumor microenvironment, fibrosis progression of liver, lung, and kidney, and cardiovascular fibrosis.[203] Fibrosis occurs in a number of major diseases such as myocardial infarction, NASH, cirrhosis, liver fibrosis, pulmonary fibrosis, and various cancers.[204-206] More importantly, overexpressed collagen can be crosslinked by LoX or degraded by MMPs with expression of pathologic patterns that depend on the stage and tissue/organ environment, as revealed by second-harmonic generation imaging.[207,208] The expression of collagen also plays an important role in nodule formation, permeability of cancer, and metastasis migration. Recent studies have also reported that collagen formation is an indication for therapeutic responses.[56] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,579,956,606]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Second, we designed a targeting moiety with a defined tertiary structure to have strong biomarker-binding affinity and wherein the \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[62,630,944,875]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 7. A, Magnetic resonance imaging of liver before and 24 hours postinjection of ProCA32.collagen1 at a dosage of $0.02\\\\\\\\mathrm{mmol / kg}$ in UM hepatic metastasis mouse model. B, Hemotoxylin-eosin staining of 6 UM metastasis tumors and its corresponding Sirius red staining, which shows the expression of collagen (red) and their corresponding locations in MRI. Tumor 2 exhibited an infiltrative pattern (green circle), whereas the other tumors exhibited a nodular pattern. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0428/9ae8f67408855f47c97a94f2d6aea59e92a18246555fb509e8a04da485e61914.jpg\",\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[39,38,486,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[37,946,450,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,945,913,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[931,946,956,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"179 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[41,89,482,399]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"addition to the ProCAs would not result in alteration of biomarker-binding affinity or reduction of metal-binding affinity and relaxivity properties of ProCAs. This is achieved by ensuring the targeting moiety for collagen type I maintains an intradisulfide bond and that the key lysine residues are well positioned to interact with collagen. A flexible hinge is used to connect the targeting moiety and the roCA scaffold, without imposing conformational constraints. With this esign, ProCA32.collagen has a strong collagen type I-binding affinity $\\\\mathrm{K_d} = 1.0~\\\\mu \\\\mathrm{M})$ as determined by enzyme-linked immunosorbent assay[16] Fig. 6A). The created ProCA32.collagen also exhibits strong binding specificity over other collagen types, including collagens III and IV. As seen in Figure 6B, it has strong patient tissue specificity for fibrotic stroma f HCC and exhibits the same pathological pattern observed with Sirius ed, suggesting its strong translational potential.[52] Importantly, the 2 etal-binding sites of ProCA32.collagen retain the same relaxation properties of high $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ relaxivity, thermodynamic stability, and metal-binding finity and stability as the parent protein ProCA32 without a targeting moiety.[116] This represents a significant milestone for ProCAs, as it addresses the challenges faced by short peptide targeting moieties with conormational variations that can lead to substantial changes in affinity nd specificity upon conjugation. Furthermore, it underscores the effectiveness of the approach to developing ProCAs, as small chelator-based As frequently experience decreased metal binding and relaxivity hen incorporating targeting moieties.[143] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[43,399,482,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Third, to ensure the quantitative capability in mapping biomarker empox spatial expression levels in the disease states, a developed CA is required to have strong tissue penetration to reach all of the overexpressed biomarkers, and this may be constrained by the size of the olecule. Figure 4C shows that, like other ProCAs developed against ER2 and CXCR4, ProCA32.collagen is $\\\\sim 2 - 3\\\\mathrm{nm}$ in diameter with a ocular weight of $14\\\\mathrm{kDa}$ , which makes it small enough to access verexpressed collagen in tumor microenvironment and fibrosis tissues. In contrast, much larger ( $\\\\sim 150\\\\mathrm{kDa}$ ) antibodies are more likely to locate lose to the blood vessels and less likely to reach the overexpressed iomarkers.[59,62] Thus, a smaller CA is not only important for high tumor/isease targeting ratio, but also because it can be more easily excreted from the kidneys and therefore poses fewer toxicity concerns related to metal deposition. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[511,90,956,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As an example, the detection of uveal melanoma (UM) lesions was demonstrated by ProCA32.collagen in a UM hepatic metastasis mouse model.115 Uveal melanoma hepatic metastatic lesions overexpress type I collagen. By $\\\\mathrm{T}_{1}$ inversion recovery pulse sequence, lesions as small as $0.250\\\\mathrm{mm}^2$ could be detected after injecting ProCA32.collagen, whereas the tumors were not detected either by the clinical CA Eovist or our nontargeted blood pool agent ProCA32 (Fig. 7A). Both hemotoxylineosin and corresponding Sirius red staining of these UM tumors confirmed the overexpression of collagen (red) in liver lesions detected by MRI with ProCA32.collagen (Fig. 7B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,219,956,309]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ProCA32-enabled MRI has been investigated for detection and staging of liver fibrosis, liver metastasis, and lung fibrosis, in different mouse models. As previously discussed, ProCA32 agents are both $\\\\mathrm{T}_{1}$ and $\\\\mathrm{T}_{2}$ CAs. Both $\\\\mathrm{T}_{1}$ and $\\\\mathrm{T}_{2}$ properties $(\\\\mathrm{T}_{2} / \\\\mathrm{T}_{1}$ ratio imaging) have been leveraged to detect liver tumors and metastatic UM in liver.[50] Similarly, we have also been able to successfully detect liver metastasis from ovarian cancer,[59] pancreatic cancer, and colon cancer (manuscript in preparation). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[513,309,956,580]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fibrosis occurs in a number of major diseases such as NASH, cirrhosis, liver fibrosis, pulmonary fibrosis, and myocardial infarction. There is a pressing need for noninvasive detection of fibrosis at early stage and the capacity to stage fibrosis for treatment, because the current criterion standard, biopsy, can produce large errors $(>33\\\\%)$ for detection of early-stage lesions, when tissues exhibit high heterogeneity. There is also an additional need to develop noninvasive imaging methods to evaluate drug responses and for drug discovery. We have achieved success in early detection of liver fibrosis from several origins including alcohol (ASH), fat (NASH), and carcinogens (DEN).7,52 A bolus of ProCA32.collagen in both TAA/alcohol-induced and NASH-induced liver fibrosis mouse models produced stage-dependent $\\\\mathbb{R}_1$ and $\\\\mathbb{R}_2$ changes verified by histological and inductively coupled plasma optical emission spectroscopy of Gd(III) analyses (Fig. 8A).52 Meanwhile, ProCA32.collagen produced no enhancement in normal liver at 24 hours postinjection. Consistent with the $\\\\mathbb{R}_1$ map, the $\\\\mathrm{T}_{2}$ map results also exhibited the same pattern at 24 hours for both early and late stages of fibrosis, with more significant changes observed in late-stage fibrotic liver (Fig. 8B). More importantly, using ProCA32.collagen with our developed imaging methodology, we can achieve the detection of early- and late-stage fibrosis with good sensitivity and specificity (Fig. 8C), as our work addresses \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[52,605,452,874]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0098/4a93432a3386d723e2e34aa769f66159541f89f864e6fc048b39423a63c5ca39.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[479,604,660,745]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0512/f800ba047cc4b996de6e7e689ce52471c47914ed80dac296c199494482c070c0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[698,614,937,741]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0037/74b57bf4fb904ae15d2c3f1cd4f4b9f1bfb5f0fcba69937f2ae57bbd488cc5ff.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[479,747,680,874]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"FIGURE 8. Early-stage detection of liver fibrosis in TAA/alcohol mouse model. A, R1 maps and $\\\\\\\\Delta R1$ values of normal, early-stage, and late-stage liver fibrosis before and 24 hours after injection of ProCA32.collagen1 with a dosage of $0.02\\\\\\\\mathrm{mmol / kg}$ . B, $\\\\\\\\Delta R2$ values derived from T2 maps demonstrating the highest enhancement for late-stage liver fibrosis at 24 hours postinjection. C, ProCA32.collagen1 can distinguish early-stage liver fibrosis from normal and late-stage fibrotic liver with $\\\\\\\\Delta R1$ derived from an R1 map at 24-hour time point. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0367/e2436311ed689658bc885d76760528ea583c33321181a731b6642240b0794168.jpg\",\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[39,41,87,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,38,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[41,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"180 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,314,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[545,946,956,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[53,91,942,359]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"IGURE 9. Detection of early- and late-stage idiopathic pulmonary fibrosis (IPF) by a bolus of $0.02\\\\\\\\mathrm{mmol / kg}$ hProCA32.collagen. UTE-MRI of the lungs of ormal (A), early-stage IPF (B), and late-stage IPF (C) hProCA32.collagen-enabled detection of heterogeneous enhancement of collagenous oneycombing at the subpleural and paraseptal areas of the lung at early stage (B) and late stage (C), highlighted by orange arrows. Magnetic resonance age changes were not observed in late-stage IPF mice at before and 3 hours after injection of Gadovist (D). E, Comparison of ProCA32.collagen attain uptake (red) in BM-induced IPF at alveolar (top) and E-cigarette-induced lung fibrosis in COPD mouse models at the bronchial airways in 3D UTE RI correlated with Sirius red staining. F, Lung signal enhancement $(\\\\\\\\%)$ of normal, nicotine-induced lung fibrosis model for COPD, and BM-induced ice (LS, late stage; $\\\\\\\\ast \\\\\\\\ast \\\\\\\\ast \\\\\\\\ast P < 0.001$ one-way analysis of variance). \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0541/5662b96d430b1d01793018e758f5e8c8ebedc77e36d77bb80d753403d0f9f6bf.jpg\",\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[39,463,482,514]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"he additional diffusive diseases of fibrosis without defined boundary f nodules and heterogeneity. Moreover, based on our results to date, his methodology will also enable us to follow drug treatment responses y MRI in vivo. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[35,514,486,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Recently, we have made another major leap in application of roCA32.collagen and MRI for detection and staging of lung fibrosis in vivo, originating from both IPF and electronic cigarette smoke inhalation, in animal models. Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we reported the development of human collagen-targeted protein MRI CA (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. We have demonstrated the robust detection of early- and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio increase and with good sensitivity and specificity using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, was noninvasively detected by multiple MRI techniques and verified by histological correlation. By using a $\\\\mathrm{T}_{1}$ -weighted ultrashort echo time (UTE) pulse sequence in a bleomycin (BM)-induced IPF mouse model, injection of hProCA32.collagen resulted in $60\\\\%$ and $80.5\\\\%$ enhancement at a 3-hour time point compared with preinjection for the early and late stage of IPF mice, respectively, whereas injection of hProCA32.collagen into healthy normal mice did not result in any noticeable MRI enhancement (Figs. 9A-C, and F). In contrast, injection of gadobutrol (GdBT-DO3A) into late-stage IPF mice did not result in significant enhancement (Fig. 9D). Both examples demonstrated the capability of ProCA32. collagen to detect and stage fibrosis in liver and lung with histological correlation. Moreover, we extended our demonstration to include \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,463,958,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the detection of fibrosis in the lung airways of a mouse model with electronic cigarette-induced COPD, using hProCA32.collagen-enabled precision MRI. Notably, the uptake of ProCA32.collagen is distinct between IPF and COPD mouse models, as depicted in Figure 9E. Magnetic resonance imaging results were validated by histological analysis. $^{116}$ The developed hProCA32. collagen is expected to have strong translational potential in the noninvasive detection and staging of lung diseases and facilitating effective treatment to halt further chronic lung disease progression. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[529,587,938,615]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PHARMACOKINETICS AND BIODISTRIBUTION OF PROCA32 CONTRAST AGENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,617,958,760]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Several key physicochemical properties of ProCA32.collagen have been determined for preclinical and clinical application. Because of the high relaxivity of ProCA32.collagen $(30/42, \\\\mathrm{r}_1 / \\\\mathrm{r}_2, \\\\mathrm{mM}^{-1} \\\\mathrm{s}^{-1}$ at $1.4 \\\\mathrm{T}$ ), ProCA32. collagen is formulated at $5 \\\\mathrm{mM}$ , which is 50- to 200-fold lower in concentration than clinical GBCAs $(0.25 - 1 \\\\mathrm{M})$ . For related studies in our laboratory, the required dose of ProCA32.collagen was calculated to be $0.017 \\\\mathrm{mmol} / \\\\mathrm{kg}$ . By using a body surface area normalization method,[209] the converted theoretical human dose was calculated to be $0.0014 \\\\mathrm{mmol} / \\\\mathrm{kg}$ . This is a 71-fold lower dose than Gd-DOTA, Gd-HP-DO3A, and Gd-DTPA $(0.1 \\\\mathrm{mmol} / \\\\mathrm{kg}$ standard dose) and 18-fold lower than Gd-EOB-DTPA $(0.025 \\\\mathrm{mmol} / \\\\mathrm{kg}$ standard dose) (Table 2). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,760,958,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pharmacokinetics of ProCA32.collagen (PEGylated and non-PEGylated) was studied in mice in our laboratory after a single intravenous injection of $0.017\\\\mathrm{mmol / kg}$ ProCA32.collagen. PEGylated ProCA32.collagen was cleared from circulation in mice with a mean plasma elimination half-life $(t_{1 / 2\\\\beta})$ of 9.93 hours,52 because PEGylation significantly increases blood retention time of the protein.132 ProCA32.collagen without PEGylation exhibited a shorter terminal half-life of $\\\\sim 4$ hours (unpublished data). PEGylated ProCA32.collagen had higher exposure time with volume of distribution $(V_{ss})$ of $1.77~\\\\mathrm{L / kg}$ (2-fold higher than that of ProCA32), indicating the contribution of the targeting ability of ProCA32.collagen and its distribution and penetration into tissues.52 The biodistribution of Gd(III) at 14 days postinjection of PEGylated ProCA32.collagen $(0.017\\\\mathrm{mmol / kg}$ dose) was measured with inductively \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,38,484,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[37,946,450,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,946,913,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[929,946,956,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"181 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[35,90,486,192]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"coupled plasma optical emission spectroscopy using harvested organs in normal mice. Lower than $0.002\\\\mu \\\\mathrm{mol}$ Gd(III) per gram of organ was detected in the liver, skin, kidney, heart, lung, muscle, bone, and brain, whereas Gd-EOB-DTPA had more than 3-folds higher residual Gd(III) in the skin, kidney, and bone compared with PEGylated ProCA32.collagen.[52] Moreover, there was only $0.0002\\\\mu \\\\mathrm{mol}$ Gd(III) per gram of organ in the brain for PEGylated ProCA32.collagen. This is more than 10-folds over residual Gd(III) than Gd-EOB-DTPA.[52,116] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,210,439,223]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CONCLUSIONS AND FUTURE PERSPECTIVE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[46,226,484,483]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In summary, we have created a platform technology for the rational design of a novel class of ProCAs that incorporate Gd(III)-binding site(s) and a isase molecular biomarker-targeting moiety such as collagen,[52,115,116] ER2,[62] PSMA,[162] GRPR,[159] CXCR4,[59] and VEGFR, into a stable scaffold protein (Fig. 1C) to detect and image several types of cancers in animal odels. Our leading CA (ProCA32.collagen) specifically targets type I collagen and exhibits significant increases in both $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ relaxivities compared with clinically approved $\\\\mathrm{Gd}^{3+}$ CAs, resulting in exceptional imaging apability, especially when combined with precision MRI, for noninvasive end quantitative mapping of tempospatial changes of collagen expression using progression and regression of diseases. The results of preclinical studies in the Yang laboratory suggest that ProCA32.collagen can detect lesions 100 times smaller than the detection limits of current clinical CAs and an also detects early-stage liver fibrosis in animal models.[52] ProCA32.collagen enables early-stage detection of hepatic liver cancer and metastasis $0.2 - 20 \\\\mathrm{~mm}$ , with fibrosis and steatosis in mouse models, with a 4-fold increase in contrast-to-noise ratio.[50,52] ProCA32.collagen also itigates metal toxicity due to its lower dosage, strong resistance to transmetallation, and exceptional metal selectivity for $\\\\mathrm{Gd}^{3+}$ over physiological metal ions, with strong translational potential. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,485,484,587]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The successful development of a protein-based MRI CA ProCA32 ith improved contrast capabilities has validated the rationale and strategy ehind its design. Coupled with a targeting moiety, ProCA32.collagen hasemonstrated its capability to achieve qualitative and quantitative precision ocular imaging of several key molecular disease biomarkers in various chronic diseases (fibrosis, metastatic cancer, etc) in multiple animal odels. The safety profile and MRI properties indicate strong potential for preclinical and clinical application of ProCA32. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,587,484,664]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The base scaffold of ProCA32 can be used to detect variable chronic diseases by combining with different biomarker-targeting moieties. Meanwhile, it can advance drug discoveries via noninvasively monitoring disease progression. ProCA32 CAs are also expected to translate into clinical practice in the near future after scale-up production. The manufacturing and large-scale production of ProCA32.collagen is currently underway. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[39,664,484,858]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Advancement of pulse sequences such as multitasking will further address respiratory and cardiac motion effects. Histological correlation with MR images will be further improved by 3D imaging processing and registration. CEST properties and multicolor molecular MRI will be explored using ProCA32. In addition, this same principle can be applied to design of Gd(III) free Mn(II)-based and biomarker-targeted CAs.[210-213] With this development of a protein CA platform having high $\\\\mathbf{r}_1$ and $\\\\mathbf{r}_2$ relaxivity values, metal-binding stability, and significantly reducing dosage, we are also moving forward to develop responsive CAs (SMART), as pioneered by Meade et al, which are able to respond to changes in biological processes such as calcium or proteases.[52,66,67,116,214,215] Despite these advances, future development of new CAs will continue to be driven by strong commitment to patient need and market demand for improved medical diagnostic imaging of the CNS, cancerous soft tissues, vasculature, and internal organs, including the liver, heart, and lungs.[7] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[175,875,346,887]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[37,888,486,928]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The authors thank Chunqi Qian for critically reviewing this article. They also thank James Prestegard, Michael Tweedle, past Yang members, important collaborators, and dedicated colleagues for the helpful \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[508,90,958,452]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"discussion and contribution. They thank the NIH Shared Instrument Grant S10OD027045 and funding support from Georgia States University to establish the Advanced Translational Imaging Facility. D.L., M.S., and S.X. were sponsored by GSU MBD fellowships, whereas Z.G. and O.I. were sponsored by GSU CDT fellowships; S.T. was sponsored by a BB fellowship. Importantly, this work is also dedicated to William Thomas (Tom) Dixon, who was a true inspiration for Jenny Yang's career development and relaxation theory. Tom graduated from the University of Minnesota with a bachelor's degree in mechanical engineering in 1967. He later attended medical school at Stanford University but moved back to Minnesota in 1969 to work at the Control Data Corporation developing new supercomputers. Tom then moved to UC San Diego where he graduated in 1980 with a degree in physics. Tom met his wife, Dabney Katherine White, while in San Diego. They were married in St Louis in 1982. In 1986, Tom moved to Atlanta to lead the Frits Philips Center for Magnetic Resonance Imaging at Emory University. Tom then worked in the private sector from 2000 to 2012, before returning to Emory and retiring in 2017. Tom was well known to his peers for his sense of humor, humility, and compassion. He was also well known for his important contributions to MRI contrast imaging, including development of new pulse sequences to enhance MR CA utility, particularly his development of a method to create images that show water only, fat only, and the difference between water and fat intensity, known as the Dixon Method (see Radiology. 1984;153:189-194). As of August 2022, the article had been cited more than 2700 times. His many contributions to science will continue to inspire the next generation of researchers and challenge us all to strive for excellence. The authors appreciate Tom's detailed discussions about relaxation theory and properties of ProCAs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[685,465,782,478]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[520,485,956,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Taylor AJ, Salerno M, Dharmakumar R, et al. T1 mapping: basic techniques and clinical applications. JACC Cardiovasc Imaging. 2016;9:67-81. \\\",\\\"2. Meijer FJ, Goraj B. Brain MRI in Parkinson's disease. 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Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[46,91,484,927]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"17. Nicolle GM, Tóth E, Schmitt-Willich H, et al. The impact of rigidity and water exchange on the relaxivity of a dendritic MRI contrast agent. Chemistry. 2002; 8:1040-1048. \\\",\\\"18. Chang CA. Magnetic resonance imaging contrast agents. Design and physicochemical properties of gadodiamide. Invest Radiol. 1993;28(Suppl 1):S21-S27. \\\",\\\"19. Kirchin MA, Pirovano GP, Spinazzi A. Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol. 1998;33:798-809. \\\",\\\"20. Rubin DL, Desser TS, Semelka R, et al. 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Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Proc Natl Acad Sci. 2015;112:6607-6612. \\\",\\\"51. Lauenstein TC, Salman K, Morreira R, et al. Gadolinium-enhanced MRI for tumor surveillance before liver transplantation: center-based experience. Am J Roentgenol. 2007;189:663-670. \\\",\\\"52. Salarian M, Turaga RC, Xue S, et al. Early detection and staging of chronic liver diseases with a protein MRI contrast agent. Nat Commun. 2019;10:4777. \\\",\\\"53. Ayuso C, Rimola J, Vilana R, et al. Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines. Eur J Radiol. 2018;101:72-81. \\\",\\\"54. Shuvaev S, Akam E, Caravan P. Molecular MR contrast agents. Invest Radiol. 2021;56:20-34. \\\",\\\"55. Polasek M, Fuchs BC, Uppal R, et al. Molecular MR imaging of liver fibrosis: a feasibility study using rat and mouse models. J Hepatol. 2012;57:549-555. \\\",\\\"56. Erstad DJ, Sojooodi M, Taylor MS, et al. 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Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[682,946,910,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[931,946,956,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"183 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[41,91,482,926]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"73. 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Eur Radiol. 2003;13:2688-2698. \\\",\\\"85. Agarwal R, Brunelli SM, Williams K, et al. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis. Nephrol Dial Transplant. 2009;24:856-863. \\\",\\\"86. European Medicines Agency. Assessment Report for Gadolinium-Containing Contrast Agents. Amsterdam, the Netherlands: European Medicines Agency; 2010. \\\",\\\"87. Morcos SK. Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition? Br J Radiol. 2007;80:73-76. \\\",\\\"88. Perazella MA. Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a link? Am Soc Nephrol. 2007;2:200-202. \\\",\\\"89. Do QN, Lenkinski RE, Tircso G, et al. How the chemical properties of GBCAs influence their safety profiles in vivo. *Molecules*. 2021;27:58. \\\",\\\"90. American College of Radiology. ACR Manual on Contrast Media. Reston, VA: ACR Committee on Drugs and Contrast Media; 2023. \\\",\\\"91. Spinazzi A. MRI Contrast Agents and Nephrogenic Systemic Fibrosis. MRI Bioeffects, Safety, and Patient Management. Los Angeles, CA: Biomedical Research Publishing Group; 2014:256-281. \\\",\\\"92. Fraum TJ, Ludwig DR, Bashir MR, et al. Gadolinium-based contrast agents: a comprehensive risk assessment. J Magn Reson Imaging. 2017;46:338-353. \\\",\\\"93. Matsumura T, Hayakawa M, Shimada F, et al. Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use. Magn Reson Med Sci. 2013;12:297-304. \\\",\\\"94. Michaely HJ, Aschauer M, Deutschmann H, et al. Gadobutrol in renally impaired patients: results of the GRIP study. Invest Radiol. 2017;52:55-60. \\\",\\\"95. Deray G, Rouviere O, Bacigalupo L, et al. 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Invest Radiol. 2019;54:475-484. \\\"]\",\n \"page_idx\": \"14\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[39,41,89,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,40,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[41,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"184 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,314,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[545,946,956,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). 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Structural and dynamic parameters obtained from 17O NMR, EPR, and NMRD studies of monomeric and \\\"]\",\n \"page_idx\": \"15\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[39,38,482,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[606,38,958,53]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Protein MRI Contrast Agents as an Effective Approach \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[37,946,448,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). 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Biochemistry. 1990;29:3937-3943. \\\"]\",\n \"page_idx\": \"16\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[511,91,956,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"200. Falke JJ, Drake SK, Hazard AL, et al. Molecular tuning of ion binding to calcium signaling proteins. Q Rev Biophys. 1994;27:219-290. \\\",\\\"201. Renner M, Danielson MA, Falke JJ. Kinetic control of ca (II) signaling: tuning the ion dissociation rates of EF-hand ca (II) binding sites. Proc Natl Acad Sci. 1993;90:6493-6497. \\\",\\\"202. Drake SK, Zimmer MA, Miller CL, et al. Optimizing the metal binding parameters of an EF-hand-like calcium chelation loop: coordinating side chains play a more important tuning role than chelation loop flexibility. Biochemistry. 1997; 36:9917-9926. \\\",\\\"203. Wahyudi H, Reynolds AA, Li Y, et al. Targeting collagen for diagnostic imaging and therapeutic delivery. J Control Release. 2016;240:323-331. \\\",\\\"204. Cox TR. The matrix in cancer. Nat Rev Cancer. 2021;21:217-238. \\\",\\\"205. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028-1040. \\\",\\\"206. Xu S, Xu H, Wang W, et al. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019;17:309. \\\",\\\"207. Scodellaro R, Bouzin M, Mingozzi F, et al. Whole-section tumor micro-architecture analysis by a two-dimensional phasor-based approach applied to polarization-dependent second harmonic imaging. Front Oncol. 2019;9:527. \\\",\\\"208. Wang B, Sun Y, Zhou J, et al. SHG/TPEF-based image technology improves liver fibrosis assessment of minimally sized needle biopsies. Hepatol Int. 2019;13: 501-509. \\\",\\\"209. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659-661. \\\",\\\"210. Ning Y, Zhou IY, Rotile NJ, et al. Dual hydrazine-equipped turn-on manganese-based probes for magnetic resonance imaging of liver fibrogenesis. J Am Chem Soc. 2022;144:16553-16558. \\\",\\\"211. Zhang J, Ning Y, Zhu H, et al. Fast detection of liver fibrosis with collagen-binding single-nanometer iron oxide nanoparticles via $\\\\\\\\mathrm{T}_{1}$ -weighted MRI. Proc Natl Acad Sci U S A. 2023;120:e2220036120. \\\",\\\"212. Woods M, Pasha A, Zhao P, et al. Investigations into whole water, prototropic and amide proton exchange in lanthanide (III) DOTA-tetraamide chelates. Dalton Trans. 2011;40:6759-6764. \\\",\\\"213. Qian C, Yu X, Pothayee N, et al. Live nephron imaging by MRI. Am J Physiol Renal Physiol. 2014;307:F1162-F1168. \\\",\\\"214. Ning Y, Zhou IY, Roberts JD Jr., et al. Molecular MRI quantification of extracellular aldehyde pairs for early detection of liver fibrogenesis and response to treatment. Sci Transl Med. 2022;14:eabq6297. \\\",\\\"215. Hingorani DV, Bernstein AS, Pagel MD. A review of responsive MRI contrast agents: 2005-2014. Contrast Media Mol Imaging. 2015;10:245-265. \\\"]\",\n \"page_idx\": \"16\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[39,41,87,51]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Li et al \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[513,40,956,54]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Investigative Radiology Volume 59, Number 2, February 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[41,946,66,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"186 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[84,946,314,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"www.investigativeradiology.com \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[547,946,956,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.1097/rli.0000000000001057"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Chemistry/Materials Science and Engineering"},"sha256":{"kind":"string","value":"d8cad2337a3bc1f21c2ddade562fa9dac6f522345b0687cb282ac38a474458fc"},"title":{"kind":"string","value":"Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging"}}},{"rowIdx":184,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Niclas Barke, Sawinee Masser, Doerte Stalling, Emanuel Wyler, Robert Patrick Zinzen, Sabrina Schreiner, Jens Bosse, Markus Landthaler"},"content_list":{"kind":"list like","value":[{"bbox":"[115,86,838,131]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Dissecting the role of RNA-binding proteins in early herpes simplex virus 1 transcription using acute protein depletion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,148,880,181]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Niclas Barke $^{1,2}$ , Sawinee Masser $^{3}$ , Doerte Stalling $^{4,5,6,7}$ , Emanuel Wyler $^{1}$ , Robert Patrick Zinzen $^{1}$ , Sabrina Schreiner $^{3,4,6}$ , Jens Bosse $^{4,5,6,7}$ , Markus Landthaler $^{1,2*}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[144,195,878,338]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany \",\"2. Institut für Biologie, Humboldt-Universität zu Berlin, Berlin, Germany \",\"3. Institute of Virology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany \",\"4. Hannover Medical School, Institute of Virology, Hannover, Germany \",\"5. Centre for Structural Systems Biology, Hamburg, Germany \",\"6. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany \",\"7. Leibniz Institute of Virology (LIV), Hamburg, Germany \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[115,355,564,370]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"*Corresponding author: markus.landthaler@mdc-berlin.de ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,409,194,425]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Abstract ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,428,880,478]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Herpes simplex virus 1 (HSV-1) infects about $50 - 80\\%$ of the entire human population and persists in the neurons of affected individuals. A fraction of affected individuals suffer from recurrent cold sores caused by reactivating virus, in rare but severe cases the virus can cause encephalitis. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,480,880,633]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"During lytic infection, the virus relies on host factors such as RNA polymerase II and accessory proteins involved in transcription to express its genes and ensure successful replication. In general, RNA molecules in cells are bound by RNA-binding proteins (RBPs) during their entire lifecycle. Importantly, RBPs are increasingly described to also regulate transcription, an aspect long time outside the scope of investigations, especially during viral infections. Here, we examined the impact of five nuclear proteins (FUBP1, SLBP, SFPQ, SPT5 and SAF-B) with known RNA-binding activities on HSV-1 transcription. Additionally, we evaluated their importance for human adenovirus C5 (HAdV) growth to assess whether these host factors are specific to HSV-1 infections or might have broader relevance for the general transcription of dsDNA viruses. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,634,880,702]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We show that the transcriptional elongation factor SPT5 coded by SUPT5H accumulates on HSV-1 genomes early during the infection and is required for the transcription of the immediate-early gene UL54. Its depletion affects also HAdV replication, indicating a general role in transcription of viruses that depend on the host transcriptional machinery. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,703,880,755]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In contrast, depletion of the transcriptional repressor and paraspeckle protein SFPQ reduces UL54 RNA levels in HSV-1 infection, but does not cause significant changes in HAdV growth. Since SFPQ does not co-localize with HSV-1 genomes, this suggests a function not directly associated to viral DNA. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,793,230,809]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,812,880,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Herpes simplex virus 1 (HSV-1) is transmitted between humans by direct contact and establishes lifelong latency in neurons of the trigeminal ganglia $^{1,2}$ . As of 2012, an estimated 3.7 billion people under the age of 49 were infected with HSV-1 worldwide $^{3}$ . While some individuals experience recurrent painful blisters and sores, typically at the lips following viral reactivation, HSV-1 can lead to severe complications such as keratitis, blindness and encephalitis $^{1,4,5}$ . Newborns, the elderly and ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,885,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[114,85,884,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"immunocompromised individuals are particularly vulnerable to these outcomes<sup>5</sup>. Furthermore, growing evidence suggests a contribution of HSV-1 infections and/or reactivations to the development and/or progression of neurodegenerative diseases, including Alzheimer's<sup>6-8</sup>. Current treatment options mainly rely on inhibitors and nucleoside analogs such as acyclovir, which are susceptible to viral resistance highlighting the urgent need for alternative drugs<sup>5,9</sup>. Despite ongoing research, an effective vaccine remains unavalable<sup>9</sup>. As a result, HSV-1 continues to pose a global health concern. Understanding and targeting the early stages of the infection may offer new opportunities to prevent and ultimately reduce this burden. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,231,884,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To initiate HSV-1 transcription mediated by the RNA polymerase II (Pol II), the tegument protein VP16 functions as an activator working together with the host transcription factors (TFs) HCF and Oct-1 to drive expression of the 5 immediate-early genes: RL2 (ICP0), RS1 (ICP4), US1 (ICP22), UL54 (ICP27) and US12 $(\\mathrm{ICP47})^{10 - 13}$ . Among these, ICP4 plays a crucial role in orchestrating the viral expression cascade by interacting with the general host transcription factors of mediator and components of the TFIID complex, to activate transcription of early and late genes $^{14 - 19}$ . It exemplifies that despite its relatively large genome of about 152 kbp, HSV-1 relies on the activity of several host factors to facilitate viral transcription and replication $^{20}$ . This includes host RNA-binding proteins (RBPs), that associate with viral RNA (vRNA) throughout the entire life cycle from nuclear transcription to translation in the cytoplasm $^{21,22}$ . While classical functions assigned to RBPs include mRNA splicing, modification, stability, localization, and translation, in recent years emerging evidence suggests that some RBPs also contribute to transcriptional regulation, a function that remains poorly understood in the context of viral infections $^{23,24}$ . While RBPs are crucial for various aspects of RNA metabolism, most virological studies have primarily focused on their involvement in innate immune recognition and decay of vRNAs, as well as their role during the intracellular transport, nuclear import/export and translation of vRNAs. Many RBPs are indispensable for cellular functions, making knockout approaches challenging. Since specific inhibitors are generally unavailable, depletion strategies often rely on CRISPR/Cas9 or RNA interference (RNAi). However, RNAi leads to a gradual decrease of protein levels over one to three days, increasing the risk of observing secondary effects such as reduced cell viability. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,569,884,843]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To address this issue and elucidate the role of RBPs in HSV-1 infection, we used an auxin-mediated protein degradation system $^{25}$ . This approach enables rapid depletion of target proteins within 2-6 hours by harnessing cellular E3-ubiquitin ligases and subsequent proteasomal degradation. Unlike RNAi, this method allows us to assess the direct, immediate impact of these proteins on the viral replication cycle, as the short depletion time reduces the possibility of secondary effects. We endogenously degron-tagged several RBPs involved in transcriptional regulation and previously identified by an RNAi screen to influence vRNA levels at early times of infection and vDNA replication $^{25}$ . Our findings indicate that the human transcription elongation factor SUPT5H, is associated with the vDNA at early times of infection and is likely essential for the transcription of HSV-1 genes. Furthermore, we demonstrate that the absence of SFPQ, a multifunctional protein involved in splicing and paraspeckle formation, leads to a reduction of vRNA levels but does not completely block transcription $^{26-29}$ . To facilitate comparative analysis, we also included adenovirus C5, another double-stranded DNA virus replicating in the nucleus in our study. Despite its genome being only a quarter to a third the size of HSV-1, they share a broadly similar replication strategy $^{30}$ . This comparative approach allows us to distinguish factors specific to HSV-1 from those with more general functions for dsDNA viruses replicating in the nucleus. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,86,317,101]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Material and Methods ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,108,394,124]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cell lines and culturing conditions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,126,882,227]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HCT116 (ATCC, CCL-247) cells were cultured in McCoy's 5A (Modified) Medium (ThermoFisher) with 2 mM L-glutamine (ThermoFisher) and $9 - 10\\%$ fetal bovine serum (ThermoFisher). HaCaT cells for EdC-labeled virus stock production were kept in DMEM (high glucose) (Sigma-Aldrich) supplemented with GlutaMAX and $10\\%$ FBS. N- and C-termini of genes of interest were tagged with minilAA7(AID) in F-box protein AtAFB2 expressing HCT116 cells as described in Boehm et al. $^{31}$ . Used sgRNAs are listed in Table 1. Cells were maintained at $37^{\\circ}C$ and $5\\%$ CO2 in a humidified incubator. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,239,880,305]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A549 cells (ATCC, CCL-185) and HEK293 (ATCC, CRL-1573) were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with $5\\%$ fetal calf serum, $100\\mathrm{U}$ of penicillin, $100\\mu \\mathrm{g}$ of streptomycin per ml in a $5\\%$ CO2 atmosphere at $37^{\\circ}C$ . All cell lines are frequently tested for mycoplasma contamination. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,342,878,439]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0031/81325d887e5c532b5ab4befe4ca1039d76a48071b123bbf26fcb4d65080ba2a0.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":"<table><tr><td>sgRNA pairs</td><td>sequence (5’->3’)</td></tr><tr><td>sgSUPT5H_Top_c2</td><td>CACCGCTTCATCCGACGAAGTCCAC</td></tr><tr><td>sgSUPT5H_Bot_c2</td><td>AAACGTGGACTTCGTCGGATGAAGC</td></tr><tr><td>sgSFPQ_Top_c2</td><td>CACCGTTCCGGAGTCGTGGCGGTGG</td></tr><tr><td>sgSFPQ_Bot_c2</td><td>AAACCCACCGCCACGACTCCGGAAC</td></tr></table>","table_caption":"[\"Table 1: List of sgRNAs used to AID-tag HCT116 cells by CRISPR/Cas9 genome editing \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,466,477,481]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Herpes simplex virus 1 stocks and infections ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,483,882,653]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HCT116 cells were infected with HSV1(17+) or HSV1(17+)Lox- $\\cdot_{\\mathsf{pMCMV}}$ GFP at a MOI of $0.04^{32,33}$ . 4 days post infection (dpi), the supernatant was harvested, transferred to 50 ml tubes and centrifuged at $3000\\times g$ and $4^{\\circ}C$ for 5 min to remove cell debris. Virus was enriched from the remaining supernatant by size excluding filtration using Centricon Plus-70 (Merck) with a threshold of 100 kDa. Beforehand, Centricons had been washed with $\\mathrm{H}_2\\mathrm{O}$ , disinfected with $70\\%$ ethanol and again washed with $\\mathrm{H}_2\\mathrm{O}$ . The corresponding centrifugation steps were carried out at $1000\\times g$ and $4^{\\circ}C$ for 15 min. 60 ml of virus-containing supernatant were transferred into single Centricons and subsequent centrifugation was performed at $1000\\times g$ and $4^{\\circ}C$ for 60 min. Enriched virus stocks were eluted in the provided concentrate recovery tubes by a 2 min centrifugation step at $1000\\times g$ and $4^{\\circ}C$ . Vital titers were determined by plaque assays on VeroE6 cells. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,665,413,681]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Adenovirus C5 stocks and infections ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,684,880,820]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A replication-competent HAdV-C5 delta E3 virus, encoding a CMV promoter-driven eGFP expression cassette, was further used in this study $^{34}$ . The virus was propagated and titrated in HEK293 cells. Virus titer was determined by immunofluorescence staining of the adenoviral DNA binding protein $\\mathrm{E2A}^{35}$ . A549 cells were infected with HAdV-C5 delta E3 virus at a MOI of 0.5 in non-supplemented DMEM. After incubation for $1\\text{h}$ at $37^{\\circ}\\mathrm{C}$ , the infection was stopped by replacing virus containing medium with fresh DMEM medium with supplements. Degron-tagged HCT116 cells were infected with HSV-1 strain 17 at a MOI of 0.5. After an incubation period of $30\\text{min}$ at $37^{\\circ}\\mathrm{C}$ and $5\\%$ $\\mathrm{CO}_{2}$ , medium was discarded and conditioned medium added. At defined times post infection, samples were harvested. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,833,260,847]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RNA interference ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,850,880,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"HCT116 or A549 cells were seeded out in a 12-well format at a density of $4 \\times 10^{4}$ or $3 \\times 10^{3}$ cells per well, respectively. Cells were transfected with respecting siRNAs using RNAiMAX (Thermo Fisher). In short, $671 \\mu l$ OptiMEM (Thermo Fisher) with $4.5 \\mu l$ siRNA ( $20 \\mu M$ ), and $648 \\mu l$ OptiMEM with $27 \\mu l$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[114,85,880,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RNAiMAX were prepared. The mixtures were combined and had been incubated for 10 min at room temperature. The final amount of siRNA per well was 8.34 pmol. Catalog numbers of siRNAs used in this study are listed in Table 2. 48 hours post transfection (hpt) supplemented media was added. The following day infections were performed. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,179,852,470]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0357/a9aabbe2de7db5e291cd8d4b9f0d23c395d021400da4703fd43da1d8b5e52181.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>Catalog Number</td><td>Product Name</td></tr><tr><td>J-012286-05-0002</td><td>ON-TARGETplus Human SLBP (7884) siRNA - Individual, 2 nmol</td></tr><tr><td>J-011548-05-0002</td><td>ON-TARGETplus Human FUBP1 (8880) siRNA - Individual, 2 nmol</td></tr><tr><td>J-006455-06-0002</td><td>ON-TARGETplus Human SFPQ (6421) siRNA - Individual, 2 nmol</td></tr><tr><td>J-016234-05-0002</td><td>ON-TARGETplus Human SUPT5H (6829) siRNA - Individual, 2 nmol</td></tr><tr><td>J-005150-05-0002</td><td>ON-TARGETplus Human SAFB (6294) siRNA - Individual, 2 nmol</td></tr><tr><td>D-001810-01-05</td><td>ON-TARGETplus Non-targeting siRNA #1, 5 nmol</td></tr></table>","table_caption":"[\"Table 2: List of used siRNAs from Horizon Discovery/Dharmacon \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,498,273,512]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RNA/DNA isolation ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,516,873,633]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For isolation of cellular RNA and DNA, cells were thoroughly resuspended in $300\\mu \\mathrm{l}$ Trizol (ThermoFisher). If both RNA and DNA were extracted from Trizol, one third was processed using the DNA Trizol kit (Zymo). The remaining sample or otherwise the entire $300\\mu \\mathrm{l}$ were used as input for the Direct-zol RNA miniprep kit (Zymo) to digest DNA and extract RNA by following the manufacturer's instructions. RNA integrity was confirmed by running an RNA ScreenTape Analysis (Agilent Technologies) on a TapeStation and concentrations were determined by NanoDrop measurements. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,646,376,663]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reverse transcription and qPCR ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,665,882,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"500 ng of extracted RNA from each sample was reverse transcribed with the SuperScript™ III Reverse Transcriptase (ThermoFisher) according to the manufacturer's recommendations using RNaseOUT™ Recombinant RNase Inhibitor (ThermoFisher) and 100 ng random primers (ThermoFisher). The resulting cDNA was diluted 1:20 with DNA-/RNA-free water. Per qPCR reaction, $3.75\\mu l$ of the diluted cDNA were amplified using the GoTaq qPCR Kit (Promega) and $1\\mu M$ each of the previously described primers, shown in Table $3^{36}$ . For normalization purposes, raw UL54 RNA values were normalized using GAPDH, and raw UL54 DNA values using the BBC3as primer pair which targets the human genome. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[117,819,878,900]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0453/db1c702148aa2274d3d8fdc25967d6a27d955237752b48c5b7862f65de144b58.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":"<table><tr><td>primer pairs</td><td>sequence (5’->3’)</td></tr><tr><td>GAPDH_fwd</td><td>AGCCACATCGCTCAGACAC</td></tr><tr><td>GAPDH_rev</td><td>GCCCAATACGACCAAATCC</td></tr><tr><td>BBC3as-2_fwd</td><td>GGACTCACACGGGACTGG</td></tr><tr><td>BBC3as-2_rev</td><td>CATCTCAGTGTTTGTGTGCAAG</td></tr><tr><td>UL54_fwd</td><td>AGACGCCTCGTCCGACGGA</td></tr><tr><td>UL54_rev</td><td>GAGGCGCGACCACACACTGT</td></tr></table>","table_caption":"[\"Table 3 primers \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[117,82,878,135]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":"[]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[115,162,589,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Preparation of virus stocks for co-localization experiments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,180,882,350]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To produce EdC-labeled viruses, HaCaT cells were seeded in $10 \\times 15$ cm dishes (Day 0). On the following day, cells were washed once with PBS and infected with HSV-1 strain 17 ( $1.2 \\times 10^{7}$ PFU/ml) at a MOI of 0.01, using 2 ml inoculum per dish. At 1 h post-infection (hpi), $1.5 \\mu \\mathrm{M}$ Ethynyl-dCTP (EdC) (ThermoFisher) was added to four plates per virus (in 18 ml medium per plate). Controls (one plate per virus) received an equivalent volume of DMSO. On Days 2 and 3, $1.5 \\mu \\mathrm{M}$ EdC or the equivalent amount of DMSO was added to the respective plates. On Day 4, virus-containing supernatants were harvested, and pre-cleared by centrifugation ( $500 \\times g$ , 5 min, $4^{\\circ} \\mathrm{C}$ ). Supernatants were filtered through a $0.45 \\mu \\mathrm{m}$ membrane, and concentrated by centrifugation ( $14.000 \\times g$ , 1.5 h, $4^{\\circ} \\mathrm{C}$ ) over a $5 \\%$ OptiPrep cushion. The virus pellet was resuspended in $500 \\mu \\mathrm{l}$ PBS. Viral titers were determined by performing plaque assays on Vero cells. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,362,294,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Western blot analysis ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,380,880,500]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For protein analysis, cells were resuspended in RIPA lysis buffer (50 mM Tris-HCl [pH 8,0], 150 mM NaCl, 5 mM EDTA, 1% [vol/vol] Nonident P-40, 0.1% [wt/vol] SDS, 0.5% [wt/vol] sodium deoxycholate) supplemented with a fresh protease inhibitor cocktail containing 0.2 mM PMSF, 1 mg/mL pepstatin A, 5 mg/mL aprotinin, and 20 mg/mL leupeptin. After 30 min incubation on ice, the lysates were sonicated and cell debris was pelleted at 14.800 g at $4^{\\circ}\\mathrm{C}$ for 3 min. Cell lysates were boiled for 3 min at $95^{\\circ}\\mathrm{C}$ in 5x Laemmli buffer. Proteins were separated by SDS-PAGE, transferred to nitrocellulose blotting membranes $(0.45\\mu \\mathrm{m})$ and visualized by immunoblotting. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,510,880,595]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Primary antibodies specific for HAdV proteins used in this study included mouse monoclonal antibody (Mab) mouse B6-8 (anti-E2A), MAb mouse AC-15 (anti- $\\beta$ -actin; Sigma-Aldrich) $^{35}$ . Primary antibodies specific for cellular expressed proteins included HNRNPU (abcam; Cat# ab10297), SAF-B (Santa Cruz Biotechnology; Cat# sc-135618), SFPQ (abcam; Cat# ab38148), SLBP (abcam; Cat# ab181972), SUPT5H (abcam; Cat# ab126592), FUBP1 (abcam; Cat# ab181111), GAPDH (Sigma-Aldrich; Cat# G8795). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,606,880,655]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Secondary antibodies conjugated to horseradish peroxidase (HRP) for detection of proteins by immunoblotting were anti-rabbit IgG, anti-mouse IgG, and anti-rat IgG (Jackson/Dianova or Dako) used in a dilution of 1:10.000. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,667,880,785]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Degron-tagged HCT116 cells subjected to RNA extraction and subsequent RT-qPCR were seeded at a density of $8 \\times 10^{6}$ cells per well in a 12-well plate. Before the infection, cells were treated with $500 \\mu \\mathrm{M}$ indole-3-acetic acid (IAA) (Sigma-Aldrich) for $4 \\mathrm{~h}$ or $22 \\mathrm{~h}$ to induce protein depletion or remained untreated, respectively. The infection was carried out with HSV1(17+)Lox- $\\mathsf{p} \\mathsf{M} \\mathsf{C} \\mathsf{M} \\mathsf{V}$ GFP at a MOI of 1. After an incubation period of $30 \\mathrm{~min}$ at $37^{\\circ} \\mathrm{C}$ and $5 \\%$ $\\mathrm{CO}_{2}$ , medium was discarded and conditioned medium added. At 2hpi and 4hpi, the medium was discarded and cells were lysed in $300 \\mu \\mathrm{l}$ Trizol (ThermoFisher). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,797,557,813]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Fixation of infected cells and fluorescence microscopy ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,816,880,902]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For the purpose of imaging, immunofluorescently labeled RBPs and HSV-1EdC-labeled genomes, parental HCT116 cells and degron-tagged cell lines were seeded at 50.000 cells per well in 8-well plates (ibidi). Cells were pretreated with $500~\\mu \\mathrm{M}$ IAA (Sigma-Aldrich;) 4 hours before infection to induce protein depletion where applicable. Cells were infected with HSV-1EdC or HSV-1DMSO at an MOI of 10. At 3 hpi, cells were washed with PBS and fixed with $4 \\%$ PFA for 15 minutes at room temperature ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[114,85,880,168]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"(RT). Following fixation, samples were washed three times with PBS, permeabilized with $0.1\\%$ Triton X-100 for 20 minutes, and blocked with $3\\%$ BSA for 15 minutes at RT. Following two additional PBS washes, the click chemistry reaction was performed with the Click-iT Plus Alexa Fluor 488 Picolyl Azide Toolkit according to the manufacturer's protocol (ThermoFisher). After the click reaction, cells were washed once in $3\\%$ BSA and twice with PBS. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,180,884,317]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Quantitative image analysis was performed in ImageJ Fiji (Schindelin et al., 2012) using the plugin Trackmate v7.13.2 (Ershov et al., 2022) to identify viral genomes, applying a detection threshold of 750. The median intensity of each protein was then measured. To establish protein-specific intensity thresholds, the median intensity was determined at three randomly selected nuclear positions. The threshold was set at 1,000 for SUPT5H and 2,500 for SFPQ, since SFPQ exhibited a higher baseline intensity. Colocalization events were defined as signals exceeding the respective thresholds, and the proportion of colocalized spots relative to DNA signals was calculated. A total of 95 and 118 genomes were analyzed for SUPT5H and SFPQ, respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,328,878,395]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For immunostaining, cells were incubated with an anti-V5 primary antibody (1:500) (Cell Signaling) for 1 hour at RT, washed three times with PBS, and incubated with a goat anti-rabbit secondary antibody (1:1000) (ThermoFisher). Nuclei were counterstained with Hoechst (1:1000) (ThermoFisher). Samples were imaged using a Spinning Disk microscope (Nikon). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,406,878,439]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To evaluate viral transcription/replication, the signal of GFP expressing HSV1 or HAdV was imaged and measured, respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,451,184,467]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,473,872,508]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"siRNA-mediated knockdown of RBPs involved in transcriptional regulation impairs HSV-1 and HAdV gene expression while reducing cell growth ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,510,878,558]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To investigate the impact of cellular RBPs on early HSV-1 transcription, we initially focused on five candidates with known nuclear localization. These five RBPs were selected based on previous reports, such as an HSV-1 siRNA knockdown screen.[37] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,562,880,663]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The first protein of interest, Far Upstream Element Binding Protein 1 (FUBP1), was mainly described as a transcriptional activator of c-myc expression, which in turn acts as a transcription factor for cell growth and proliferation $^{38}$ . Mechanistically, FUBP1 interacts with transcription factor II H (TFIIH), an essential component of pre-initiation complexes, to facilitate promoter escape of RNA polymerase II (RNAPII) by stimulating TFIIHs helicase activity $^{38,39}$ . While knockdown of FUBP1 was already described to reduce HAdV replication, its impact on HSV-1 replication is unknown $^{40}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,665,880,835]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"At the beginning of infection, HSV-1 genomes brought into the cell by virus particles are free from histones but quickly get chromatinized after their entry into the nucleus $^{41-43}$ . Similar to the host, viral transcription depends on epigenetic regulation allowing or restricting access of the transcriptional machinery to the genome. Whereas cellular genes are regulated individually due to different chromatin states, the epigenetic regulation of HSV-1 DNA occurs on a genome-wide level with transcription factors controlling the fine-tuned activation of separate viral genes $^{44}$ . Histone modifications on the entire HSV-1 genome could therefore determine globally silenced or permissive chromatin states and thus dictate whether cells undergo lytic or latent infection $^{44}$ . Since the Stem-Loop Histone mRNA Binding Protein (SLBP) is required for processing histone mRNAs, we wondered whether its depletion would affect viral transcription competence $^{45,46}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,837,880,888]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Another RBP of interest, Splicing Factor Proline And Glutamine Rich (SFPQ), is described to have multiple functions that depending on the virus under investigation can be pro- or antiviral $^{47-51}$ . Besides its role in alternative splicing, SFPQ acts as a transcriptional repressor and is a component of ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[114,85,880,117]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"paraspeckles, which are nuclear entities sequestering RNA molecules for RNA editing and are further involved in transcriptional regulation of HSV-1 genes $^{26,28,52-54}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,118,882,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Spt5, encoded by the SPT5 Homolog, DSIF Elongation Factor Subunit (SUPT5H) gene, is part of the DSIF (DRB-sensitivity inducing factor) complex that associates with RNA polymerase II and affects promoter-proximal pausing and elongation $^{55}$ . Moreover, SUPT5H was previously shown to be particularly important for the transcription of G+C-rich genes $^{56}$ . As those are highly prevalent in the HSV-1 genome, SUPT5H is likely relevant for viral transcription as well, possibly through an interaction with the viral protein Icp22. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,223,880,255]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, the Scaffold attachment factor B (SAFB) was described to link transcription to splicing and thus represents an interesting candidate to study in the context of viral infection $^{57}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,267,884,387]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To assess the role of these five RBPs in early viral transcription, we depleted their mRNAs in A549 cells and HCT116 cells using siRNAs for $72\\mathrm{h}$ , resulting in a strong reduction in protein levels (Supplementary Figure 1A). At this time point, we infected cells with 0.5 MOI of HSV-1, and quantified the immediate early transcript UL54 by RT-qPCR at 2 hpi (hours post infection) (Figure 1A). Depletion of SFPQ and SUPT5H resulted in a strong reduction in viral RNA levels, whereas the other three candidates showed no substantial effect. However, vDNA levels remained largely unchanged, indicating that viral entry and genome delivery were not impaired by the knockdowns (Figure 1B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,397,882,448]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Microscopic inspection of cells after $72\\mathrm{h}$ of RNAi revealed altered cell morphology in some conditions compared to the control siRNA treatment (Figure 1C). In addition, cell counts at seeding and harvesting indicated that knockdowns of SFPQ and SUPT5H considerably impaired cell growth (Figure 1D). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,458,882,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"For our comparative approach with human adenovirus C5 (HAdV C5), we carried out the RNAi experiment in A549 cells using a GFP-expressing adenovirus. Cells were infected $48\\mathrm{h}$ post siRNA transfection, and viral replication was assessed $24\\mathrm{h}$ later by counting GFP-positive cells (Supplementary Figure 1B). Similar to HSV-1, the knockdown of SUPT5H strongly impaired viral replication (Figure 5E+F). However, the knockdown of SFPQ did not produce a strong effect, suggesting that parallel experiments with different DNA viruses can help to distinguish general host factors essential for nuclear-replicating DNA viruses from those specific for HSV-1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,588,880,671]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Taken together, while comparative viral studies provide valuable insight, the prolonged RNAi treatment required for robust protein depletion significantly affects cell morphology and growth. These secondary effects may well complicate functional analyses of essential regulatory RBPs, raising the possibility that observed differences in viral transcription and replication result from secondary effects of RNAi rather than direct involvement of the proteins of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,684,660,700]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Generation of AID-tagged cell lines and validation of RBP depletion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,702,882,890]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To more precisely assess the direct consequences of specific RBP depletion on viral transcription, we utilized an auxin-inducible degron (AID) system. In HCT116 cells stably expressing the F-box protein AtAFB2 (HCT116 AFB2 cells), we endogenously tagged SFPQ and SUPT5H with a miniAA7 tag (AID-tag) (Figure 2A). Upon addition of indole-3-acetic acid (auxin), this tag allows for the recruitment of the exogenously expressed plant AtAFB2 receptor that interacts with cellular components of an E3-ubiquitin ligase complex. As a result, the tagged protein undergoes polyubiquitinylation and is rapidly degraded by the proteasome. To validate the depletion of SUPT5H and SFPQ, we treated AID-degron tagged HCT116 AFB2 cells with auxin and monitored protein levels over a 24 h time course by Western blot analysis. We observed a significant reduction in SUPT5H and SFPQ protein levels within 2 h and 4 h after the addition of auxin, respectively confirming the functionality of our genome-edited HCT116 AFB2 cells (Figure 2B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[114,85,880,118]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In summary, by using the AID system, we achieved rapid and robust depletion of SUPT5H and SFPQ within 4 h, providing a considerably faster alternative to RNAi knockdowns. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,129,821,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Reduction of early viral transcription in SFPQ-degron cells depends on the timespan of depletion of infection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,167,882,287]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine whether RBP depletion using the AID system affects early viral transcription, we infected cells 4h (SUPT5H and SFPQ) or 22h (SFPQ) after auxin addition (Figure 3A). At 2 and 4 hpi, we extracted total RNA from the cells, and quantified viral transcription by RT-qPCR of the early gene UL54. For SUPT5H, depletion of the protein for 4h prior to the infection resulted in a strong reduction of vRNA at both 2 hpi and 4 hpi (Figure 3B). This can be expected since SUPT5H is a component of the RNAPII machinery. Alternatively, the deletion of SUPT5H had been reported to destabilize a core component of RNAPII, namely $\\text{RPB1}^{58}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,297,884,483]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In contrast, SFPQ depletion for 4h before infection decreased vRNA levels by about $60\\%$ at 2hpi. However, at 4hpi viral transcription had recovered, showing no difference from untreated cells (Figure 3C). Interestingly, when SFPQ was depleted for 22 hours before infection, the reduction in vRNA effect at 2hpi was more pronounced compared to the shorter depletion, and was also persistent at 4hpi (Figure 3C). This suggests that prolonged depletion of SFPQ might lead to secondary effects such as disintegration of paraspeckles since SFPQ is critical for the structural integrity of these subnuclear bodies<sup>59</sup>. Thus, the observed reduction in viral transcription might stem from broader nuclear structural alterations rather than a direct role of SFPQ in viral transcription or RNA processing. The findings highlight the advantage of the AID system in distinguishing primary effects of RBPs depletion from secondary consequences, enabling a more precise dissection of host factors involved in viral transcription. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,495,865,531]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The transcription elongation factor SUPT5H, but not SFPQ, co-localizes with HSV-1 genomes in early infection ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,533,882,670]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Given that both, SUPT5H and SFPQ, affect viral mRNA levels, we sought to determine whether they act directly on viral genomes to regulate transcription or modulate HSV-1 gene expression through alternative mechanisms. Since protein co-localization with DNA is a strong indicator of transcription-regulated functions, we investigated whether SUPT5H and SFPQ are in close-proximity to viral genomes. To this end, SUPT5H- and SFPQ-degron cells were infected with HSV-1 either containing EdC-labeled or unlabeled (DMSO control) genomes. At 3 hpi, cells were fixed and stained with a V5-specific antibody to detect SFPQ or SUPT5H, while viral DNA was fluorescently labeled using click-chemistry. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,680,880,800]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We observed distinct SUPT5H foci at sites of fluorescently labeled HSV-1 genomes, which were absent upon SUPT5H depletion (Figure 2A and Supplementary Figure 2A), indicating its accumulation at viral DNA. In contrast, SFPQ did not show increased signal intensities at HSV-1 genomic sites (Figure 2B). To confirm our visional impression, we quantified the relative number of viral DNA foci at locations of protein enriched foci. Indeed, $89\\%$ $(\\mathrm{SD} = 1,45\\%)$ of vDVA foci occurred at spots with accumulated SUPT5H signal, whereas the relative number of SFPQ and vDNA co-localization were markedly lower $(16\\%; \\mathrm{SD} = 13,3\\%)$ (Supplementary Figure 3). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,810,880,878]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"While the association of SUPT5H with viral DNA aligns with the dependence of HSV-1 on the host transcriptional machinery and the role of SUPT5H as a transcription elongation factor, we found no evidence of SFPQ co-localization with HSV-1 genomes. Thus, SFPQ likely influences viral gene expression through a mechanism independent of direct interaction with viral DNA. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,87,213,101]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,105,882,310]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In this study, we initially focused on 5 RNA-interacting proteins (FUBP1, SLBP, SFPQ, SUPT5H and SAFB) that reside in the nucleus. Although their involvement in host transcriptional regulation has been reported already, mechanistic insights are still elusive or their contribution to viral transcription is largely unknown. We conducted protein depletion experiments and measured the expression of the immediate-early gene UL54 in order to examine the consequences for HSV-1 transcription. Of our 5 candidates, siRNA-mediated knockdown of SUPT5H or SFPQ resulted in the most pronounced decrease of UL54 mRNA. To gain a better understanding if these RNA interacting proteins are exclusively important for HSV-1 gene expression or have broader implications for the replication of dsDNA viruses, we extended our experiment to adenovirus C5. We observed that the knockdown of SUPT5H drastically reduces the growth of adenovirus C5. In contrast, depletion of SFPQ did not result in prominent changes, which confirms a previous finding that knockdown of SFPQ using RNAi does not affect adenovirus titer $^{51}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,321,884,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"SUPT5H positively regulates several events during RNAPII-mediated transcription beginning with promoter-proximal pause release and followed by elongation and termination $^{58,60}$ . Due to SUPT5Hs central role in global host transcription, we anticipated severe consequences for viral gene expression upon its depletion, which holds true. Our results thus suggest that SUPT5H is not only required for the host but also for HSV-1 and adenovirus C5 transcription, which is further in line with our evidence showing its co-localization with HSV-1 genomes. It has been reported that depletion of SUPT5H results in the degradation of RPB1, a core subunit of RNAPII, which could mechanistically explain our results $^{58}$ . The degradation happens during early elongation and is controlled by $\\mathrm{CDK9}^{58}$ . Similar to a previous study, inhibition of CDK9 and subsequent induction of SUPT5H depletion at the start of infection could allow us to analyze SUPT5H's importance for elongation and termination of viral genes without being stopped by RPB1 degradation $^{58}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,520,882,656]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In contrast to SUPT5H, SFPQ was not found in co-localization with HSV-1 genomes in our study, indicating a function that is not exerted on viral DNA during early times of infection. SFPQ is pivotal for the formation of paraspeckles, nuclear entities consisting of NEAT1_2 IncRNA, PSC1, NONO, and SFPQ, which were shown to be induced upon different cellular stress including HSV-1 infection $^{52,59,61-63}$ . Despite RNA processing, nuclear retention of RNAs and transcriptional regulation have all been attributed to paraspeckle formation, their precise function especially during infection is not fully understood $^{28,64,65}$ . Considering that depletion of SFPQ disintegrates paraspeckles, it might affect HSV-1 transcription even though the underlying mechanism needs to be clarified $^{59}$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,658,882,778]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"On the other hand, SFPQ acts as a transcriptional repressor that is relieved during infection, likely redistributes to paraspeckles and thereby allows expression of genes involved in the immune response, as it was described already for IL8 and $\\mathsf{RELA}^{52,66}$ . This mechanism could establish an antiviral state of cells that are being primed before the HSV-1 infection even started and could in part explain why cells that had been subjected to siRNA-mediated knockdown for multiple days or auxin-inducible degradation of SFPQ over an extended timespan (22 h) showed a stronger decrease in UL54 RNA levels compared to a faster depletion strategy (4 h). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[114,778,882,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Furthermore, this observation exemplifies the advantage of the AID system over RNAi. Due to relatively long half-lives of proteins, RNAi experiments often suffer from long incubation periods of siRNA-transfected cells in order to achieve target depletion. In addition, studies on the function of essential genes by deletion or RNAi are inherently restricted by the loss of cell viability. As demonstrated in our approach for SFPQ, the duration of protein depletion matters since it influences the observed effect size. While secondary effects of protein depletion can never be fully ruled out, the AID system minimizes the period of time for these effects to occur. Owing to its temporal flexibility, it ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[114,85,880,154]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"further helps to dissect immediate and belated consequences of protein depletion. Currently, only a few studies in the field of virology take advantage of auxin-inducible degradation. However, we are convinced by its potential to foster our understanding of how RNA-interacting proteins and other essential host factors contribute to viral transcription and replication. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[115,158,282,174]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Acknowledgments ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[114,177,882,262]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"We thank Ouidad Benlasfer and Nouhad Benlasfer for technical assistance, as well as members of the Landthaler lab for discussions and comments. This work was supported by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) in the framework of the Research Unit FOR5200 DEEP-DV (443644894) project BO 4158/5-1, SCHR 1479/5-1 and LA 2941/18-1 to J.B., S.S. and M.L., respectively. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[100,4,885,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[117,86,218,101]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[115,105,873,897]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: overview on relevant clinicopathological features. J Oral Pathol Med. 2008;37(2):107-121. doi:10.1111/J.1600-0714.2007.00586.X \",\"2. Quinn JP, Dalziel RG, Nash AA. Herpes virus latency in sensory ganglia - A comparison with endogenous neuronal gene expression. Prog Neurobiol. 2000;60(2):167-179. doi:10.1016/S0301-0082(99)00024-6 \",\"3. Looker KJ, Magaret AS, May MT, et al. 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","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,84,873,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"15. Watson RJ, Clements JB. A herpes simplex virus type 1 function continuously required for early and late virus RNA synthesis. Nature. 1980;285(5763):329-330. doi:10.1038/285329a0 \",\"16. Dixon RA, Schaffer PA. Fine-structure mapping and functional analysis of temperature-sensitive mutants in the gene encoding the herpes simplex virus type 1 immediate early protein VP175. J Virol. 1980;36(1):189-203. doi:10.1128/jvi.36.1.189-203.1980 \",\"17. Natarajan M, Schiralli Lester GM, Lee C, et al. Negative elongation factor (NELF) coordinates RNA polymerase II pausing, premature termination, and chromatin remodeling to regulate HIV transcription. J Biol Chem. 2013;288(36):25995-26003. doi:10.1074/JBC.M113.496489 \",\"18. Lester JT, DeLuca NA. Herpes simplex virus 1 ICP4 forms complexes with TFIID and mediator in virus-infected cells. J Virol. 2011;85(12):5733-5744. doi:10.1128/JVI.00385-11 \",\"19. Wagner LM, DeLuca NA. Temporal association of herpes simplex virus ICP4 with cellular complexes functioning at multiple steps in PolII transcription. PLoS One. 2013;8(10):e78242. doi:10.1371/JOURNAL.PONE.0078242 \",\"20. Smith S, Reuven N, Mohni KN, Schumacher AJ, Weller SK. Structure of the Herpes Simplex Virus 1 Genome: Manipulation of Nicks and Gaps Can Abrogate Infectivity and Alter the Cellular DNA Damage Response. J Virol. 2014;88(17):10146-10156. doi:10.1128/JVI.01723-14 \",\"21. Garcia-Moreno M, Järvelin AI, Castello A. Unconventional RNA-binding proteins step into the virus-host battlefront. Wiley Interdiscip Rev RNA. 2018;9(6). doi:10.1002/wrna.1498 \",\"22. Girardi E, Pfeffer S, Baumert TF, Majzoub K. Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell. Semin Cell Dev Biol. 2021;111:86-100. doi:10.1016/j.semcdb.2020.08.006 \",\"23. Hentze MW, Castello A, Schwarzl T, Preiss T. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol. 2018;19(5):327-341. doi:10.1038/nrm.2017.130 \",\"24. Eidem TM, Kugel JF, Goodrich JA. Noncoding RNAs: Regulators of the Mammalian Transcription Machinery. J Mol Biol. 2016;428(12):2652-2659. doi:10.1016/J.JMB.2016.02.019 \",\"25. Li S, Prasanna X, Salo VT, Vattulainen I, Ikonen E. An efficient auxin-inducible degron system with low basal degradation in human cells. Nat Methods. 2019;16(9):866-869. doi:10.1038/s41592-019-0512-x \",\"26. Patton JG, Mayer SA, Tempst P, Nadal-Ginard B. Characterization and molecular cloning of polypyrimidine tract-binding protein: a component of a complex necessary for pre-mRNA splicing. Genes Dev. 1991;5(7):1237-1251. doi:10.1101/GAD.5.7.1237 \",\"27. Yarosh CA, Iacona JR, Lutz CS, Lynch KW. PSF: nuclear busy-body or nuclear facilitator? Wiley Interdiscip Rev RNA. 2015;6(4):351-367. doi:10.1002/wRNA.1280 \",\"28. Prasanth K V., Prasanth SG, Xuan Z, et al. Regulating gene expression through RNA nuclear retention. Cell. 2005;123(2):249-263. doi:10.1016/J.CELL.2005.08.033 \",\"29. Bond CS, Fox AH. Paraspeckles: nuclear bodies built on long noncoding RNA. J Cell Biol. 2009;186(5):637-644. doi:10.1083/JCB.200906113 \",\"30. Hoeben RC, Uil TG. Adenovirus DNA replication. Cold Spring Harb Perspect Biol. 2013;5(3):a013003. doi:10.1101/CSHPERSPECT.A013003 \",\"31. Boehm V, Wallmeroth D, Wulf PO, et al. Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated transcriptome in human cells. bioRxiv. Published online \"]","page_idx":"11","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"11","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,84,873,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"March 8, 2024. doi:10.1101/2024.03.04.583328 \",\"32. Sandbaumhüter M, Döhner K, Schipke J, et al. Cytosolic herpes simplex virus capsids not only require binding inner tegument protein pUL36 but also pUL37 for active transport prior to secondary envelopment. Cell Microbiol. 2013;15(2):248-269. doi:10.1111/CMI.12075 \",\"33. Döhner K, Ramos-Nascimento A, Bialy D, et al. Importin α1 is required for nuclear import of herpes simplex virus proteins and capsid assembly in fibroblasts and neurons. PLoS Pathog. 2018;14(1):e1006823. doi:10.1371/JOURNAL.PPAT.1006823 \",\"34. Hofmann S, Mai J, Masser S, et al. ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity. Adv Sci (Weinheim, Baden-Wurttemberg, Ger. 2020;7(8):1902130. doi:10.1002/ADVS.201902130 \",\"35. Reich NC, Sarnow P, Duprey E, Levine AJ. Monoclonal antibodies which recognize native and denatured forms of the adenovirus DNA-binding protein. Virology. 1983;128(2):480-484. doi:10.1016/0042-6822(83)90274-X \",\"36. Wyler E, Menegatti J, Franke V, et al. Widespread activation of antisense transcription of the host genome during herpes simplex virus 1 infection. Genome Biol. 2017;18(1):209. doi:10.1186/S13059-017-1329-5/TABLES/2 \",\"37. Griffiths SJ, Koegl M, Boutell C, et al. A systematic analysis of host factors reveals a Med23-interferon- $\\\\lambda$ regulatory axis against herpes simplex virus type 1 replication. PLoS Pathog. 2013;9(8). doi:10.1371/JOURNAL.PPAT.1003514 \",\"38. Liu J, Akoulitchev S, Weber A, et al. Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. Cell. 2001;104(3):353-363. doi:10.1016/S0092-8674(01)00223-9 \",\"39. Petrenko N, Jin Y, Dong L, Wong KH, Struhl K. Requirements for RNA polymerase II preinitiation complex formation in vivo. Elife. 2019;8:e43654. doi:10.7554/ELIFE.43654 \",\"40. Frost JR, Mendez M, Soriano AM, et al. Adenovirus 5 E1A-Mediated Suppression of p53 via FUBP1. J Virol. 2018;92(14):e00439-18. doi:10.1128/JVI.00439-18 \",\"41. Oh J, Fraser NW. Temporal association of the herpes simplex virus genome with histone proteins during a lytic infection. *J Virol.* 2008;82(7):3530-3537. doi:10.1128/JVI.00586-07 \",\"42. Pignatti PF, Cassai E. Analysis of herpes simplex virus nucleoprotein complexes extracted from infected cells. J Virol. 1980;36(3):816-828. doi:10.1128/JVI.36.3.816-828.1980 \",\"43. Kent JR, Zeng P-Y, Atanasiu D, Gardner J, Fraser NW, Berger SL. During lytic infection herpes simplex virus type 1 is associated with histones bearing modifications that correlate with active transcription. J Virol. 2004;78(18):10178-10186. doi:10.1128/JVI.78.18.10178-10186.2004 \",\"44. Hu MY, Depledge DP, Cortes EF, Breuer J, Schang LM. Chromatin dynamics and the transcriptional competence of HSV-1 genomes during lytic infections. PLoS Pathog. 2019;15(11):e1008076. doi:10.1371/JOURNAL.PPAT.1008076 \",\"45. Wang ZF, Whitfield ML, Ingledue TC, Dominski Z, Marzluff WF. The protein that binds the $3^{\\\\prime}$ end of histone mRNA: a novel RNA-binding protein required for histone pre-mRNA processing. Genes Dev. 1996;10(23):3028-3040. doi:10.1101/GAD.10.23.3028 \",\"46. Sullivan KD, Mullen TE, Marzluff WF, Wagner EJ. Knockdown of SLBP results in nuclear retention of histone mRNA. RNA. 2009;15(3):459-472. doi:10.1261/RNA.1205409 \",\"47. Flather D, Nguyen JHC, Semler BL, Gershon PD. Exploitation of nuclear functions by human \"]","page_idx":"12","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,84,867,913]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"rhinovirus, a cytoplasmic RNA virus. PLoS Pathog. 2018;14(8). doi:10.1371/JOURNAL.PPAT.1007277 \",\"48. Zhou B, Wu F, Han J, Qi F, Ni T, Qian F. Exploitation of nuclear protein SFPQ by the encephalomyocarditis virus to facilitate its replication. Biochem Biophys Res Commun. 2019;510(1):65-71. doi:10.1016/J.BBRC.2019.01.032 \",\"49. Murray-Nerger LA, Lozano C, Burton EM, et al. The nucleic acid binding protein SFPQ represses EBV lytic reactivation by promoting histone H1 expression. Nat Commun. 2024;15(1). doi:10.1038/S41467-024-48333-X \",\"50. Labeau A, Fery-Simonian L, Lefevre-Utile A, et al. Characterization and functional interrogation of the SARS-CoV-2 RNA interactome. Cell Rep. 2022;39(4). doi:10.1016/J.CELREP.2022.110744 \",\"51. Landeras-Bueno S, Jorba N, Pérez-Cidoncha M, Ortín J. The splicing factor proline-glutamine rich (SFPQ/PSF) is involved in influenza virus transcription. PLoS Pathog. 2011;7(11). doi:10.1371/JOURNAL.PPAT.1002397 \",\"52. Imamura K, Imamachi N, Akizuki G, et al. Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli. Mol Cell. 2014;53(3):393-406. doi:10.1016/J.MOLCEL.2014.01.009 \",\"53. Mathur M, Tucker PW, Samuels HH. PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors. Mol Cell Biol. 2001;21(7):2298-2311. doi:10.1128/MCB.21.7.2298-2311.2001 \",\"54. Li K, Wang Z. Speckles and paraspeckles coordinate to regulate HSV-1 genes transcription. Commun Biol. 2021;4(1):1207. doi:10.1038/S42003-021-02742-6 \",\"55. Aoi Y, Shilatifard A. Transcriptional elongation control in developmental gene expression, aging, and disease. Mol Cell. 2023;83(22):3972-3999. doi:10.1016/J.MOLCEL.2023.10.004 \",\"56. Deng N, Zhang Y, Ma Z, et al. DSIF modulates RNA polymerase II occupancy according to template G + C content. NAR genomics Bioinforma. 2022;4(3). doi:10.1093/NARGAB/LQAC054 \",\"57. Nayler O, Strätling W, Bourquin JP, et al. SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements. *Nucleic Acids Res.* 1998;26(15):3542-3549. doi:10.1093/NAR/26.15.3542 \",\"58. Aoi Y, Takahashi Y hei, Shah AP, et al. SPT5 stabilization of promoter-proximal RNA polymerase II. Mol Cell. 2021;81(21):4413-4424.e5. doi:10.1016/J.MOLCEL.2021.08.006 \",\"59. Sasaki YTF, Ideue T, Sano M, Mituyama T, Hirose T. MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc Natl Acad Sci U S A. 2009;106(8):2525-2530. doi:10.1073/PNAS.0807899106 \",\"60. Hu S, Peng L, Xu C, Wang Z, Song A, Chen FX. SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape. Mol Cell. 2021;81(21):4425-4439.e6. doi:10.1016/J.MOLCEL.2021.08.029 \",\"61. Choudhry H, Albukhari A, Morotti M, et al. Tumor hypoxia induces nuclear paraspeckle formation through HIF-2 $\\\\alpha$ dependent transcriptional activation of NEAT1 leading to cancer cell survival. Oncogene. 2015;34(34):4482-4490. doi:10.1038/ONC.2014.378 \",\"62. Mohammad Lellahi S, Rosenlund IA, Hedberg A, et al. The long noncoding RNA NEAT1 and nuclear paraspeckles are up-regulated by the transcription factor HSF1 in the heat shock \"]","page_idx":"13","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"13","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[115,84,875,330]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"response. J Biol Chem. 2018;293(49):18965-18976. doi:10.1074/JBC.RA118.004473 \",\"63. Yucel-Polat A, Campos-Melo D, Alikhah A, Strong MJ. Dynamic Localization of Paraspeckle Components under Osmotic Stress. Non-coding RNA. 2024;10(2):23. doi:10.3390/NCRNA10020023/S1 \",\"64. Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N, Hirose T. Alternative $3^{\\\\prime}$ -end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 2012;31(20):4020-4034. doi:10.1038/EMBOJ.2012.251/SUPPL_FILE/EMBJ2012251.REVIEWER_COMMENTS.PDF \",\"65. Wang Z, Li K, Huang W. Long non-coding RNA NEAT1-centric gene regulation. Cell Mol Life Sci. 2020;77(19):3769-3779. doi:10.1007/S00018-020-03503-0/METRICS \",\"66. Zhou B, Qi F, Wu F, et al. Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression. MBio. 2019;10(4). doi:10.1128/MBIO.00937-19 \"]","page_idx":"14","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[100,4,885,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"14","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,65,381,256]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0173/45a1736592c2a7ee8c26ab42218b13c22182ee3c6df158244241cc95326d45c9.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[386,65,761,263]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0036/729a49e37090cc031a97635d7bb6bcb0cf000d6062cc0104645bf59eef963ddd.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[764,65,905,271]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0571/8c431d0d083aa01589b7b411cbd77f7ba0720f99bea07481df064f23a90db168.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[87,268,381,507]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0089/1119d97779a4f4e6fba1a58058a4b4378b1d5754d5fee58888486b8542ed93ac.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[384,268,665,506]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0435/073f4ce4272da219a3bd165fa8f551d619dc821484c3c60c38783750b67088e9.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[670,271,907,458]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1: RNA interference to study influence of RNA binding proteins on herpes simplex virus 1 and adenovirus C5 infection. A, HCT116 cells were transfected with the indicated siRNAs. At $72\\\\mathrm{h}$ post transfection, cells were infected with an MOI of 0.5. Further $2\\\\mathrm{h}$ later, intracellular RNA was collected, and viral RNA (UL54 transcript) quantified by RT-qPCR. B, as in A, but for intracellular viral DNA quantified by qPCR. C, phase contrast microscopy of the cells used for Fig. 1A at $72\\\\mathrm{h}$ after transfection of the indicated siRNA. D, for the same experiment as in C, the barplot shows for each treatment indicated on the left, relative to siCtrl, the number of seeded cells (upper, brighter bar) and cell count $72\\\\mathrm{h}$ after RNAi (lower, darker bar). E, A549 cells were transfected with the indicated siRNAs. At 48 hpost transfection, cells were infected with 0.5 MOI GFP-expressing adenovirus C5, and again 24 hlater GFP signal from the virus was quantified. Shown are median and standard deviation from three measurements. F, representative microscopy images for, from top siCtrl/not infected, siCtrl/infected, siSUPT5H/infected. \"]","image_footnote":"[]","img_path":"images/0431/752ff2674ac356a459dbc7fa0bddde57ef6eb7b879c21aa7fd6dd479ff10fe8d.jpg","list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"15","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[117,108,450,186]","code_body":null,"code_caption":null,"image_caption":"[\"A \"]","image_footnote":"[]","img_path":"images/0904/f986af0e9d8720a8aabef1c85560409c3d65306027954e1bf60b1e6493a91393.jpg","list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[460,101,880,197]","code_body":null,"code_caption":null,"image_caption":"[\"B \",\"Figure 2: Auxin-inducible degradation of SFPQ and SUPT5H. A, host RNA-interacting proteins SFPQ and SUPT5H were tagged at N- (grey) or C-terminus (blue) with a Glycine/Serine-linker, a minilAA7 degron, and a V5-tag. Schemes of the modified proteins are depicted. Created in BioRender. Landthaler, M. (2025) https://BioRender.com/w18y704 B, HCT116 AFB2 cells with minilAA7 (AID)-tagged proteins were treated with $500~\\\\mu \\\\mathrm{M}$ indole-3-acetic acid (auxin) or left untreated (untr.). At indicated times after treatment, cells were lysed and a Western blot analysis was performed with 20 $\\\\mu \\\\mathrm{g}$ of each protein sample loaded per lane. Blots were probed with protein-specific antibodies indicated on the right. \"]","image_footnote":"[]","img_path":"images/0088/2c653dc8be45ffa5329e2cc6d711a22288eec50ee03907ea177bdba27840a851.jpg","list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"16","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[90,65,823,206]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0506/a91175559d7519e71bbf03d140957131f5ac33b0af40b25e644cc21dea31ed2c.jpg","list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[90,210,297,429]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0759/dd76045cd44c49b81016d599f5217b5461081c33cf7e7dd8c70715000775925f.jpg","list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[309,210,594,429]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 3: Early HSV-1 transcription is reduced following SUPT5H/SFPQ depletion. A, schematic overview of the experiments. For SUPT5H, auxin was added $4\\\\mathrm{~h}$ before infection, for SFPQ either 4 or $22\\\\mathrm{~h}$ before. At 2 and 4 hpi, RNA was harvested for RT-qPCR. B, viral RNA (UL54) was quantified using RT-qPCR from the experiment with SUPT5H depletion. C, as for B, but from the experiment with SFPQ depletion. \"]","image_footnote":"[]","img_path":"images/0441/7d70ce4596d42f7f8cfde309c9374b94e6de036256b0da8ec7115067ccb0f15e.jpg","list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"17","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[119,89,867,381]","code_body":null,"code_caption":null,"image_caption":"[\"A \"]","image_footnote":"[]","img_path":"images/0054/2fe10c4fc148830e9fe34954784e1da35b38c0be31950b756ecf04b3044f12c9.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[119,395,867,681]","code_body":null,"code_caption":null,"image_caption":"[\"B \",\"Figure 4: SUPT5H co-localizes with viral genomes early in HSV-1 infection. A, SUPT5H-degron cells were either infected with HSV-1 carrying unlabeled (DMSO) or EdC-labeled DNA. At 3 hpi, all cells were fixed, their nuclei were stained with Hoechst, viral DNA was fluorescently stained by a click reaction, SUPT5H was immunostained with a V5-antibody and images were taken. Arrows indicate a signal of viral DNA. B, as in A, but for SFPQ-degron cells. \"]","image_footnote":"[]","img_path":"images/0733/a1e36da1d8b7a3b50765f24e6bee7160cb5ea23e2a676f76a2c40b2bfd24534f.jpg","list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[100,4,887,36]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"18","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. ","text_format":null,"text_level":null,"type":"header"}],"string":"[\n {\n \"bbox\": \"[115,86,838,131]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Dissecting the role of RNA-binding proteins in early herpes simplex virus 1 transcription using acute protein depletion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,148,880,181]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Niclas Barke $^{1,2}$ , Sawinee Masser $^{3}$ , Doerte Stalling $^{4,5,6,7}$ , Emanuel Wyler $^{1}$ , Robert Patrick Zinzen $^{1}$ , Sabrina Schreiner $^{3,4,6}$ , Jens Bosse $^{4,5,6,7}$ , Markus Landthaler $^{1,2*}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[144,195,878,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany \\\",\\\"2. Institut für Biologie, Humboldt-Universität zu Berlin, Berlin, Germany \\\",\\\"3. Institute of Virology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany \\\",\\\"4. Hannover Medical School, Institute of Virology, Hannover, Germany \\\",\\\"5. Centre for Structural Systems Biology, Hamburg, Germany \\\",\\\"6. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany \\\",\\\"7. Leibniz Institute of Virology (LIV), Hamburg, Germany \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[115,355,564,370]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"*Corresponding author: markus.landthaler@mdc-berlin.de \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,409,194,425]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Abstract \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,428,880,478]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Herpes simplex virus 1 (HSV-1) infects about $50 - 80\\\\%$ of the entire human population and persists in the neurons of affected individuals. A fraction of affected individuals suffer from recurrent cold sores caused by reactivating virus, in rare but severe cases the virus can cause encephalitis. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,480,880,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"During lytic infection, the virus relies on host factors such as RNA polymerase II and accessory proteins involved in transcription to express its genes and ensure successful replication. In general, RNA molecules in cells are bound by RNA-binding proteins (RBPs) during their entire lifecycle. Importantly, RBPs are increasingly described to also regulate transcription, an aspect long time outside the scope of investigations, especially during viral infections. Here, we examined the impact of five nuclear proteins (FUBP1, SLBP, SFPQ, SPT5 and SAF-B) with known RNA-binding activities on HSV-1 transcription. Additionally, we evaluated their importance for human adenovirus C5 (HAdV) growth to assess whether these host factors are specific to HSV-1 infections or might have broader relevance for the general transcription of dsDNA viruses. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,634,880,702]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We show that the transcriptional elongation factor SPT5 coded by SUPT5H accumulates on HSV-1 genomes early during the infection and is required for the transcription of the immediate-early gene UL54. Its depletion affects also HAdV replication, indicating a general role in transcription of viruses that depend on the host transcriptional machinery. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,703,880,755]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In contrast, depletion of the transcriptional repressor and paraspeckle protein SFPQ reduces UL54 RNA levels in HSV-1 infection, but does not cause significant changes in HAdV growth. Since SFPQ does not co-localize with HSV-1 genomes, this suggests a function not directly associated to viral DNA. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,793,230,809]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,812,880,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Herpes simplex virus 1 (HSV-1) is transmitted between humans by direct contact and establishes lifelong latency in neurons of the trigeminal ganglia $^{1,2}$ . As of 2012, an estimated 3.7 billion people under the age of 49 were infected with HSV-1 worldwide $^{3}$ . While some individuals experience recurrent painful blisters and sores, typically at the lips following viral reactivation, HSV-1 can lead to severe complications such as keratitis, blindness and encephalitis $^{1,4,5}$ . Newborns, the elderly and \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,885,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[114,85,884,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"immunocompromised individuals are particularly vulnerable to these outcomes<sup>5</sup>. Furthermore, growing evidence suggests a contribution of HSV-1 infections and/or reactivations to the development and/or progression of neurodegenerative diseases, including Alzheimer's<sup>6-8</sup>. Current treatment options mainly rely on inhibitors and nucleoside analogs such as acyclovir, which are susceptible to viral resistance highlighting the urgent need for alternative drugs<sup>5,9</sup>. Despite ongoing research, an effective vaccine remains unavalable<sup>9</sup>. As a result, HSV-1 continues to pose a global health concern. Understanding and targeting the early stages of the infection may offer new opportunities to prevent and ultimately reduce this burden. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,231,884,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To initiate HSV-1 transcription mediated by the RNA polymerase II (Pol II), the tegument protein VP16 functions as an activator working together with the host transcription factors (TFs) HCF and Oct-1 to drive expression of the 5 immediate-early genes: RL2 (ICP0), RS1 (ICP4), US1 (ICP22), UL54 (ICP27) and US12 $(\\\\mathrm{ICP47})^{10 - 13}$ . Among these, ICP4 plays a crucial role in orchestrating the viral expression cascade by interacting with the general host transcription factors of mediator and components of the TFIID complex, to activate transcription of early and late genes $^{14 - 19}$ . It exemplifies that despite its relatively large genome of about 152 kbp, HSV-1 relies on the activity of several host factors to facilitate viral transcription and replication $^{20}$ . This includes host RNA-binding proteins (RBPs), that associate with viral RNA (vRNA) throughout the entire life cycle from nuclear transcription to translation in the cytoplasm $^{21,22}$ . While classical functions assigned to RBPs include mRNA splicing, modification, stability, localization, and translation, in recent years emerging evidence suggests that some RBPs also contribute to transcriptional regulation, a function that remains poorly understood in the context of viral infections $^{23,24}$ . While RBPs are crucial for various aspects of RNA metabolism, most virological studies have primarily focused on their involvement in innate immune recognition and decay of vRNAs, as well as their role during the intracellular transport, nuclear import/export and translation of vRNAs. Many RBPs are indispensable for cellular functions, making knockout approaches challenging. Since specific inhibitors are generally unavailable, depletion strategies often rely on CRISPR/Cas9 or RNA interference (RNAi). However, RNAi leads to a gradual decrease of protein levels over one to three days, increasing the risk of observing secondary effects such as reduced cell viability. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,569,884,843]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To address this issue and elucidate the role of RBPs in HSV-1 infection, we used an auxin-mediated protein degradation system $^{25}$ . This approach enables rapid depletion of target proteins within 2-6 hours by harnessing cellular E3-ubiquitin ligases and subsequent proteasomal degradation. Unlike RNAi, this method allows us to assess the direct, immediate impact of these proteins on the viral replication cycle, as the short depletion time reduces the possibility of secondary effects. We endogenously degron-tagged several RBPs involved in transcriptional regulation and previously identified by an RNAi screen to influence vRNA levels at early times of infection and vDNA replication $^{25}$ . Our findings indicate that the human transcription elongation factor SUPT5H, is associated with the vDNA at early times of infection and is likely essential for the transcription of HSV-1 genes. Furthermore, we demonstrate that the absence of SFPQ, a multifunctional protein involved in splicing and paraspeckle formation, leads to a reduction of vRNA levels but does not completely block transcription $^{26-29}$ . To facilitate comparative analysis, we also included adenovirus C5, another double-stranded DNA virus replicating in the nucleus in our study. Despite its genome being only a quarter to a third the size of HSV-1, they share a broadly similar replication strategy $^{30}$ . This comparative approach allows us to distinguish factors specific to HSV-1 from those with more general functions for dsDNA viruses replicating in the nucleus. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[115,86,317,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Material and Methods \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,108,394,124]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cell lines and culturing conditions \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,126,882,227]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HCT116 (ATCC, CCL-247) cells were cultured in McCoy's 5A (Modified) Medium (ThermoFisher) with 2 mM L-glutamine (ThermoFisher) and $9 - 10\\\\%$ fetal bovine serum (ThermoFisher). HaCaT cells for EdC-labeled virus stock production were kept in DMEM (high glucose) (Sigma-Aldrich) supplemented with GlutaMAX and $10\\\\%$ FBS. N- and C-termini of genes of interest were tagged with minilAA7(AID) in F-box protein AtAFB2 expressing HCT116 cells as described in Boehm et al. $^{31}$ . Used sgRNAs are listed in Table 1. Cells were maintained at $37^{\\\\circ}C$ and $5\\\\%$ CO2 in a humidified incubator. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,239,880,305]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A549 cells (ATCC, CCL-185) and HEK293 (ATCC, CRL-1573) were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with $5\\\\%$ fetal calf serum, $100\\\\mathrm{U}$ of penicillin, $100\\\\mu \\\\mathrm{g}$ of streptomycin per ml in a $5\\\\%$ CO2 atmosphere at $37^{\\\\circ}C$ . All cell lines are frequently tested for mycoplasma contamination. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,342,878,439]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0031/81325d887e5c532b5ab4befe4ca1039d76a48071b123bbf26fcb4d65080ba2a0.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>sgRNA pairs</td><td>sequence (5’->3’)</td></tr><tr><td>sgSUPT5H_Top_c2</td><td>CACCGCTTCATCCGACGAAGTCCAC</td></tr><tr><td>sgSUPT5H_Bot_c2</td><td>AAACGTGGACTTCGTCGGATGAAGC</td></tr><tr><td>sgSFPQ_Top_c2</td><td>CACCGTTCCGGAGTCGTGGCGGTGG</td></tr><tr><td>sgSFPQ_Bot_c2</td><td>AAACCCACCGCCACGACTCCGGAAC</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 1: List of sgRNAs used to AID-tag HCT116 cells by CRISPR/Cas9 genome editing \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,466,477,481]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Herpes simplex virus 1 stocks and infections \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,483,882,653]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HCT116 cells were infected with HSV1(17+) or HSV1(17+)Lox- $\\\\cdot_{\\\\mathsf{pMCMV}}$ GFP at a MOI of $0.04^{32,33}$ . 4 days post infection (dpi), the supernatant was harvested, transferred to 50 ml tubes and centrifuged at $3000\\\\times g$ and $4^{\\\\circ}C$ for 5 min to remove cell debris. Virus was enriched from the remaining supernatant by size excluding filtration using Centricon Plus-70 (Merck) with a threshold of 100 kDa. Beforehand, Centricons had been washed with $\\\\mathrm{H}_2\\\\mathrm{O}$ , disinfected with $70\\\\%$ ethanol and again washed with $\\\\mathrm{H}_2\\\\mathrm{O}$ . The corresponding centrifugation steps were carried out at $1000\\\\times g$ and $4^{\\\\circ}C$ for 15 min. 60 ml of virus-containing supernatant were transferred into single Centricons and subsequent centrifugation was performed at $1000\\\\times g$ and $4^{\\\\circ}C$ for 60 min. Enriched virus stocks were eluted in the provided concentrate recovery tubes by a 2 min centrifugation step at $1000\\\\times g$ and $4^{\\\\circ}C$ . Vital titers were determined by plaque assays on VeroE6 cells. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,665,413,681]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Adenovirus C5 stocks and infections \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,684,880,820]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A replication-competent HAdV-C5 delta E3 virus, encoding a CMV promoter-driven eGFP expression cassette, was further used in this study $^{34}$ . The virus was propagated and titrated in HEK293 cells. Virus titer was determined by immunofluorescence staining of the adenoviral DNA binding protein $\\\\mathrm{E2A}^{35}$ . A549 cells were infected with HAdV-C5 delta E3 virus at a MOI of 0.5 in non-supplemented DMEM. After incubation for $1\\\\text{h}$ at $37^{\\\\circ}\\\\mathrm{C}$ , the infection was stopped by replacing virus containing medium with fresh DMEM medium with supplements. Degron-tagged HCT116 cells were infected with HSV-1 strain 17 at a MOI of 0.5. After an incubation period of $30\\\\text{min}$ at $37^{\\\\circ}\\\\mathrm{C}$ and $5\\\\%$ $\\\\mathrm{CO}_{2}$ , medium was discarded and conditioned medium added. At defined times post infection, samples were harvested. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,833,260,847]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RNA interference \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,850,880,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"HCT116 or A549 cells were seeded out in a 12-well format at a density of $4 \\\\times 10^{4}$ or $3 \\\\times 10^{3}$ cells per well, respectively. Cells were transfected with respecting siRNAs using RNAiMAX (Thermo Fisher). In short, $671 \\\\mu l$ OptiMEM (Thermo Fisher) with $4.5 \\\\mu l$ siRNA ( $20 \\\\mu M$ ), and $648 \\\\mu l$ OptiMEM with $27 \\\\mu l$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[114,85,880,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RNAiMAX were prepared. The mixtures were combined and had been incubated for 10 min at room temperature. The final amount of siRNA per well was 8.34 pmol. Catalog numbers of siRNAs used in this study are listed in Table 2. 48 hours post transfection (hpt) supplemented media was added. The following day infections were performed. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,179,852,470]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0357/a9aabbe2de7db5e291cd8d4b9f0d23c395d021400da4703fd43da1d8b5e52181.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Catalog Number</td><td>Product Name</td></tr><tr><td>J-012286-05-0002</td><td>ON-TARGETplus Human SLBP (7884) siRNA - Individual, 2 nmol</td></tr><tr><td>J-011548-05-0002</td><td>ON-TARGETplus Human FUBP1 (8880) siRNA - Individual, 2 nmol</td></tr><tr><td>J-006455-06-0002</td><td>ON-TARGETplus Human SFPQ (6421) siRNA - Individual, 2 nmol</td></tr><tr><td>J-016234-05-0002</td><td>ON-TARGETplus Human SUPT5H (6829) siRNA - Individual, 2 nmol</td></tr><tr><td>J-005150-05-0002</td><td>ON-TARGETplus Human SAFB (6294) siRNA - Individual, 2 nmol</td></tr><tr><td>D-001810-01-05</td><td>ON-TARGETplus Non-targeting siRNA #1, 5 nmol</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 2: List of used siRNAs from Horizon Discovery/Dharmacon \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,498,273,512]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RNA/DNA isolation \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,516,873,633]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For isolation of cellular RNA and DNA, cells were thoroughly resuspended in $300\\\\mu \\\\mathrm{l}$ Trizol (ThermoFisher). If both RNA and DNA were extracted from Trizol, one third was processed using the DNA Trizol kit (Zymo). The remaining sample or otherwise the entire $300\\\\mu \\\\mathrm{l}$ were used as input for the Direct-zol RNA miniprep kit (Zymo) to digest DNA and extract RNA by following the manufacturer's instructions. RNA integrity was confirmed by running an RNA ScreenTape Analysis (Agilent Technologies) on a TapeStation and concentrations were determined by NanoDrop measurements. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,646,376,663]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reverse transcription and qPCR \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,665,882,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"500 ng of extracted RNA from each sample was reverse transcribed with the SuperScript™ III Reverse Transcriptase (ThermoFisher) according to the manufacturer's recommendations using RNaseOUT™ Recombinant RNase Inhibitor (ThermoFisher) and 100 ng random primers (ThermoFisher). The resulting cDNA was diluted 1:20 with DNA-/RNA-free water. Per qPCR reaction, $3.75\\\\mu l$ of the diluted cDNA were amplified using the GoTaq qPCR Kit (Promega) and $1\\\\mu M$ each of the previously described primers, shown in Table $3^{36}$ . For normalization purposes, raw UL54 RNA values were normalized using GAPDH, and raw UL54 DNA values using the BBC3as primer pair which targets the human genome. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[117,819,878,900]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0453/db1c702148aa2274d3d8fdc25967d6a27d955237752b48c5b7862f65de144b58.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>primer pairs</td><td>sequence (5’->3’)</td></tr><tr><td>GAPDH_fwd</td><td>AGCCACATCGCTCAGACAC</td></tr><tr><td>GAPDH_rev</td><td>GCCCAATACGACCAAATCC</td></tr><tr><td>BBC3as-2_fwd</td><td>GGACTCACACGGGACTGG</td></tr><tr><td>BBC3as-2_rev</td><td>CATCTCAGTGTTTGTGTGCAAG</td></tr><tr><td>UL54_fwd</td><td>AGACGCCTCGTCCGACGGA</td></tr><tr><td>UL54_rev</td><td>GAGGCGCGACCACACACTGT</td></tr></table>\",\n \"table_caption\": \"[\\\"Table 3 primers \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[117,82,878,135]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": \"[]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[115,162,589,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Preparation of virus stocks for co-localization experiments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,180,882,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To produce EdC-labeled viruses, HaCaT cells were seeded in $10 \\\\times 15$ cm dishes (Day 0). On the following day, cells were washed once with PBS and infected with HSV-1 strain 17 ( $1.2 \\\\times 10^{7}$ PFU/ml) at a MOI of 0.01, using 2 ml inoculum per dish. At 1 h post-infection (hpi), $1.5 \\\\mu \\\\mathrm{M}$ Ethynyl-dCTP (EdC) (ThermoFisher) was added to four plates per virus (in 18 ml medium per plate). Controls (one plate per virus) received an equivalent volume of DMSO. On Days 2 and 3, $1.5 \\\\mu \\\\mathrm{M}$ EdC or the equivalent amount of DMSO was added to the respective plates. On Day 4, virus-containing supernatants were harvested, and pre-cleared by centrifugation ( $500 \\\\times g$ , 5 min, $4^{\\\\circ} \\\\mathrm{C}$ ). Supernatants were filtered through a $0.45 \\\\mu \\\\mathrm{m}$ membrane, and concentrated by centrifugation ( $14.000 \\\\times g$ , 1.5 h, $4^{\\\\circ} \\\\mathrm{C}$ ) over a $5 \\\\%$ OptiPrep cushion. The virus pellet was resuspended in $500 \\\\mu \\\\mathrm{l}$ PBS. Viral titers were determined by performing plaque assays on Vero cells. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,362,294,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Western blot analysis \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,380,880,500]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For protein analysis, cells were resuspended in RIPA lysis buffer (50 mM Tris-HCl [pH 8,0], 150 mM NaCl, 5 mM EDTA, 1% [vol/vol] Nonident P-40, 0.1% [wt/vol] SDS, 0.5% [wt/vol] sodium deoxycholate) supplemented with a fresh protease inhibitor cocktail containing 0.2 mM PMSF, 1 mg/mL pepstatin A, 5 mg/mL aprotinin, and 20 mg/mL leupeptin. After 30 min incubation on ice, the lysates were sonicated and cell debris was pelleted at 14.800 g at $4^{\\\\circ}\\\\mathrm{C}$ for 3 min. Cell lysates were boiled for 3 min at $95^{\\\\circ}\\\\mathrm{C}$ in 5x Laemmli buffer. Proteins were separated by SDS-PAGE, transferred to nitrocellulose blotting membranes $(0.45\\\\mu \\\\mathrm{m})$ and visualized by immunoblotting. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,510,880,595]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Primary antibodies specific for HAdV proteins used in this study included mouse monoclonal antibody (Mab) mouse B6-8 (anti-E2A), MAb mouse AC-15 (anti- $\\\\beta$ -actin; Sigma-Aldrich) $^{35}$ . Primary antibodies specific for cellular expressed proteins included HNRNPU (abcam; Cat# ab10297), SAF-B (Santa Cruz Biotechnology; Cat# sc-135618), SFPQ (abcam; Cat# ab38148), SLBP (abcam; Cat# ab181972), SUPT5H (abcam; Cat# ab126592), FUBP1 (abcam; Cat# ab181111), GAPDH (Sigma-Aldrich; Cat# G8795). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,606,880,655]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Secondary antibodies conjugated to horseradish peroxidase (HRP) for detection of proteins by immunoblotting were anti-rabbit IgG, anti-mouse IgG, and anti-rat IgG (Jackson/Dianova or Dako) used in a dilution of 1:10.000. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,667,880,785]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Degron-tagged HCT116 cells subjected to RNA extraction and subsequent RT-qPCR were seeded at a density of $8 \\\\times 10^{6}$ cells per well in a 12-well plate. Before the infection, cells were treated with $500 \\\\mu \\\\mathrm{M}$ indole-3-acetic acid (IAA) (Sigma-Aldrich) for $4 \\\\mathrm{~h}$ or $22 \\\\mathrm{~h}$ to induce protein depletion or remained untreated, respectively. The infection was carried out with HSV1(17+)Lox- $\\\\mathsf{p} \\\\mathsf{M} \\\\mathsf{C} \\\\mathsf{M} \\\\mathsf{V}$ GFP at a MOI of 1. After an incubation period of $30 \\\\mathrm{~min}$ at $37^{\\\\circ} \\\\mathrm{C}$ and $5 \\\\%$ $\\\\mathrm{CO}_{2}$ , medium was discarded and conditioned medium added. At 2hpi and 4hpi, the medium was discarded and cells were lysed in $300 \\\\mu \\\\mathrm{l}$ Trizol (ThermoFisher). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,797,557,813]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Fixation of infected cells and fluorescence microscopy \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,816,880,902]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For the purpose of imaging, immunofluorescently labeled RBPs and HSV-1EdC-labeled genomes, parental HCT116 cells and degron-tagged cell lines were seeded at 50.000 cells per well in 8-well plates (ibidi). Cells were pretreated with $500~\\\\mu \\\\mathrm{M}$ IAA (Sigma-Aldrich;) 4 hours before infection to induce protein depletion where applicable. Cells were infected with HSV-1EdC or HSV-1DMSO at an MOI of 10. At 3 hpi, cells were washed with PBS and fixed with $4 \\\\%$ PFA for 15 minutes at room temperature \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[114,85,880,168]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"(RT). Following fixation, samples were washed three times with PBS, permeabilized with $0.1\\\\%$ Triton X-100 for 20 minutes, and blocked with $3\\\\%$ BSA for 15 minutes at RT. Following two additional PBS washes, the click chemistry reaction was performed with the Click-iT Plus Alexa Fluor 488 Picolyl Azide Toolkit according to the manufacturer's protocol (ThermoFisher). After the click reaction, cells were washed once in $3\\\\%$ BSA and twice with PBS. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,180,884,317]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Quantitative image analysis was performed in ImageJ Fiji (Schindelin et al., 2012) using the plugin Trackmate v7.13.2 (Ershov et al., 2022) to identify viral genomes, applying a detection threshold of 750. The median intensity of each protein was then measured. To establish protein-specific intensity thresholds, the median intensity was determined at three randomly selected nuclear positions. The threshold was set at 1,000 for SUPT5H and 2,500 for SFPQ, since SFPQ exhibited a higher baseline intensity. Colocalization events were defined as signals exceeding the respective thresholds, and the proportion of colocalized spots relative to DNA signals was calculated. A total of 95 and 118 genomes were analyzed for SUPT5H and SFPQ, respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,328,878,395]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For immunostaining, cells were incubated with an anti-V5 primary antibody (1:500) (Cell Signaling) for 1 hour at RT, washed three times with PBS, and incubated with a goat anti-rabbit secondary antibody (1:1000) (ThermoFisher). Nuclei were counterstained with Hoechst (1:1000) (ThermoFisher). Samples were imaged using a Spinning Disk microscope (Nikon). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,406,878,439]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To evaluate viral transcription/replication, the signal of GFP expressing HSV1 or HAdV was imaged and measured, respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,451,184,467]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,473,872,508]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"siRNA-mediated knockdown of RBPs involved in transcriptional regulation impairs HSV-1 and HAdV gene expression while reducing cell growth \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,510,878,558]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To investigate the impact of cellular RBPs on early HSV-1 transcription, we initially focused on five candidates with known nuclear localization. These five RBPs were selected based on previous reports, such as an HSV-1 siRNA knockdown screen.[37] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,562,880,663]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The first protein of interest, Far Upstream Element Binding Protein 1 (FUBP1), was mainly described as a transcriptional activator of c-myc expression, which in turn acts as a transcription factor for cell growth and proliferation $^{38}$ . Mechanistically, FUBP1 interacts with transcription factor II H (TFIIH), an essential component of pre-initiation complexes, to facilitate promoter escape of RNA polymerase II (RNAPII) by stimulating TFIIHs helicase activity $^{38,39}$ . While knockdown of FUBP1 was already described to reduce HAdV replication, its impact on HSV-1 replication is unknown $^{40}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,665,880,835]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"At the beginning of infection, HSV-1 genomes brought into the cell by virus particles are free from histones but quickly get chromatinized after their entry into the nucleus $^{41-43}$ . Similar to the host, viral transcription depends on epigenetic regulation allowing or restricting access of the transcriptional machinery to the genome. Whereas cellular genes are regulated individually due to different chromatin states, the epigenetic regulation of HSV-1 DNA occurs on a genome-wide level with transcription factors controlling the fine-tuned activation of separate viral genes $^{44}$ . Histone modifications on the entire HSV-1 genome could therefore determine globally silenced or permissive chromatin states and thus dictate whether cells undergo lytic or latent infection $^{44}$ . Since the Stem-Loop Histone mRNA Binding Protein (SLBP) is required for processing histone mRNAs, we wondered whether its depletion would affect viral transcription competence $^{45,46}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,837,880,888]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Another RBP of interest, Splicing Factor Proline And Glutamine Rich (SFPQ), is described to have multiple functions that depending on the virus under investigation can be pro- or antiviral $^{47-51}$ . Besides its role in alternative splicing, SFPQ acts as a transcriptional repressor and is a component of \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[114,85,880,117]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"paraspeckles, which are nuclear entities sequestering RNA molecules for RNA editing and are further involved in transcriptional regulation of HSV-1 genes $^{26,28,52-54}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,118,882,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Spt5, encoded by the SPT5 Homolog, DSIF Elongation Factor Subunit (SUPT5H) gene, is part of the DSIF (DRB-sensitivity inducing factor) complex that associates with RNA polymerase II and affects promoter-proximal pausing and elongation $^{55}$ . Moreover, SUPT5H was previously shown to be particularly important for the transcription of G+C-rich genes $^{56}$ . As those are highly prevalent in the HSV-1 genome, SUPT5H is likely relevant for viral transcription as well, possibly through an interaction with the viral protein Icp22. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,223,880,255]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, the Scaffold attachment factor B (SAFB) was described to link transcription to splicing and thus represents an interesting candidate to study in the context of viral infection $^{57}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,267,884,387]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To assess the role of these five RBPs in early viral transcription, we depleted their mRNAs in A549 cells and HCT116 cells using siRNAs for $72\\\\mathrm{h}$ , resulting in a strong reduction in protein levels (Supplementary Figure 1A). At this time point, we infected cells with 0.5 MOI of HSV-1, and quantified the immediate early transcript UL54 by RT-qPCR at 2 hpi (hours post infection) (Figure 1A). Depletion of SFPQ and SUPT5H resulted in a strong reduction in viral RNA levels, whereas the other three candidates showed no substantial effect. However, vDNA levels remained largely unchanged, indicating that viral entry and genome delivery were not impaired by the knockdowns (Figure 1B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,397,882,448]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Microscopic inspection of cells after $72\\\\mathrm{h}$ of RNAi revealed altered cell morphology in some conditions compared to the control siRNA treatment (Figure 1C). In addition, cell counts at seeding and harvesting indicated that knockdowns of SFPQ and SUPT5H considerably impaired cell growth (Figure 1D). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,458,882,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"For our comparative approach with human adenovirus C5 (HAdV C5), we carried out the RNAi experiment in A549 cells using a GFP-expressing adenovirus. Cells were infected $48\\\\mathrm{h}$ post siRNA transfection, and viral replication was assessed $24\\\\mathrm{h}$ later by counting GFP-positive cells (Supplementary Figure 1B). Similar to HSV-1, the knockdown of SUPT5H strongly impaired viral replication (Figure 5E+F). However, the knockdown of SFPQ did not produce a strong effect, suggesting that parallel experiments with different DNA viruses can help to distinguish general host factors essential for nuclear-replicating DNA viruses from those specific for HSV-1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,588,880,671]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Taken together, while comparative viral studies provide valuable insight, the prolonged RNAi treatment required for robust protein depletion significantly affects cell morphology and growth. These secondary effects may well complicate functional analyses of essential regulatory RBPs, raising the possibility that observed differences in viral transcription and replication result from secondary effects of RNAi rather than direct involvement of the proteins of interest. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,684,660,700]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Generation of AID-tagged cell lines and validation of RBP depletion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,702,882,890]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To more precisely assess the direct consequences of specific RBP depletion on viral transcription, we utilized an auxin-inducible degron (AID) system. In HCT116 cells stably expressing the F-box protein AtAFB2 (HCT116 AFB2 cells), we endogenously tagged SFPQ and SUPT5H with a miniAA7 tag (AID-tag) (Figure 2A). Upon addition of indole-3-acetic acid (auxin), this tag allows for the recruitment of the exogenously expressed plant AtAFB2 receptor that interacts with cellular components of an E3-ubiquitin ligase complex. As a result, the tagged protein undergoes polyubiquitinylation and is rapidly degraded by the proteasome. To validate the depletion of SUPT5H and SFPQ, we treated AID-degron tagged HCT116 AFB2 cells with auxin and monitored protein levels over a 24 h time course by Western blot analysis. We observed a significant reduction in SUPT5H and SFPQ protein levels within 2 h and 4 h after the addition of auxin, respectively confirming the functionality of our genome-edited HCT116 AFB2 cells (Figure 2B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[114,85,880,118]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In summary, by using the AID system, we achieved rapid and robust depletion of SUPT5H and SFPQ within 4 h, providing a considerably faster alternative to RNAi knockdowns. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,129,821,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Reduction of early viral transcription in SFPQ-degron cells depends on the timespan of depletion of infection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,167,882,287]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine whether RBP depletion using the AID system affects early viral transcription, we infected cells 4h (SUPT5H and SFPQ) or 22h (SFPQ) after auxin addition (Figure 3A). At 2 and 4 hpi, we extracted total RNA from the cells, and quantified viral transcription by RT-qPCR of the early gene UL54. For SUPT5H, depletion of the protein for 4h prior to the infection resulted in a strong reduction of vRNA at both 2 hpi and 4 hpi (Figure 3B). This can be expected since SUPT5H is a component of the RNAPII machinery. Alternatively, the deletion of SUPT5H had been reported to destabilize a core component of RNAPII, namely $\\\\text{RPB1}^{58}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,297,884,483]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In contrast, SFPQ depletion for 4h before infection decreased vRNA levels by about $60\\\\%$ at 2hpi. However, at 4hpi viral transcription had recovered, showing no difference from untreated cells (Figure 3C). Interestingly, when SFPQ was depleted for 22 hours before infection, the reduction in vRNA effect at 2hpi was more pronounced compared to the shorter depletion, and was also persistent at 4hpi (Figure 3C). This suggests that prolonged depletion of SFPQ might lead to secondary effects such as disintegration of paraspeckles since SFPQ is critical for the structural integrity of these subnuclear bodies<sup>59</sup>. Thus, the observed reduction in viral transcription might stem from broader nuclear structural alterations rather than a direct role of SFPQ in viral transcription or RNA processing. The findings highlight the advantage of the AID system in distinguishing primary effects of RBPs depletion from secondary consequences, enabling a more precise dissection of host factors involved in viral transcription. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,495,865,531]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The transcription elongation factor SUPT5H, but not SFPQ, co-localizes with HSV-1 genomes in early infection \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,533,882,670]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Given that both, SUPT5H and SFPQ, affect viral mRNA levels, we sought to determine whether they act directly on viral genomes to regulate transcription or modulate HSV-1 gene expression through alternative mechanisms. Since protein co-localization with DNA is a strong indicator of transcription-regulated functions, we investigated whether SUPT5H and SFPQ are in close-proximity to viral genomes. To this end, SUPT5H- and SFPQ-degron cells were infected with HSV-1 either containing EdC-labeled or unlabeled (DMSO control) genomes. At 3 hpi, cells were fixed and stained with a V5-specific antibody to detect SFPQ or SUPT5H, while viral DNA was fluorescently labeled using click-chemistry. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,680,880,800]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We observed distinct SUPT5H foci at sites of fluorescently labeled HSV-1 genomes, which were absent upon SUPT5H depletion (Figure 2A and Supplementary Figure 2A), indicating its accumulation at viral DNA. In contrast, SFPQ did not show increased signal intensities at HSV-1 genomic sites (Figure 2B). To confirm our visional impression, we quantified the relative number of viral DNA foci at locations of protein enriched foci. Indeed, $89\\\\%$ $(\\\\mathrm{SD} = 1,45\\\\%)$ of vDVA foci occurred at spots with accumulated SUPT5H signal, whereas the relative number of SFPQ and vDNA co-localization were markedly lower $(16\\\\%; \\\\mathrm{SD} = 13,3\\\\%)$ (Supplementary Figure 3). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,810,880,878]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"While the association of SUPT5H with viral DNA aligns with the dependence of HSV-1 on the host transcriptional machinery and the role of SUPT5H as a transcription elongation factor, we found no evidence of SFPQ co-localization with HSV-1 genomes. Thus, SFPQ likely influences viral gene expression through a mechanism independent of direct interaction with viral DNA. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[115,87,213,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,105,882,310]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In this study, we initially focused on 5 RNA-interacting proteins (FUBP1, SLBP, SFPQ, SUPT5H and SAFB) that reside in the nucleus. Although their involvement in host transcriptional regulation has been reported already, mechanistic insights are still elusive or their contribution to viral transcription is largely unknown. We conducted protein depletion experiments and measured the expression of the immediate-early gene UL54 in order to examine the consequences for HSV-1 transcription. Of our 5 candidates, siRNA-mediated knockdown of SUPT5H or SFPQ resulted in the most pronounced decrease of UL54 mRNA. To gain a better understanding if these RNA interacting proteins are exclusively important for HSV-1 gene expression or have broader implications for the replication of dsDNA viruses, we extended our experiment to adenovirus C5. We observed that the knockdown of SUPT5H drastically reduces the growth of adenovirus C5. In contrast, depletion of SFPQ did not result in prominent changes, which confirms a previous finding that knockdown of SFPQ using RNAi does not affect adenovirus titer $^{51}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,321,884,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"SUPT5H positively regulates several events during RNAPII-mediated transcription beginning with promoter-proximal pause release and followed by elongation and termination $^{58,60}$ . Due to SUPT5Hs central role in global host transcription, we anticipated severe consequences for viral gene expression upon its depletion, which holds true. Our results thus suggest that SUPT5H is not only required for the host but also for HSV-1 and adenovirus C5 transcription, which is further in line with our evidence showing its co-localization with HSV-1 genomes. It has been reported that depletion of SUPT5H results in the degradation of RPB1, a core subunit of RNAPII, which could mechanistically explain our results $^{58}$ . The degradation happens during early elongation and is controlled by $\\\\mathrm{CDK9}^{58}$ . Similar to a previous study, inhibition of CDK9 and subsequent induction of SUPT5H depletion at the start of infection could allow us to analyze SUPT5H's importance for elongation and termination of viral genes without being stopped by RPB1 degradation $^{58}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,520,882,656]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In contrast to SUPT5H, SFPQ was not found in co-localization with HSV-1 genomes in our study, indicating a function that is not exerted on viral DNA during early times of infection. SFPQ is pivotal for the formation of paraspeckles, nuclear entities consisting of NEAT1_2 IncRNA, PSC1, NONO, and SFPQ, which were shown to be induced upon different cellular stress including HSV-1 infection $^{52,59,61-63}$ . Despite RNA processing, nuclear retention of RNAs and transcriptional regulation have all been attributed to paraspeckle formation, their precise function especially during infection is not fully understood $^{28,64,65}$ . Considering that depletion of SFPQ disintegrates paraspeckles, it might affect HSV-1 transcription even though the underlying mechanism needs to be clarified $^{59}$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,658,882,778]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"On the other hand, SFPQ acts as a transcriptional repressor that is relieved during infection, likely redistributes to paraspeckles and thereby allows expression of genes involved in the immune response, as it was described already for IL8 and $\\\\mathsf{RELA}^{52,66}$ . This mechanism could establish an antiviral state of cells that are being primed before the HSV-1 infection even started and could in part explain why cells that had been subjected to siRNA-mediated knockdown for multiple days or auxin-inducible degradation of SFPQ over an extended timespan (22 h) showed a stronger decrease in UL54 RNA levels compared to a faster depletion strategy (4 h). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,778,882,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Furthermore, this observation exemplifies the advantage of the AID system over RNAi. Due to relatively long half-lives of proteins, RNAi experiments often suffer from long incubation periods of siRNA-transfected cells in order to achieve target depletion. In addition, studies on the function of essential genes by deletion or RNAi are inherently restricted by the loss of cell viability. As demonstrated in our approach for SFPQ, the duration of protein depletion matters since it influences the observed effect size. While secondary effects of protein depletion can never be fully ruled out, the AID system minimizes the period of time for these effects to occur. Owing to its temporal flexibility, it \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[114,85,880,154]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"further helps to dissect immediate and belated consequences of protein depletion. Currently, only a few studies in the field of virology take advantage of auxin-inducible degradation. However, we are convinced by its potential to foster our understanding of how RNA-interacting proteins and other essential host factors contribute to viral transcription and replication. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,158,282,174]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Acknowledgments \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[114,177,882,262]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"We thank Ouidad Benlasfer and Nouhad Benlasfer for technical assistance, as well as members of the Landthaler lab for discussions and comments. This work was supported by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) in the framework of the Research Unit FOR5200 DEEP-DV (443644894) project BO 4158/5-1, SCHR 1479/5-1 and LA 2941/18-1 to J.B., S.S. and M.L., respectively. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[100,4,885,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[117,86,218,101]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"10\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"References \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[115,105,873,897]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: overview on relevant clinicopathological features. J Oral Pathol Med. 2008;37(2):107-121. doi:10.1111/J.1600-0714.2007.00586.X \\\",\\\"2. Quinn JP, Dalziel RG, Nash AA. 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Published online \\\"]\",\n \"page_idx\": \"11\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"11\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 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Exploitation of nuclear functions by human \\\"]\",\n \"page_idx\": \"12\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"12\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[115,84,867,913]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"rhinovirus, a cytoplasmic RNA virus. PLoS Pathog. 2018;14(8). doi:10.1371/JOURNAL.PPAT.1007277 \\\",\\\"48. Zhou B, Wu F, Han J, Qi F, Ni T, Qian F. Exploitation of nuclear protein SFPQ by the encephalomyocarditis virus to facilitate its replication. Biochem Biophys Res Commun. 2019;510(1):65-71. doi:10.1016/J.BBRC.2019.01.032 \\\",\\\"49. Murray-Nerger LA, Lozano C, Burton EM, et al. The nucleic acid binding protein SFPQ represses EBV lytic reactivation by promoting histone H1 expression. Nat Commun. 2024;15(1). doi:10.1038/S41467-024-48333-X \\\",\\\"50. Labeau A, Fery-Simonian L, Lefevre-Utile A, et al. 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The long noncoding RNA NEAT1 and nuclear paraspeckles are up-regulated by the transcription factor HSF1 in the heat shock \\\"]\",\n \"page_idx\": \"13\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"13\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[115,84,875,330]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"response. J Biol Chem. 2018;293(49):18965-18976. doi:10.1074/JBC.RA118.004473 \\\",\\\"63. Yucel-Polat A, Campos-Melo D, Alikhah A, Strong MJ. Dynamic Localization of Paraspeckle Components under Osmotic Stress. Non-coding RNA. 2024;10(2):23. doi:10.3390/NCRNA10020023/S1 \\\",\\\"64. Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N, Hirose T. Alternative $3^{\\\\\\\\prime}$ -end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 2012;31(20):4020-4034. doi:10.1038/EMBOJ.2012.251/SUPPL_FILE/EMBJ2012251.REVIEWER_COMMENTS.PDF \\\",\\\"65. Wang Z, Li K, Huang W. Long non-coding RNA NEAT1-centric gene regulation. Cell Mol Life Sci. 2020;77(19):3769-3779. doi:10.1007/S00018-020-03503-0/METRICS \\\",\\\"66. Zhou B, Qi F, Wu F, et al. Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression. MBio. 2019;10(4). doi:10.1128/MBIO.00937-19 \\\"]\",\n \"page_idx\": \"14\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[100,4,885,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"14\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,65,381,256]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0173/45a1736592c2a7ee8c26ab42218b13c22182ee3c6df158244241cc95326d45c9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[386,65,761,263]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0036/729a49e37090cc031a97635d7bb6bcb0cf000d6062cc0104645bf59eef963ddd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[764,65,905,271]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0571/8c431d0d083aa01589b7b411cbd77f7ba0720f99bea07481df064f23a90db168.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[87,268,381,507]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0089/1119d97779a4f4e6fba1a58058a4b4378b1d5754d5fee58888486b8542ed93ac.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[384,268,665,506]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0435/073f4ce4272da219a3bd165fa8f551d619dc821484c3c60c38783750b67088e9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[670,271,907,458]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1: RNA interference to study influence of RNA binding proteins on herpes simplex virus 1 and adenovirus C5 infection. A, HCT116 cells were transfected with the indicated siRNAs. At $72\\\\\\\\mathrm{h}$ post transfection, cells were infected with an MOI of 0.5. Further $2\\\\\\\\mathrm{h}$ later, intracellular RNA was collected, and viral RNA (UL54 transcript) quantified by RT-qPCR. B, as in A, but for intracellular viral DNA quantified by qPCR. C, phase contrast microscopy of the cells used for Fig. 1A at $72\\\\\\\\mathrm{h}$ after transfection of the indicated siRNA. D, for the same experiment as in C, the barplot shows for each treatment indicated on the left, relative to siCtrl, the number of seeded cells (upper, brighter bar) and cell count $72\\\\\\\\mathrm{h}$ after RNAi (lower, darker bar). E, A549 cells were transfected with the indicated siRNAs. At 48 hpost transfection, cells were infected with 0.5 MOI GFP-expressing adenovirus C5, and again 24 hlater GFP signal from the virus was quantified. Shown are median and standard deviation from three measurements. F, representative microscopy images for, from top siCtrl/not infected, siCtrl/infected, siSUPT5H/infected. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0431/752ff2674ac356a459dbc7fa0bddde57ef6eb7b879c21aa7fd6dd479ff10fe8d.jpg\",\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"15\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[117,108,450,186]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"A \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0904/f986af0e9d8720a8aabef1c85560409c3d65306027954e1bf60b1e6493a91393.jpg\",\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[460,101,880,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"B \\\",\\\"Figure 2: Auxin-inducible degradation of SFPQ and SUPT5H. A, host RNA-interacting proteins SFPQ and SUPT5H were tagged at N- (grey) or C-terminus (blue) with a Glycine/Serine-linker, a minilAA7 degron, and a V5-tag. Schemes of the modified proteins are depicted. Created in BioRender. Landthaler, M. (2025) https://BioRender.com/w18y704 B, HCT116 AFB2 cells with minilAA7 (AID)-tagged proteins were treated with $500~\\\\\\\\mu \\\\\\\\mathrm{M}$ indole-3-acetic acid (auxin) or left untreated (untr.). At indicated times after treatment, cells were lysed and a Western blot analysis was performed with 20 $\\\\\\\\mu \\\\\\\\mathrm{g}$ of each protein sample loaded per lane. Blots were probed with protein-specific antibodies indicated on the right. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0088/2c653dc8be45ffa5329e2cc6d711a22288eec50ee03907ea177bdba27840a851.jpg\",\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"16\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[90,65,823,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0506/a91175559d7519e71bbf03d140957131f5ac33b0af40b25e644cc21dea31ed2c.jpg\",\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[90,210,297,429]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0759/dd76045cd44c49b81016d599f5217b5461081c33cf7e7dd8c70715000775925f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[309,210,594,429]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 3: Early HSV-1 transcription is reduced following SUPT5H/SFPQ depletion. A, schematic overview of the experiments. For SUPT5H, auxin was added $4\\\\\\\\mathrm{~h}$ before infection, for SFPQ either 4 or $22\\\\\\\\mathrm{~h}$ before. At 2 and 4 hpi, RNA was harvested for RT-qPCR. B, viral RNA (UL54) was quantified using RT-qPCR from the experiment with SUPT5H depletion. C, as for B, but from the experiment with SFPQ depletion. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0441/7d70ce4596d42f7f8cfde309c9374b94e6de036256b0da8ec7115067ccb0f15e.jpg\",\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"17\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[119,89,867,381]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"A \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0054/2fe10c4fc148830e9fe34954784e1da35b38c0be31950b756ecf04b3044f12c9.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[119,395,867,681]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"B \\\",\\\"Figure 4: SUPT5H co-localizes with viral genomes early in HSV-1 infection. A, SUPT5H-degron cells were either infected with HSV-1 carrying unlabeled (DMSO) or EdC-labeled DNA. At 3 hpi, all cells were fixed, their nuclei were stained with Hoechst, viral DNA was fluorescently stained by a click reaction, SUPT5H was immunostained with a V5-antibody and images were taken. Arrows indicate a signal of viral DNA. B, as in A, but for SFPQ-degron cells. \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0733/a1e36da1d8b7a3b50765f24e6bee7160cb5ea23e2a676f76a2c40b2bfd24534f.jpg\",\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[100,4,887,36]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"18\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"bioRxiv preprint doi: https://doi.org/10.1101/2025.02.10.637450; this version posted February 11, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":""},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Life Sciences"},"sha256":{"kind":"string","value":"5a46aee5aea172ebb7eb391b5f0f1a3bf605073a6835fc26b1007aeb1dd1f92e"},"title":{"kind":"string","value":"Dissecting the role of RNA-binding proteins in early herpes simplex virus 1 transcription using acute protein depletion"}}},{"rowIdx":185,"cells":{"abstract":{"kind":"string","value":""},"author":{"kind":"string","value":"Pires, Gabriel Natan|Bezerra, Andréia Gomes|Oliveira, Thainá Baenninger de|Chen, Samuel Fen I|Malfatti, Victor Davis Apostolakis|Mello, Victoria Feiner Ferreira de|Niyama, Alyne|Pinto, Vitor Luiz Selva|Andersen, Monica Levy|Tufik, Sergio"},"content_list":{"kind":"list like","value":[{"bbox":"[67,102,290,141]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,145,287,170]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Official Publication of the Instituto Israelita de Ensino e Pesquisa Albert Einstein ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,204,285,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ISSN: 1679-4508 | e-ISSN: 2317-6385 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,568,200,578]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"How to cite this article: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,580,268,641]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, et al. COVID-19 meta-analyses: a scoping review and quality assessment. einstein (São Paulo). 2021;19:eAO6002. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,648,191,659]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Corresponding author: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,660,164,670]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gabriel Natan Pires ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,672,268,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Departamento de Psicobiologia \nUniversidade Federal de Sao Paulo \nRua Napoleao de Barros, 925 \nVila Clementino \nZip code: 04024-002 - Sao Paulo, SP, Braz \nPhone: (55 11) 2149-0155 \nE-mail: gnspires@gmail.com ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,764,141,775]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Received on: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,776,129,788]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"July 9, 2020 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,795,142,807]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Accepted on: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,807,134,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Oct 30, 2020 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,825,174,837]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflict of interest: ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,839,99,849]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"none. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,860,152,872]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Copyright 2021 ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[67,873,115,886]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0482/fa8c7fdd4d4b24d40b62ed0e213733f676a09a7e97ca9aedc8961fc58497ee46.jpg","list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[67,887,198,910]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"This content is licensed under a Creative Commons ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,910,233,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Attribution 4.0 International License. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[344,74,480,89]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ORIGINAL ARTICLE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[337,112,843,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COVID-19 meta-analyses: a scoping review and quality assessment ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[337,179,781,224]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Metanálises sobre COVID-19: revisão de escopoes analise de qualidade ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[337,233,917,279]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gabriel Natan Pires<sup>1</sup>, Andréia Gomes Bezerra<sup>1</sup>, Thainá Baenninger de Oliveira<sup>2</sup>, Samuel Fen I Chen<sup>2</sup>, Victor Davis Apostolakis Malfatti<sup>2</sup>, Victoria Feiner Ferreira de Mello<sup>2</sup>, Alyne Niyama<sup>2</sup>, Vitor Luiz Selva Pinto<sup>2</sup>, Monica Levy Andersen<sup>1</sup>, Sergio Tufik<sup>1</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[337,288,742,313]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1 Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil. \",\"2 Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brazil. \"]","page_idx":"0","sub_type":"text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[337,324,613,339]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DOI: 10.31744/einstein_journal/2021A06002 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[339,366,438,380]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ABSTRACT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[336,385,929,636]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objective: To carry out a scoping review of the meta-analyses published regarding about coronavirus disease 2019 (COVID-19), evaluating their main characteristics, publication trends and methodological quality. Methods: A bibliometric search was performed in PubMed, Scopus and Web of Science, focusing on meta-analyses about COVID-2019 disease. Bibliometric and descriptive data for the included articles were extracted and the methodological quality of the included meta-analyses was evaluated using A Measurement Tool to Assess Systematic Reviews. Results: A total of 348 meta-analyses were considered eligible. The first meta-analysis about COVID-19 disease was published on February 26, 2020, and the number of meta-analyses has grown rapidly since then. Most of them were published in infectious disease and virology journals. The greatest number come from China, followed by the United States, Italy and the United Kingdom. On average, these meta-analyses included 23 studies and 15,200 participants. Overall quality was remarkably low, and only $8.9\\%$ of them could be considered as of high confidence level. Conclusion: Although well-designed meta-analyses about COVID-19 disease have already been published, the majority are of low quality. Thus, all stakeholders playing a role in COVID-19 diseases, including policy makers, researchers, publishers and journals, should prioritize well-designed meta-analyses, performed only when the background information seem suitable, and discouraging those of low quality or that use suboptimal methods. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[337,651,929,682]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Keywords: Bibliometrics; Coronavirus; COVID-19; Meta-analysis; Betacoronavirus; SARS-CoV-2; Scientometrics; Systematic review ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[339,709,421,725]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESUMO ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[336,728,929,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Objetivo: Realizar uma revisão de escope das metanálises publiadas sobre a doença pelo coronavirus 2019 (COVID-19), avaliando suas principais caractésticas, tendências de publicação e优质的 metodológica. Métodos: Uma busca bibliometrica foi realizada em PubMed, Scopus e Web of Science, com foco em metanálises sobre a doença pelo COVID-19. Foram extraídos dados bibliometricos e descritivos dos artigos inclusos, e a优质的 metodológica foi avaliada using a ferramenta A Measurement Tool to Assess Systematic Reviews. Resultados: Um total de 348 metanálises foram consideradas elegveis. A primaira delas fois publicity em 26 de fevereiro de 2020, e, desde进去,o número dessas publicações cresceu rapidamente. A maior fei publicity em periodicos de infectologia e virologia. Grande parte é proveniente da China, seguida dos Estados Unidos, da Itália e do Reino Unido. Em media, as metanálises incluiam 23 estudos e 15.200 participantes. Em geral, a优质的 metodológica fei baixa, e apenas $8,9\\%$ delas poder consideradas de algum grau de confiabilitad Conclusao: Emboraagemas metanálises bem conducidas sobre a doença pelo COVID-19 tenham sido publicadas, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[492,967,502,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"1 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[776,959,929,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[63,66,487,157]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"a maioría aparena baixa calidad. Todos os envolvidos na abordagem da doença pelo COVID-19, incluindo formuladores de políticas, pesquisadores, editoras e periodicos, devem dar prioridade a metanálises de alta calidad, realizadas apenas quando os dados são viaveis, e desencorajar as de baixa calidad ou conducidas com métodos subótimos. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,174,485,206]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Descritores: Bibliometria; Coronavirus; COVID-19; Metanálise; Betacoronavirus; SARS-CoV-2; Cientometria; Revisão sistémática ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,234,201,250]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"INTRODUCTION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[63,255,487,390]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Since coronavirus disease 2019 (COVID-19) was recognized as a serious public health threat, researchers from all over the world have devoted a great deal of time and effort to characterize and understand this new disease, resulting in an unprecedented surge in the number of publications. $^{(1-3)}$ On average, more than 200 new articles about COVID-19 have been indexed in PubMed $^{\\text{®}}$ , every day. $^{(4)}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,393,487,562]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All stakeholders involved in academic research and scientific publishing have directed efforts to enable an efficient publication outflow: governments and supporting agencies are releasing special funding and grants for research about COVID-19; ethics committees and other regulatory agencies are prioritizing COVID-19-related projects;<sup>(5)</sup> publishers are applying open access policies to COVID-19 articles; and journals are reviewing COVID-19 articles using fast-track processes.<sup>(6,7)</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,564,487,733]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All these efforts have the ultimate goal of enhancing knowledge and generating evidence about COVID-19. From an evidence-based perspective, meta-analyses are usually regarded as the experimental approach that generates the highest level of scientific evidence. Thus, not surprisingly, meta-analyses regarding COVID-19 are already being published. Prompted by this remarkable and constant growth in publication output, a discussion in respect of the quality and ethical standards of these articles has already begun.[6,8-10] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,735,487,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Both the need to release and publish data rapidly, and the shortened peer-review times, can result in a reduction in the quality of the published reports. Since meta-analyses are also subjected to same publication environment, this reduction in quality might also be true for them. In order to quantify the problem and foresee potential drawbacks in the evidence synthesis of COVID-19 research, it is important to quantify the amount of meta-analyses being published, their characteristics, their methods and the average quality of these reports. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,66,611,81]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OBJECTIVE ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,85,929,153]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To carry out a scoping review of the meta-analyses published regarding coronavirus disease 2019, evaluating their main characteristics, publication trends and methodological quality. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,181,603,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"METHODS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,201,929,341]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A bibliometric search was performed in PubMed, Scopus and Web of Science, to retrieve all meta-analyses published relating to COVID-19. The search strategy, which was initially designed for PubMed and adapted to other databases, is described below. It was performed on August 18, 2020 and no publication filters were used. The protocol used was registered in the Open Science Framework (https://osf.io/tnps2/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,343,929,482]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Search was performed using the following terms: (meta-analysis [publication type] OR meta-analysis as topic [mesh] OR meta-analysis [tiab] OR meta-analyses [tiab] OR meta-analysis [tiab] OR metaanalyses [tiab] OR meta-analysis [tiab] OR metanalyses [tiab]) AND (covid-19 [supplementary concept] OR pandemic-19 OR pandemic19 OR “novel coronavirus” OR “sars-cov-2” OR “2019-ncov”). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,484,929,924]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The resulting articles were screened and evaluated in a two-step process. In the first, titles and abstracts were reviewed by two independent authors. Discrepancies were resolved by consensus. Next, the full texts of the articles selected in the first step were evaluated by a single author per article and double-checked by a second reviewer. Only meta-analyses dealing with COVID-19-related issues were considered eligible. Regarding the PI(E)CO strategy, COVID-19 could be addressed as an intervention (I), exposure (E) or outcome (O), while there was no restriction regarding the population (P) or comparators (C). Six main exclusion criteria were applied: articles published before 2019; protocols of systematic reviews and meta-analyses; research designs other than meta-analyses (systematic reviews with no meta-analyses were excluded); meta-analyses not related to COVID-19; meta-analyses for which data came from sources other than previously published articles (e.g., meta-analyses of geographical or meteorological data), and articles for which the full text could not be found. Meta-analyses in which COVID-19 data were considered concurrently with other diseases, such as the severe acute respiratory syndrome (SARS) or the Middle East respiratory syndrome (MERS), were also considered eligible. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,21,524,32]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[843,25,929,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,959,220,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[492,967,504,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"2 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[63,66,487,534]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data extraction was performed by a single author per article. The following data was extracted: bibliometric information (author, publication year, publication date, journal and country – based on the first affiliation of the first author), number of articles and individuals included in the meta-analyses, pre-publication registration (e.g., International Prospective Register of Systematic Reviews – PROSPERO), databases screened and research designs considered eligible (only randomized controlled trials (RCT), only non-randomized designs or both). The articles were classified into the same 13 categories used by PROSPERO to categorize COVID-19-related protocols of systematic reviews. Finally, the methodological quality of the included meta-analyses was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR 2.0).[11] All authors applying tool had undergone training with a senior reviewer, and the evaluation criteria of each item were discussed and standardized in a meeting. To assure consistency and accuracy in data abstraction, two rounds of calibration were performed: in the first, all the authors involved in data extraction analyzed a set of ten articles from the sample. In the second round, a sample of 130 articles were evaluated by pairs of reviewers. Reviewers could start data extraction and quality assessment independently, only when consistency was assured. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,535,487,674]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All data were analyzed qualitatively, presented in a descriptive fashion when needed (percentages and absolute frequency for categorical data, and mean and standard deviation for numeric variables). This scoping review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. $^{(12)}$ ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,675,487,728]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The assignment of authors to each step in this systematic review is disclosed in the registered protocol (https://osf.io/tnps2/). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,761,152,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RESULTS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[65,781,487,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Out of 1,296 meta-analyses, 348 were considered eligible (Figure 1). The first article in this sample was indexed on February 26, 2020. $^{(13)}$ In this short period since the publication of this article (176 days until August 18), an average of 1.95 meta-analyses were published per day. This number has been increasing, as shown in figure 2. Among these articles, 336 $(96.5\\%)$ focused only on COVID-19, while 12 $(3.4\\%)$ merged ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,66,929,134]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COVID-19 data with data for other diseases (SARS: 12; MERS: 11; Ebola and influenza: 1). The meta-analyses included an average of $22.94 \\pm 21.49$ studies (median: 16) and $15,250.57 \\pm 46,876.16$ participants (median: 4,121). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[515,225,926,475]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[\"WOS: Web of Science. \"]","img_path":"images/0154/7bc72141f5b94176d58a55e626bb94ec98e18a943ac278a6e926833b874c6c12.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[521,601,929,838]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 1. Flowchart of article identification and inclusion \",\"Figure 2. Temporal analysis of publication output. Number of meta-analyses published per month is shown since the publication of the first meta-analysis (February 26). Articles whose publication date could not be determined, or that are scheduled for September 2020 onwards are not counted $(n = 329)$ . Data from August should not be interpreted as a reduction in the number of meta-analyses published, as the search strategy was made on August 18, 2020 \"]","image_footnote":"[]","img_path":"images/0998/bd00afb567a88cada6603bb931ca50b630980fc71b4a1d75c95e8c7b5451f167.jpg","list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[67,23,152,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[818,21,927,32]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COVID-19 meta-analyses ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,967,504,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"3 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[776,959,929,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[63,66,487,298]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The studies were published in 193 different journals. The Journal of Medical Virology contributed the most, publishing 35 meta-analyses on COVID-19 $(9.1\\%)$ , followed by the Journal of Infection, with 19 articles $(4.9\\%)$ . Eight journals published between six and nine meta-analyses each, 39 published between two and four meta-analyses each, and the remaining 144 journals published a single meta-analysis each. Most meta-analyses were published in infectious disease or virology journals (78 articles in 15 journals), followed by clinical/internal/general medicine (38 articles in 19 journals), cardiology and vascular medicine (24 articles in 20 journals) and gastroenterology (19 articles in 14 journals) (Figures 3A and 3B). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,298,485,380]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A total of 37 countries were listed in the publication output (Figure 3C). China was the most productive country, with 117 articles $(33.6\\%)$ , followed by the United States with 54 articles $(15.1\\%)$ , and Italy and the United Kingdom, with 22 articles each $(12.6\\%)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,382,485,484]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Only 58 meta-analyses $(16.7\\%)$ registered a protocol, being PROSPERO the most commonly used protocol registry. Six meta-analyses $(1.6\\%)$ included only RCT, while the remaining were based on observational studies, or on a combination of multiple research designs. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,66,929,283]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Regarding the search strategies of the meta-analyses, 107 of them $(30.7\\%)$ screened five or more databases; while 23 $(6.6\\%)$ screened a single database, a non-recommended practice due to the increased risk of selection bias. PubMed and MEDLINE were the most frequently employed database (342 articles; $98.3\\%$ ), followed by Embase (204 articles; $58.6\\%$ ), Web of Science (130 articles; $37.4\\%$ ), Cochrane Central (129 articles; $37.1\\%$ ), and Scopus (94 articles; $27.0\\%$ ). Preprint sources, such as medRxiv and bioRxiv, were used in 74 articles $(21.3\\%)$ . Regional databases from China were used in 74 articles $(21.3\\%)$ . ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,284,929,375]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The most common focuses of the included meta-analyses were disease prognosis (200 articles; $57.5\\%$ ), epidemiology (130 articles; $37.4\\%$ ), diagnosis (48 articles; $13.8\\%$ ), health impacts (43 articles; $12.4\\%$ ) and treatments (42 articles; $12.1\\%$ ). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,375,929,484]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Quality assessment using AMSTAR 2.0 revealed that only 31 of the meta-analyses $(8.9\\%)$ were of a quality that allowed a high overall confidence in the results of the review, while 186 $(53.4\\%)$ were of a critically low level. Quality analyses according to each item in AMSTAR 2.0 are shown in figure 4. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[82,624,448,863]","code_body":null,"code_caption":null,"image_caption":"[\"A \"]","image_footnote":"[]","img_path":"images/0276/a36cb4fb07db5da2d320e4c44ac6a3035ae1a01ac28318dd50441e014050a9dd.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[450,627,652,863]","code_body":null,"code_caption":null,"image_caption":"[\"B \"]","image_footnote":"[]","img_path":"images/0079/2504973ebcefa30386df95d191094e5a50514fb352b6d7a5c12e9ac5b483b09b.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[652,627,922,863]","code_body":null,"code_caption":null,"image_caption":"[\"C \",\"Figure 3. Publication output per subject area and country. (A) Number of articles on each subject area; (B) Number of journals in each subject area; (C) Number of articles per country. The time since the first local case of COVID-19, the ability to include studies published in local languages, and the recent surge in the publication of meta-analyses in general may have contributed to China being ranked as producer of the largest number of analyses, with an output double that of the United States \"]","image_footnote":"[]","img_path":"images/0043/05876316254d03351f5ae05adce6adf87ec6524bcd3c0e07205c41f8ceb0ea75.jpg","list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[67,21,524,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[843,25,929,42]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[67,959,220,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[492,967,504,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"4 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[80,81,400,277]","code_body":null,"code_caption":null,"image_caption":"[]","image_footnote":"[]","img_path":"images/0337/c92fb8f88217a08f13ff62296d3f6a5fa4869f95087b0b268fa603559841e22b.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[436,78,915,277]","code_body":null,"code_caption":null,"image_caption":"[\"Figure 4. Quality assessment of meta-analyses about COVID-19 using A Measurement Tool to Assess Systematic Reviews. (A) Number of meta-analyses according to different levels of confidence; (B) Evaluation of each criterion included in A Measurement Tool to Assess Systematic Reviews. Green means that an item was adequately addressed; yellow means it was partially addressed, and red means it was not addressed \"]","image_footnote":"[]","img_path":"images/0894/ccac1131e8ae0b9a135f3b83c5150d1c95174890f68edc1d193e824db43865d7.jpg","list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"image"},{"bbox":"[65,432,181,447]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DISCUSSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[63,453,485,651]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Meta-analyses are regarded as the highest level of evidence. Therefore, healthcare decision makers frequently rely on them for evidence-based guidance. $^{(14)}$ In the current pandemic situation, healthcare practices and policies need to be developed in a rapid fashion, making meta-analyses an important source of evidence. However, it must be kept in mind that the quality of the meta-analyses does not rely solely on the methodology used, but also on the number and quality of the articles included. Thus, the main question to answer is: do we have enough high-quality studies to perform meta-analyses about COVID-19?. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,654,485,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The building blocks of meta-analyses are the studies they include. The reasonability about performing a meta-analyses depends on the number of articles being analyzed, and the robustness of its results depends on the quality of the articles included (according to the concept of \"garbage in, garbage out\"). Appropriate statistical methods need to be employed in meta-analyses. Indeed, increasing the amount of low-bias meta-analyses (i.e. those with reliable methods and robust methodology) might increase the proportion of reliable scientific findings overall.[15] Although the total number of articles about COVID-19 is considerable, questions have been raised about the overall quality of the studies,[6,8-10] and in respect of meta-analyses, some cases of methodologically flawed studies have already been reported.[16,17] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,432,929,621]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The meta-analyses included in this study comprise a fair amount of data, with an average of 23 studies and 15,000 participants per article. This is a surprising finding, since we would expect the meta-analyses published to be much smaller, given that they were published a short time after the start of the pandemic. It probably reflects the fact that epidemiological studies on COVID-19, with very large cohorts, were published relatively soon after the initial outbreak. However, although there does not seem to be lack of data, the quality of these meta-analyses is remarkably low, with only 31 (8.9%) considered to be of high quality. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,622,929,747]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"It should also be noted that no meta-analysis based on RCT only has yet been published. This is explained by several meta-analyses performed on topics that are only solvable by observational studies (such as prevalence of risk factors). However, meta-analyses about themes that depend on properly performed RCT (such as pharmacological interventions and vaccines) do not seem feasible in the short term. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,747,929,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The sources and topics of the meta-analyses also provided interesting results. More than $50\\%$ of studies come from only four countries: China, United States, Italy and United Kingdom. Although these countries are among those most affected by COVID-19, it would be misleading to make this correlation, since they were already among the top six meta-analyses producers, even before the pandemic.[18] It is interesting to note that China's production is almost twice that of the United States, probably reflecting the geometric increase in their meta-analyses publication output, as from 2009.[19] ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[67,23,152,40]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[820,21,927,32]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"COVID-19 meta-analyses ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[492,967,504,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"5 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[776,959,929,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[68,66,484,228]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Most of the meta-analyses were published in virology and infectious disease journals, addressing prognostic factors and epidemiology. This is to be expected, given that these were the first topics for which a reasonable amount of data became available. Although PROSPERO has already been registering systematic reviews about treatments and vaccines, meta-analyses on these topics seem rather unfeasible in the short term (and will be less informative if based on the limited number of completed the RCT available). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,230,484,390]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"One positive aspect of the included meta-analyses is the inclusion of pre-print sources (18.0%) and national databases (mostly Chinese; 22.5%). It is estimated that about a quarter of all relevant evidence about COVID-19 is not in PubMed, but might be available in pre-print sources[20] and not including them represents an obvious publication bias. The same is true in respect of the inclusion of national databases, since a fair amount of data about epidemiology and clinical description are available only in Chinese. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,390,484,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The overall number of meta-analyses being published has increased considerably in recent years,[21] and this mass publication of meta-analyses has been heavily criticized.[22,23] Among the main problems relating to the increased number of meta-analyses being published are duplicated efforts, conflicting results, low quality and limited practical value.[22] While our study focused on an analysis of the quality of the studies, one might expect these same problems are also present in COVID-19-related meta-analyses. One example of conflicting results in meta-analyses about COVID-19 was found in respect of smoking. A meta-analysis published in May 2020 concluded that smoking does not represent a risk factor for severe cases of COVID-19.[24] However, two subsequent meta-analyses highlighted methodological errors in the original analysis, and came to an opposite conclusion.[16,25] Since then, several other systematic reviews have been performed in relation to smoking, including a recent meta-analysis performed using robust methods (a living review with Bayesian meta-analysis, currently in its seventh edition).[26] Its conclusions reinforced the complexity of this association, since they found current smokers are at reduced risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but former smokers are at increased risk of severe cases and death from COVID-19. Thus, despite the growing number of meta-analyses about COVID-19 inconsistencies, low quality and methodological weaknesses among them might reduce their potential to generate applicable findings. This is particularly important for policymakers and health care managers, who might wish to use meta-analyses to drive their practices and policies. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,66,927,245]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The idea that meta-analyses represent the unequivocal highest level of medical evidence is outdated,[27] and this affirmation can certainly not be applied to all individual meta-analyses. Weak or imprecise meta-analyses actually produce less evidence than, for instance, a well conducted large observational study or a proper multicenter randomized controlled trial. Based on these considerations and the results of our review, we make the following recommendations to different stakeholders about how to deal with meta-analyses regarding COVID-19. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,247,927,393]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To policy makers: meta-analyses are undeniably important for policy makers, so that they can design and implement policies employing on reliable evidence-based information. However, current meta-analyses about COVID-19 are of limited quality and, in some cases, have discrepant results. Thus, in these times of uncertain evidence, decision-making should not blindly rely on meta-analyses, but rather on a deep analysis of literature and the evidence it contains. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,395,927,740]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To researchers and authors of meta-analyses: new meta-analyses about COVID-19 are welcome, as long as they provide new high-quality evidence. Low-quality meta-analyses (premature, redundant, dubious, inconclusive, or performed with suboptimal practices) are counterproductive, for impairing proper evidence synthesis. Thus, we suggest that prospective authors of meta-analyses perform a serious critical appraisal about the need for their meta-analyses. The following factors should be evaluated: whether there is enough data to perform a meta-analysis; if the available data seems reliable, comparable and free from heterogeneity; whether other meta-analyses in the same field have already been published or protocols have been registered. Researchers should rely on a search of protocol registrations for systematic reviews and meta-analyses to avoid duplicated and redundant efforts. Quality and methodological robustness should not be overlooked in favor of rapid publication, or it is likely that the quality of the review will be poor (as seen in our results). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[512,742,927,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To journals and publishers: meta-analyses usually lead to a fair amount of citations and good visibility to journals publishing them.[28] Thus, in the current situation, journals might feel tempted to publish meta-analyses, while ignoring faulty methods and low-quality procedures. Interestingly, as the number of articles about COVID-19 has increased, so has the number of articles being withdrawn and retracted.[29] Journals should comply with their social role of being a media for evidence-based science. Recent discussions have highlighted the role of journals in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[68,22,524,32]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[845,25,929,41]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,960,220,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[494,967,504,978]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"6 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[63,66,487,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"promoting the publication of high-quality meta-analyses, while discouraging those that do not follow optimal methodological standards. $^{(30)}$ This is especially relevant in the current situation. Peer review can be made faster, as long as its quality and fairness are not compromised. We would suggest that a researcher with experience in meta-analyses is always included as a reviewer, or to have a statistician on the editorial board, to ensure that faulty or low-quality meta-analyses are not published. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,215,487,561]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A few points need to be considered for a proper interpretation of our study: this is a scoping review, rather than a systematic review. Thus, rather than aiming to perform a meta-analysis ourselves, our review was intended to describe a panorama about the current meta-analyses about COVID-19, focusing on the general framework of the field, instead of on the individual aspects of each study; - we decided to exclude systematic reviews with no meta-analyses. This is because our focus was on evidence synthesis, which is much reduced in reviews not including meta-analyses, and also, in many cases, the term \"systematic review\" is misused.[31] However, an enormous amount of systematic reviews has been published, whose quality has already been appraised in a previous article.[32] This is a time-restrained review. In the near future, meta-analyses on most aspects of COVID-19 will probably become viable. However, a study focusing attention on the quality of meta-analyses published so far in respect of COVID-19 is timely; and the call to prioritize attention on high-quality meta-analyses is important. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[65,588,184,604]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CONCLUSION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[63,607,487,757]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Meta-analyses are an important tool in evidence-based medicine. The number of meta-analyses in respect of COVID-19 is increasing and will continue to rise. We believe that meta-analyses will play an important role in COVID-19, defining its epidemiological characteristics, the most suitable treatments, and supporting policymaking. However, while we do support the need for meta-analyses about COVID-19, it should not be taken as a license to produce them indiscriminately. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[63,757,487,923]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Although some very well-designed meta-analyses about COVID-19 have already been published, the majority published so far are of poor quality, and are likely to causes more harm than good. Few meta-analysis about COVID-19 in our review could be considered as of high quality, while more than a half were considered of critically low quality. Thus, all stakeholders playing a role in COVID-19 research and publication (including policy makers, researchers, publishers and journals) should focus on proper evidence-based research, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,66,929,132]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"supporting well designed meta-analyses, performed only when the background information seems suitable, and discourage those of low quality or that use suboptimal methods. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,160,685,176]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACKNOWLEDGMENT ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[507,181,929,350]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gabriel Natan Pires is supported by grants and funding from the Associacao Fundo de Incentivo à Pesquisa (AFIP). Sergio Tufik and Monica Levy Andersen are supported by grants and funding from AFIP, Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES - Finance Code 001) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Samuel Fen I Chen, Thainá Baenninger de Oliveira and Victor Luiz Selva Pinto are supported by grants from CAPES. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[521,387,721,402]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"AUTHOR' INFORMATION ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[519,406,813,419]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pires GN: http://orcid.org/0000-0003-0411-0111 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[521,421,831,433]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Bezerra AG: http://orcid.org/0000-0001-5534-6138 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,435,828,448]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Oliveira TB: http://orcid.org/0000-0003-2552-9851 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,448,811,462]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chen SF: http://orcid.org/0000-0002-6870-9169 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,462,833,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Malfatti VD: http://orcid.org/0000-0003-2037-5013 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,477,816,490]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Mello VF: http://orcid.org/0000-0002-6711-2299 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,491,818,504]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Niyama A: http://orcid.org/0000-0002-7343-8893 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,505,813,518]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pinto VL: http://orcid.org/0000-0001-8565-7017 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,519,843,530]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Andersen ML: http://orcid.org/0000-0002-1894-6748 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[522,532,800,544]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Tufik S: http://orcid.org/0000-0002-3804-8865 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,588,626,602]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REFERENCES ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[510,607,929,921]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"1. 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Alexander PE, Debono VB, Mammen MJ, Iorio A, Aryal K, Deng D, et al. COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine. J Clin Epidemiol. 2020;123:120-6. Review. \",\"11. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. \",\"12. Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and explanation. Ann Intern Med. 2018;169(7):467-73. \",\"13. Sun P, Qie S, Liu Z, Ren J, Li K, Xi J. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis. J Med Virol. 2020;92(6):612-7. \",\"14. Mulrow CD. Rationale for systematic reviews. BMJ. 1994;309(6954):597-9. \",\"15. Ioannidis JP. 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PLoS One. 2013; 8(6):e65602. \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[510,66,929,459]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"20. Shokraneh F, Russell-Rose T. Lessons from COVID-19 to future evidence synthesis efforts: first living search strategy and out of date scientific publishing and indexing industry (submitted). J Clin Epidemiol. 2020;123:171-3. \",\"21. Gurevitch J, Koricheva J, Nakagawa S, Stewart G. Meta-analysis and the science of research synthesis. Nature. 2018;555(7695):175-82. Review. \",\"22. Ioannidis JP. The mass production of redundant, misleading, and conflicted systematic reviews and meta-analyses. Milbank Q. 2016;94(3):485-514. \",\"23. Chevret S, Ferguson ND, Bellomo R. Are systematic reviews and meta-analyses still useful research? No. Intensive Care Med. 2018;44(4):515-7. \",\"24. Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med. 2020;75:107-8. \",\"25. Guo FR. Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis. Tob Induc Dis. 2020;18:37. \",\"26. Simons D, Shahab L, Brown J, Perski O. The association of smoking status with SARS-CoV-2 infection, hospitalization and mortality from COVID-19: a living rapid evidence review with Bayesian meta-analyses (version 7). Addiction. 2020 Oct 2:10.1111/add.15276. Review. \",\"27. Murad MH, Asi N, Alsawas M, Allahdab F. New evidence pyramid. Evid Based Med. 2016;21(4):125-7. \",\"28. Patsopoulos NA, Analatos AA, Ioannidis JP. Relative citation impact of various study designs in the health sciences. JAMA. 2005;293(19):2362-6. \",\"29. Agoramoorthy G, Hsu MJ, Shieh P. Queries on the COVID-19 quick publishing ethics. Bioethics. 2020;34(6):633-4. \",\"30. Annane D, Jaeschke R, Guyatt G. Are systematic reviews and meta-analyses still useful research? Yes. Intensive Care Med. 2018;44(4):512-4. \",\"31. Paul M, Leibovici L. Systematic review or meta-analysis? Their place in the evidence hierarchy. Clin Microbiol Infect. 2014;20(2):97-100. Review. \",\"32. Pericas JM, Torrallardona-Murphy O, Arenas A, Valero H, Nicolas D. Profile and quality of published reviews on COVID-19. Eur J Clin Invest. 2020 May 30:e13293. doi: 10.1111/eci.13293. [Epub ahead of print]. \"]","page_idx":"7","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[67,21,524,34]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[843,25,929,42]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[68,959,220,970]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"einstein (São Paulo). 2021;19:1-8 ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[492,967,504,979]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"8 ","text_format":null,"text_level":null,"type":"page_number"}],"string":"[\n {\n \"bbox\": \"[67,102,290,141]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,145,287,170]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Official Publication of the Instituto Israelita de Ensino e Pesquisa Albert Einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,204,285,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ISSN: 1679-4508 | e-ISSN: 2317-6385 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,568,200,578]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"How to cite this article: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,580,268,641]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, et al. COVID-19 meta-analyses: a scoping review and quality assessment. einstein (São Paulo). 2021;19:eAO6002. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,648,191,659]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Corresponding author: \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,660,164,670]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gabriel Natan Pires \",\n \"text_format\": null,\n 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\"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[67,887,198,910]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"This content is licensed under a Creative Commons \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,910,233,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Attribution 4.0 International License. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[344,74,480,89]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ORIGINAL ARTICLE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,112,843,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COVID-19 meta-analyses: a scoping review and quality assessment \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,179,781,224]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Metanálises sobre COVID-19: revisão de escopoes analise de qualidade \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,233,917,279]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gabriel Natan Pires<sup>1</sup>, Andréia Gomes Bezerra<sup>1</sup>, Thainá Baenninger de Oliveira<sup>2</sup>, Samuel Fen I Chen<sup>2</sup>, Victor Davis Apostolakis Malfatti<sup>2</sup>, Victoria Feiner Ferreira de Mello<sup>2</sup>, Alyne Niyama<sup>2</sup>, Vitor Luiz Selva Pinto<sup>2</sup>, Monica Levy Andersen<sup>1</sup>, Sergio Tufik<sup>1</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,288,742,313]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1 Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil. \\\",\\\"2 Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brazil. \\\"]\",\n \"page_idx\": \"0\",\n \"sub_type\": \"text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[337,324,613,339]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DOI: 10.31744/einstein_journal/2021A06002 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[339,366,438,380]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ABSTRACT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[336,385,929,636]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objective: To carry out a scoping review of the meta-analyses published regarding about coronavirus disease 2019 (COVID-19), evaluating their main characteristics, publication trends and methodological quality. Methods: A bibliometric search was performed in PubMed, Scopus and Web of Science, focusing on meta-analyses about COVID-2019 disease. Bibliometric and descriptive data for the included articles were extracted and the methodological quality of the included meta-analyses was evaluated using A Measurement Tool to Assess Systematic Reviews. Results: A total of 348 meta-analyses were considered eligible. The first meta-analysis about COVID-19 disease was published on February 26, 2020, and the number of meta-analyses has grown rapidly since then. Most of them were published in infectious disease and virology journals. The greatest number come from China, followed by the United States, Italy and the United Kingdom. On average, these meta-analyses included 23 studies and 15,200 participants. Overall quality was remarkably low, and only $8.9\\\\%$ of them could be considered as of high confidence level. Conclusion: Although well-designed meta-analyses about COVID-19 disease have already been published, the majority are of low quality. Thus, all stakeholders playing a role in COVID-19 diseases, including policy makers, researchers, publishers and journals, should prioritize well-designed meta-analyses, performed only when the background information seem suitable, and discouraging those of low quality or that use suboptimal methods. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[337,651,929,682]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Keywords: Bibliometrics; Coronavirus; COVID-19; Meta-analysis; Betacoronavirus; SARS-CoV-2; Scientometrics; Systematic review \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[339,709,421,725]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESUMO \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[336,728,929,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Objetivo: Realizar uma revisão de escope das metanálises publiadas sobre a doença pelo coronavirus 2019 (COVID-19), avaliando suas principais caractésticas, tendências de publicação e优质的 metodológica. Métodos: Uma busca bibliometrica foi realizada em PubMed, Scopus e Web of Science, com foco em metanálises sobre a doença pelo COVID-19. Foram extraídos dados bibliometricos e descritivos dos artigos inclusos, e a优质的 metodológica foi avaliada using a ferramenta A Measurement Tool to Assess Systematic Reviews. Resultados: Um total de 348 metanálises foram consideradas elegveis. A primaira delas fois publicity em 26 de fevereiro de 2020, e, desde进去,o número dessas publicações cresceu rapidamente. A maior fei publicity em periodicos de infectologia e virologia. Grande parte é proveniente da China, seguida dos Estados Unidos, da Itália e do Reino Unido. Em media, as metanálises incluiam 23 estudos e 15.200 participantes. Em geral, a优质的 metodológica fei baixa, e apenas $8,9\\\\%$ delas poder consideradas de algum grau de confiabilitad Conclusao: Emboraagemas metanálises bem conducidas sobre a doença pelo COVID-19 tenham sido publicadas, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[492,967,502,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"1 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[776,959,929,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[63,66,487,157]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"a maioría aparena baixa calidad. Todos os envolvidos na abordagem da doença pelo COVID-19, incluindo formuladores de políticas, pesquisadores, editoras e periodicos, devem dar prioridade a metanálises de alta calidad, realizadas apenas quando os dados são viaveis, e desencorajar as de baixa calidad ou conducidas com métodos subótimos. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,174,485,206]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Descritores: Bibliometria; Coronavirus; COVID-19; Metanálise; Betacoronavirus; SARS-CoV-2; Cientometria; Revisão sistémática \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,234,201,250]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"INTRODUCTION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,255,487,390]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Since coronavirus disease 2019 (COVID-19) was recognized as a serious public health threat, researchers from all over the world have devoted a great deal of time and effort to characterize and understand this new disease, resulting in an unprecedented surge in the number of publications. $^{(1-3)}$ On average, more than 200 new articles about COVID-19 have been indexed in PubMed $^{\\\\text{®}}$ , every day. $^{(4)}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,393,487,562]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All stakeholders involved in academic research and scientific publishing have directed efforts to enable an efficient publication outflow: governments and supporting agencies are releasing special funding and grants for research about COVID-19; ethics committees and other regulatory agencies are prioritizing COVID-19-related projects;<sup>(5)</sup> publishers are applying open access policies to COVID-19 articles; and journals are reviewing COVID-19 articles using fast-track processes.<sup>(6,7)</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,564,487,733]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All these efforts have the ultimate goal of enhancing knowledge and generating evidence about COVID-19. From an evidence-based perspective, meta-analyses are usually regarded as the experimental approach that generates the highest level of scientific evidence. Thus, not surprisingly, meta-analyses regarding COVID-19 are already being published. Prompted by this remarkable and constant growth in publication output, a discussion in respect of the quality and ethical standards of these articles has already begun.[6,8-10] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,735,487,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Both the need to release and publish data rapidly, and the shortened peer-review times, can result in a reduction in the quality of the published reports. Since meta-analyses are also subjected to same publication environment, this reduction in quality might also be true for them. In order to quantify the problem and foresee potential drawbacks in the evidence synthesis of COVID-19 research, it is important to quantify the amount of meta-analyses being published, their characteristics, their methods and the average quality of these reports. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,66,611,81]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"OBJECTIVE \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,85,929,153]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To carry out a scoping review of the meta-analyses published regarding coronavirus disease 2019, evaluating their main characteristics, publication trends and methodological quality. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,181,603,197]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"METHODS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,201,929,341]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A bibliometric search was performed in PubMed, Scopus and Web of Science, to retrieve all meta-analyses published relating to COVID-19. The search strategy, which was initially designed for PubMed and adapted to other databases, is described below. It was performed on August 18, 2020 and no publication filters were used. The protocol used was registered in the Open Science Framework (https://osf.io/tnps2/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,343,929,482]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Search was performed using the following terms: (meta-analysis [publication type] OR meta-analysis as topic [mesh] OR meta-analysis [tiab] OR meta-analyses [tiab] OR meta-analysis [tiab] OR metaanalyses [tiab] OR meta-analysis [tiab] OR metanalyses [tiab]) AND (covid-19 [supplementary concept] OR pandemic-19 OR pandemic19 OR “novel coronavirus” OR “sars-cov-2” OR “2019-ncov”). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,484,929,924]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The resulting articles were screened and evaluated in a two-step process. In the first, titles and abstracts were reviewed by two independent authors. Discrepancies were resolved by consensus. Next, the full texts of the articles selected in the first step were evaluated by a single author per article and double-checked by a second reviewer. Only meta-analyses dealing with COVID-19-related issues were considered eligible. Regarding the PI(E)CO strategy, COVID-19 could be addressed as an intervention (I), exposure (E) or outcome (O), while there was no restriction regarding the population (P) or comparators (C). Six main exclusion criteria were applied: articles published before 2019; protocols of systematic reviews and meta-analyses; research designs other than meta-analyses (systematic reviews with no meta-analyses were excluded); meta-analyses not related to COVID-19; meta-analyses for which data came from sources other than previously published articles (e.g., meta-analyses of geographical or meteorological data), and articles for which the full text could not be found. Meta-analyses in which COVID-19 data were considered concurrently with other diseases, such as the severe acute respiratory syndrome (SARS) or the Middle East respiratory syndrome (MERS), were also considered eligible. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,21,524,32]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[843,25,929,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,959,220,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[492,967,504,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"2 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[63,66,487,534]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data extraction was performed by a single author per article. The following data was extracted: bibliometric information (author, publication year, publication date, journal and country – based on the first affiliation of the first author), number of articles and individuals included in the meta-analyses, pre-publication registration (e.g., International Prospective Register of Systematic Reviews – PROSPERO), databases screened and research designs considered eligible (only randomized controlled trials (RCT), only non-randomized designs or both). The articles were classified into the same 13 categories used by PROSPERO to categorize COVID-19-related protocols of systematic reviews. Finally, the methodological quality of the included meta-analyses was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR 2.0).[11] All authors applying tool had undergone training with a senior reviewer, and the evaluation criteria of each item were discussed and standardized in a meeting. To assure consistency and accuracy in data abstraction, two rounds of calibration were performed: in the first, all the authors involved in data extraction analyzed a set of ten articles from the sample. In the second round, a sample of 130 articles were evaluated by pairs of reviewers. Reviewers could start data extraction and quality assessment independently, only when consistency was assured. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,535,487,674]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All data were analyzed qualitatively, presented in a descriptive fashion when needed (percentages and absolute frequency for categorical data, and mean and standard deviation for numeric variables). This scoping review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. $^{(12)}$ \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,675,487,728]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The assignment of authors to each step in this systematic review is disclosed in the registered protocol (https://osf.io/tnps2/). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,761,152,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RESULTS \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,781,487,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Out of 1,296 meta-analyses, 348 were considered eligible (Figure 1). The first article in this sample was indexed on February 26, 2020. $^{(13)}$ In this short period since the publication of this article (176 days until August 18), an average of 1.95 meta-analyses were published per day. This number has been increasing, as shown in figure 2. Among these articles, 336 $(96.5\\\\%)$ focused only on COVID-19, while 12 $(3.4\\\\%)$ merged \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,66,929,134]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COVID-19 data with data for other diseases (SARS: 12; MERS: 11; Ebola and influenza: 1). The meta-analyses included an average of $22.94 \\\\pm 21.49$ studies (median: 16) and $15,250.57 \\\\pm 46,876.16$ participants (median: 4,121). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[515,225,926,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[\\\"WOS: Web of Science. \\\"]\",\n \"img_path\": \"images/0154/7bc72141f5b94176d58a55e626bb94ec98e18a943ac278a6e926833b874c6c12.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[521,601,929,838]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 1. Flowchart of article identification and inclusion \\\",\\\"Figure 2. Temporal analysis of publication output. Number of meta-analyses published per month is shown since the publication of the first meta-analysis (February 26). Articles whose publication date could not be determined, or that are scheduled for September 2020 onwards are not counted $(n = 329)$ . Data from August should not be interpreted as a reduction in the number of meta-analyses published, as the search strategy was made on August 18, 2020 \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0998/bd00afb567a88cada6603bb931ca50b630980fc71b4a1d75c95e8c7b5451f167.jpg\",\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[67,23,152,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[818,21,927,32]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COVID-19 meta-analyses \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,967,504,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"3 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[776,959,929,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[63,66,487,298]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The studies were published in 193 different journals. The Journal of Medical Virology contributed the most, publishing 35 meta-analyses on COVID-19 $(9.1\\\\%)$ , followed by the Journal of Infection, with 19 articles $(4.9\\\\%)$ . Eight journals published between six and nine meta-analyses each, 39 published between two and four meta-analyses each, and the remaining 144 journals published a single meta-analysis each. Most meta-analyses were published in infectious disease or virology journals (78 articles in 15 journals), followed by clinical/internal/general medicine (38 articles in 19 journals), cardiology and vascular medicine (24 articles in 20 journals) and gastroenterology (19 articles in 14 journals) (Figures 3A and 3B). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,298,485,380]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A total of 37 countries were listed in the publication output (Figure 3C). China was the most productive country, with 117 articles $(33.6\\\\%)$ , followed by the United States with 54 articles $(15.1\\\\%)$ , and Italy and the United Kingdom, with 22 articles each $(12.6\\\\%)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,382,485,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Only 58 meta-analyses $(16.7\\\\%)$ registered a protocol, being PROSPERO the most commonly used protocol registry. Six meta-analyses $(1.6\\\\%)$ included only RCT, while the remaining were based on observational studies, or on a combination of multiple research designs. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,66,929,283]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Regarding the search strategies of the meta-analyses, 107 of them $(30.7\\\\%)$ screened five or more databases; while 23 $(6.6\\\\%)$ screened a single database, a non-recommended practice due to the increased risk of selection bias. PubMed and MEDLINE were the most frequently employed database (342 articles; $98.3\\\\%$ ), followed by Embase (204 articles; $58.6\\\\%$ ), Web of Science (130 articles; $37.4\\\\%$ ), Cochrane Central (129 articles; $37.1\\\\%$ ), and Scopus (94 articles; $27.0\\\\%$ ). Preprint sources, such as medRxiv and bioRxiv, were used in 74 articles $(21.3\\\\%)$ . Regional databases from China were used in 74 articles $(21.3\\\\%)$ . \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,284,929,375]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The most common focuses of the included meta-analyses were disease prognosis (200 articles; $57.5\\\\%$ ), epidemiology (130 articles; $37.4\\\\%$ ), diagnosis (48 articles; $13.8\\\\%$ ), health impacts (43 articles; $12.4\\\\%$ ) and treatments (42 articles; $12.1\\\\%$ ). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,375,929,484]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Quality assessment using AMSTAR 2.0 revealed that only 31 of the meta-analyses $(8.9\\\\%)$ were of a quality that allowed a high overall confidence in the results of the review, while 186 $(53.4\\\\%)$ were of a critically low level. Quality analyses according to each item in AMSTAR 2.0 are shown in figure 4. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[82,624,448,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"A \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0276/a36cb4fb07db5da2d320e4c44ac6a3035ae1a01ac28318dd50441e014050a9dd.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[450,627,652,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"B \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0079/2504973ebcefa30386df95d191094e5a50514fb352b6d7a5c12e9ac5b483b09b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[652,627,922,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"C \\\",\\\"Figure 3. Publication output per subject area and country. (A) Number of articles on each subject area; (B) Number of journals in each subject area; (C) Number of articles per country. The time since the first local case of COVID-19, the ability to include studies published in local languages, and the recent surge in the publication of meta-analyses in general may have contributed to China being ranked as producer of the largest number of analyses, with an output double that of the United States \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0043/05876316254d03351f5ae05adce6adf87ec6524bcd3c0e07205c41f8ceb0ea75.jpg\",\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[67,21,524,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[843,25,929,42]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[67,959,220,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[492,967,504,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"4 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[80,81,400,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0337/c92fb8f88217a08f13ff62296d3f6a5fa4869f95087b0b268fa603559841e22b.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[436,78,915,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": \"[\\\"Figure 4. Quality assessment of meta-analyses about COVID-19 using A Measurement Tool to Assess Systematic Reviews. (A) Number of meta-analyses according to different levels of confidence; (B) Evaluation of each criterion included in A Measurement Tool to Assess Systematic Reviews. Green means that an item was adequately addressed; yellow means it was partially addressed, and red means it was not addressed \\\"]\",\n \"image_footnote\": \"[]\",\n \"img_path\": \"images/0894/ccac1131e8ae0b9a135f3b83c5150d1c95174890f68edc1d193e824db43865d7.jpg\",\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"image\"\n },\n {\n \"bbox\": \"[65,432,181,447]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DISCUSSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,453,485,651]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Meta-analyses are regarded as the highest level of evidence. Therefore, healthcare decision makers frequently rely on them for evidence-based guidance. $^{(14)}$ In the current pandemic situation, healthcare practices and policies need to be developed in a rapid fashion, making meta-analyses an important source of evidence. However, it must be kept in mind that the quality of the meta-analyses does not rely solely on the methodology used, but also on the number and quality of the articles included. Thus, the main question to answer is: do we have enough high-quality studies to perform meta-analyses about COVID-19?. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,654,485,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The building blocks of meta-analyses are the studies they include. The reasonability about performing a meta-analyses depends on the number of articles being analyzed, and the robustness of its results depends on the quality of the articles included (according to the concept of \\\"garbage in, garbage out\\\"). Appropriate statistical methods need to be employed in meta-analyses. Indeed, increasing the amount of low-bias meta-analyses (i.e. those with reliable methods and robust methodology) might increase the proportion of reliable scientific findings overall.[15] Although the total number of articles about COVID-19 is considerable, questions have been raised about the overall quality of the studies,[6,8-10] and in respect of meta-analyses, some cases of methodologically flawed studies have already been reported.[16,17] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,432,929,621]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The meta-analyses included in this study comprise a fair amount of data, with an average of 23 studies and 15,000 participants per article. This is a surprising finding, since we would expect the meta-analyses published to be much smaller, given that they were published a short time after the start of the pandemic. It probably reflects the fact that epidemiological studies on COVID-19, with very large cohorts, were published relatively soon after the initial outbreak. However, although there does not seem to be lack of data, the quality of these meta-analyses is remarkably low, with only 31 (8.9%) considered to be of high quality. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,622,929,747]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"It should also be noted that no meta-analysis based on RCT only has yet been published. This is explained by several meta-analyses performed on topics that are only solvable by observational studies (such as prevalence of risk factors). However, meta-analyses about themes that depend on properly performed RCT (such as pharmacological interventions and vaccines) do not seem feasible in the short term. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[505,747,929,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The sources and topics of the meta-analyses also provided interesting results. More than $50\\\\%$ of studies come from only four countries: China, United States, Italy and United Kingdom. Although these countries are among those most affected by COVID-19, it would be misleading to make this correlation, since they were already among the top six meta-analyses producers, even before the pandemic.[18] It is interesting to note that China's production is almost twice that of the United States, probably reflecting the geometric increase in their meta-analyses publication output, as from 2009.[19] \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[67,23,152,40]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[820,21,927,32]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COVID-19 meta-analyses \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[492,967,504,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"5 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[776,959,929,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[68,66,484,228]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Most of the meta-analyses were published in virology and infectious disease journals, addressing prognostic factors and epidemiology. This is to be expected, given that these were the first topics for which a reasonable amount of data became available. Although PROSPERO has already been registering systematic reviews about treatments and vaccines, meta-analyses on these topics seem rather unfeasible in the short term (and will be less informative if based on the limited number of completed the RCT available). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,230,484,390]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"One positive aspect of the included meta-analyses is the inclusion of pre-print sources (18.0%) and national databases (mostly Chinese; 22.5%). It is estimated that about a quarter of all relevant evidence about COVID-19 is not in PubMed, but might be available in pre-print sources[20] and not including them represents an obvious publication bias. The same is true in respect of the inclusion of national databases, since a fair amount of data about epidemiology and clinical description are available only in Chinese. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,390,484,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The overall number of meta-analyses being published has increased considerably in recent years,[21] and this mass publication of meta-analyses has been heavily criticized.[22,23] Among the main problems relating to the increased number of meta-analyses being published are duplicated efforts, conflicting results, low quality and limited practical value.[22] While our study focused on an analysis of the quality of the studies, one might expect these same problems are also present in COVID-19-related meta-analyses. One example of conflicting results in meta-analyses about COVID-19 was found in respect of smoking. A meta-analysis published in May 2020 concluded that smoking does not represent a risk factor for severe cases of COVID-19.[24] However, two subsequent meta-analyses highlighted methodological errors in the original analysis, and came to an opposite conclusion.[16,25] Since then, several other systematic reviews have been performed in relation to smoking, including a recent meta-analysis performed using robust methods (a living review with Bayesian meta-analysis, currently in its seventh edition).[26] Its conclusions reinforced the complexity of this association, since they found current smokers are at reduced risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but former smokers are at increased risk of severe cases and death from COVID-19. Thus, despite the growing number of meta-analyses about COVID-19 inconsistencies, low quality and methodological weaknesses among them might reduce their potential to generate applicable findings. This is particularly important for policymakers and health care managers, who might wish to use meta-analyses to drive their practices and policies. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,66,927,245]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The idea that meta-analyses represent the unequivocal highest level of medical evidence is outdated,[27] and this affirmation can certainly not be applied to all individual meta-analyses. Weak or imprecise meta-analyses actually produce less evidence than, for instance, a well conducted large observational study or a proper multicenter randomized controlled trial. Based on these considerations and the results of our review, we make the following recommendations to different stakeholders about how to deal with meta-analyses regarding COVID-19. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,247,927,393]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To policy makers: meta-analyses are undeniably important for policy makers, so that they can design and implement policies employing on reliable evidence-based information. However, current meta-analyses about COVID-19 are of limited quality and, in some cases, have discrepant results. Thus, in these times of uncertain evidence, decision-making should not blindly rely on meta-analyses, but rather on a deep analysis of literature and the evidence it contains. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,395,927,740]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To researchers and authors of meta-analyses: new meta-analyses about COVID-19 are welcome, as long as they provide new high-quality evidence. Low-quality meta-analyses (premature, redundant, dubious, inconclusive, or performed with suboptimal practices) are counterproductive, for impairing proper evidence synthesis. Thus, we suggest that prospective authors of meta-analyses perform a serious critical appraisal about the need for their meta-analyses. The following factors should be evaluated: whether there is enough data to perform a meta-analysis; if the available data seems reliable, comparable and free from heterogeneity; whether other meta-analyses in the same field have already been published or protocols have been registered. Researchers should rely on a search of protocol registrations for systematic reviews and meta-analyses to avoid duplicated and redundant efforts. Quality and methodological robustness should not be overlooked in favor of rapid publication, or it is likely that the quality of the review will be poor (as seen in our results). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[512,742,927,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To journals and publishers: meta-analyses usually lead to a fair amount of citations and good visibility to journals publishing them.[28] Thus, in the current situation, journals might feel tempted to publish meta-analyses, while ignoring faulty methods and low-quality procedures. Interestingly, as the number of articles about COVID-19 has increased, so has the number of articles being withdrawn and retracted.[29] Journals should comply with their social role of being a media for evidence-based science. Recent discussions have highlighted the role of journals in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[68,22,524,32]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[845,25,929,41]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,960,220,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[494,967,504,978]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"6 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[63,66,487,214]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"promoting the publication of high-quality meta-analyses, while discouraging those that do not follow optimal methodological standards. $^{(30)}$ This is especially relevant in the current situation. Peer review can be made faster, as long as its quality and fairness are not compromised. We would suggest that a researcher with experience in meta-analyses is always included as a reviewer, or to have a statistician on the editorial board, to ensure that faulty or low-quality meta-analyses are not published. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,215,487,561]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A few points need to be considered for a proper interpretation of our study: this is a scoping review, rather than a systematic review. Thus, rather than aiming to perform a meta-analysis ourselves, our review was intended to describe a panorama about the current meta-analyses about COVID-19, focusing on the general framework of the field, instead of on the individual aspects of each study; - we decided to exclude systematic reviews with no meta-analyses. This is because our focus was on evidence synthesis, which is much reduced in reviews not including meta-analyses, and also, in many cases, the term \\\"systematic review\\\" is misused.[31] However, an enormous amount of systematic reviews has been published, whose quality has already been appraised in a previous article.[32] This is a time-restrained review. In the near future, meta-analyses on most aspects of COVID-19 will probably become viable. However, a study focusing attention on the quality of meta-analyses published so far in respect of COVID-19 is timely; and the call to prioritize attention on high-quality meta-analyses is important. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[65,588,184,604]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CONCLUSION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,607,487,757]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Meta-analyses are an important tool in evidence-based medicine. The number of meta-analyses in respect of COVID-19 is increasing and will continue to rise. We believe that meta-analyses will play an important role in COVID-19, defining its epidemiological characteristics, the most suitable treatments, and supporting policymaking. However, while we do support the need for meta-analyses about COVID-19, it should not be taken as a license to produce them indiscriminately. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[63,757,487,923]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Although some very well-designed meta-analyses about COVID-19 have already been published, the majority published so far are of poor quality, and are likely to causes more harm than good. Few meta-analysis about COVID-19 in our review could be considered as of high quality, while more than a half were considered of critically low quality. Thus, all stakeholders playing a role in COVID-19 research and publication (including policy makers, researchers, publishers and journals) should focus on proper evidence-based research, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,66,929,132]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"supporting well designed meta-analyses, performed only when the background information seems suitable, and discourage those of low quality or that use suboptimal methods. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,160,685,176]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACKNOWLEDGMENT \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,181,929,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gabriel Natan Pires is supported by grants and funding from the Associacao Fundo de Incentivo à Pesquisa (AFIP). Sergio Tufik and Monica Levy Andersen are supported by grants and funding from AFIP, Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES - Finance Code 001) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Samuel Fen I Chen, Thainá Baenninger de Oliveira and Victor Luiz Selva Pinto are supported by grants from CAPES. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[521,387,721,402]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"AUTHOR' INFORMATION \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[519,406,813,419]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pires GN: http://orcid.org/0000-0003-0411-0111 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[521,421,831,433]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Bezerra AG: http://orcid.org/0000-0001-5534-6138 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,435,828,448]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Oliveira TB: http://orcid.org/0000-0003-2552-9851 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,448,811,462]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Chen SF: http://orcid.org/0000-0002-6870-9169 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,462,833,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Malfatti VD: http://orcid.org/0000-0003-2037-5013 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,477,816,490]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Mello VF: http://orcid.org/0000-0002-6711-2299 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,491,818,504]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Niyama A: http://orcid.org/0000-0002-7343-8893 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,505,813,518]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pinto VL: http://orcid.org/0000-0001-8565-7017 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,519,843,530]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Andersen ML: http://orcid.org/0000-0002-1894-6748 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[522,532,800,544]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Tufik S: http://orcid.org/0000-0002-3804-8865 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,588,626,602]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"REFERENCES \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,607,929,921]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": \"[\\\"1. 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Milbank Q. 2016;94(3):485-514. \\\",\\\"23. Chevret S, Ferguson ND, Bellomo R. Are systematic reviews and meta-analyses still useful research? No. Intensive Care Med. 2018;44(4):515-7. \\\",\\\"24. Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med. 2020;75:107-8. \\\",\\\"25. Guo FR. Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis. Tob Induc Dis. 2020;18:37. \\\",\\\"26. Simons D, Shahab L, Brown J, Perski O. The association of smoking status with SARS-CoV-2 infection, hospitalization and mortality from COVID-19: a living rapid evidence review with Bayesian meta-analyses (version 7). Addiction. 2020 Oct 2:10.1111/add.15276. Review. \\\",\\\"27. Murad MH, Asi N, Alsawas M, Allahdab F. New evidence pyramid. Evid Based Med. 2016;21(4):125-7. \\\",\\\"28. Patsopoulos NA, Analatos AA, Ioannidis JP. Relative citation impact of various study designs in the health sciences. JAMA. 2005;293(19):2362-6. \\\",\\\"29. Agoramoorthy G, Hsu MJ, Shieh P. Queries on the COVID-19 quick publishing ethics. Bioethics. 2020;34(6):633-4. \\\",\\\"30. Annane D, Jaeschke R, Guyatt G. Are systematic reviews and meta-analyses still useful research? Yes. Intensive Care Med. 2018;44(4):512-4. \\\",\\\"31. Paul M, Leibovici L. Systematic review or meta-analysis? Their place in the evidence hierarchy. Clin Microbiol Infect. 2014;20(2):97-100. Review. \\\",\\\"32. Pericas JM, Torrallardona-Murphy O, Arenas A, Valero H, Nicolas D. Profile and quality of published reviews on COVID-19. Eur J Clin Invest. 2020 May 30:e13293. doi: 10.1111/eci.13293. [Epub ahead of print]. \\\"]\",\n \"page_idx\": \"7\",\n \"sub_type\": \"ref_text\",\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"list\"\n },\n {\n \"bbox\": \"[67,21,524,34]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Pires GN, Bezerra AG, Oliveira TB, Chen SF, Malfatti VD, Mello VF, Niyama A, Pinto VL, Andersen ML, Tufik S \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[843,25,929,42]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[68,959,220,970]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"einstein (São Paulo). 2021;19:1-8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[492,967,504,979]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"8 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n }\n]","isConversational":false},"doi":{"kind":"string","value":"10.31744/einstein_journal/2021ao6002"},"is_oa":{"kind":"bool","value":true,"string":"true"},"language":{"kind":"string","value":"en"},"sci_category":{"kind":"string","value":"Medicine and Health Sciences"},"sha256":{"kind":"string","value":"9243ad8865b718d09f1c82ff9eb6d2561d278758b305245a2365bcc62fe0fe4b"},"title":{"kind":"string","value":"COVID-19 meta-analyses: a scoping review and quality assessment"}}},{"rowIdx":186,"cells":{"abstract":{"kind":"string","value":"IntroductionExposure to trauma among U.S. military veterans occurs at a high rate, often resulting in continued difficulty with emotional adjustment and a diagnosis of posttraumatic stress disorder (PTSD). The present study provides data from 184 U.S. military veterans who completed a manualized posttraumatic-growth oriented training program during an integrative seven-day retreat.MethodsData was collected at baseline, after program completion, and at 18-month follow-up.ResultsResults on primary outcomes indicated significant increases, with medium to large effect sizes, in growth related outcomes. Specifically, there was a significant increase in scores by 54% on the posttraumatic growth outcome measure (PTGI-X) from baseline (M = 50.2, SD = 31.1) to endpoint (M = 77.4, SD = 29.6), t(183) = −8.78, p < 0.001. Also, results indicate that immediately following training (Day 7), participants reported a significant decrease of 49% on the PCL-5 from baseline (M = 39.7, SD = 17.6) to endpoint (M = 20.1, SD = 13.2), t(183) = 11.75, p < 0.001. Depression subscale scores decreased by 60% from baseline (M = 8.0, SD = 5.2) to endpoint (M = 3.2, SD = 3.0), t(183) = 10.68, p < 0.001; Anxiety scores decreased by 28% from baseline (M = 5.8, SD = 4.3) to endpoint (M = 4.2, SD = 3.5), t(183) = 4.08, p < 0.001; and Stress scores decreased by 50% from baseline (M = 10.0, SD = 4.4) to endpoint (M = 5.0, SD = 3.3), t(183) = 12.21, p < 0.001. Eighteen-month follow-up data was available for 74 participants and indicated that all significant changes in growth-related outcomes were maintained. Further, all significant changes in symptomatology-related outcomes were also maintained at follow-up.DiscussionThese findings demonstrate both the immediate and the long-lasting impact of an integrative posttraumatic growth-oriented training program on psychological growth and PTSD symptom reduction among U.S. military veterans."},"author":{"kind":"string","value":"Cameron T. Alldredge|Bret A. Moore|Richard G. Tedeschi|Gary R. Elkins|Joshua R. Rhodes"},"content_list":{"kind":"list like","value":[{"bbox":"[80,148,206,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Check for updates ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,187,163,197]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"OPEN ACCESS ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,205,129,214]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"EDITED BY ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,216,161,225]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Vittorio Lenz, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,225,221,237]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"University of Catania, Italy ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,243,142,252]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"REVIEWED BY ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,254,189,263]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Jenny Ann Rydberg, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,265,242,275]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Université de Lorraine, France ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,275,159,285]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Chiara Fioretti, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,286,221,297]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"University of Salerno, Italy ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,303,174,312]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"*CORRESPONDENCE ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,313,154,323]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gary R. Elkins ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,325,220,335]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"gary_elkins@baylor.edu ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,340,220,350]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RECEIVED 16 October 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,351,233,361]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"ACCEPTED 11 December 2023 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,362,226,372]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PUBLISHED 05 January 2024 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,380,126,388]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"CITATION ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,390,273,410]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes JR, Tedeschi RG, Moore BA, Alldredge CT and Elkins GR (2024) ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,411,315,453]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Posttraumatic growth-oriented peer-based training among U.S. veterans: evaluation of post-intervention and long-term follow-up outcomes. 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This is an open-access article ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,514,314,524]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"distributed under the terms of the Creative ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,524,314,533]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Commons Attribution License (CC BY). The ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,535,305,545]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"use, distribution or reproduction in other ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,546,305,556]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"forums is permitted, provided the original ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,556,312,567]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"author(s) and the copyright owner(s) are ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,568,314,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"credited and that the original publication in ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,579,290,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"this journal is cited, in accordance with ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,590,280,598]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"accepted academic practice. No use, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,599,302,609]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"distribution or reproduction is permitted ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,609,305,620]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"which does not comply with these terms. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[394,143,904,292]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Posttraumatic growth-oriented peer-based training among U.S. veterans: evaluation of post-intervention and long-term follow-up outcomes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[393,305,880,338]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Joshua R. Rhodes<sup>1</sup>, Richard G. Tedeschi<sup>2</sup>, Bret A. Moore<sup>2</sup>, Cameron T. Alldredge<sup>3</sup> and Gary R. Elkins<sup>3*</sup> ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,346,892,379]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"$^{1}$ Department of Psychology, Abilene Christian University, Abilene, TX, United States, $^{2}$ Boulder Crest Institute for Posttraumatic Growth, Bluemont, VA, United States, $^{3}$ Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,401,917,486]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Introduction: Exposure to trauma among U.S. military veterans occurs at a high rate, often resulting in continued difficulty with emotional adjustment and a diagnosis of posttraumatic stress disorder (PTSD). The present study provides data from 184 U.S. military veterans who completed a manualized posttraumatic-growth oriented training program during an integrative seven-day retreat. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,491,917,519]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Methods: Data was collected at baseline, after program completion, and at 18-month follow-up. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,523,917,765]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results: Results on primary outcomes indicated significant increases, with medium to large effect sizes, in growth related outcomes. Specifically, there was a significant increase in scores by $54\\%$ on the posttraumatic growth outcome measure (PTGI-X) from baseline $(M = 50.2, SD = 31.1)$ to endpoint $(M = 77.4, SD = 29.6)$ , $t(183) = -8.78$ , $p < 0.001$ . Also, results indicate that immediately following training (Day 7), participants reported a significant decrease of $49\\%$ on the PCL-5 from baseline $(M = 39.7, SD = 17.6)$ to endpoint $(M = 20.1, SD = 13.2)$ , $t(183) = 11.75$ , $p < 0.001$ . Depression subscale scores decreased by $60\\%$ from baseline $(M = 8.0, SD = 5.2)$ to endpoint $(M = 3.2, SD = 3.0)$ , $t(183) = 10.68$ , $p < 0.001$ ; Anxiety scores decreased by $28\\%$ from baseline $(M = 5.8, SD = 4.3)$ to endpoint $(M = 4.2, SD = 3.5)$ , $t(183) = 4.08$ , $p < 0.001$ ; and Stress scores decreased by $50\\%$ from baseline $(M = 10.0, SD = 4.4)$ to endpoint $(M = 5.0, SD = 3.3)$ , $t(183) = 12.21$ , $p < 0.001$ . Eighteen-month follow-up data was available for 74 participants and indicated that all significant changes in growth-related outcomes were maintained. Further, all significant changes in symptomatology-related outcomes were also maintained at follow-up. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,769,917,826]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion: These findings demonstrate both the immediate and the long-lasting impact of an integrative posttraumatic growth-oriented training program on psychological growth and PTSD symptom reduction among U.S. military veterans. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[394,844,450,854]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"KEYWORDS ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[393,859,897,884]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"veterans, posttraumatic growth, trauma, posttraumatic stress disorder, Boulder Crest Foundation ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,39,383,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiers | Frontiers in Psychology ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[736,38,860,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"TYPE Original Research ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[736,49,887,59]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PUBLISHED 05 January 2024 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[736,60,917,71]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"DOI 10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,211,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,948,507,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"01 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,948,915,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"0","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,90,213,105]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Introduction ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,122,487,306]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Exposure to trauma among military veterans is very prevalent, with approximately $87\\%$ of U.S. veterans reporting exposure to at least one potentially traumatic event (Wisco et al., 2014). Whether or not these reported traumatic events are directly or indirectly related to one's military service, evidence shows the effects of trauma are causing veterans to experience serious difficulties with emotional adjustment (McKinney et al., 2017), resulting in 17.2 Veteran suicides per day in 2019, a number that has remained practically unchanged since 2001 (U.S. Department of Veterans Affairs, 2021). Of this population, individuals ages 55-74 were at the highest risk, accounting for approximately $39\\%$ of veteran deaths by suicide in 2019. A notable diagnosis aiming to capture much of this struggle with emotional adjustment following trauma is posttraumatic stress disorder (PTSD). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,307,487,662]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Presentation of PTSD related symptoms may vary across individuals from distinct wars, cultures, and genders as they have been exposed to varying specific traumas (Dutra et al., 2019). Exposure to specific traumas results in differing duration of symptoms, perception of treatment, and treatment response. For example, Chard et al. (2010) found that veterans from the Vietnam war exhibited significantly less symptom reduction following cognitive processing therapy (CPT) when compared to veterans from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). The experience of trauma related symptoms is also moderated by gender as men are more likely to report trauma resulting from exposure to combat when compared to women (Macera et al., 2014; Polusny et al., 2014) and women are more likely to experience military sexual trauma (Haskell et al., 2010; Kimerling et al., 2010). The high rate of comorbidity between PTSD and other psychiatric disorders can lead to difficulty in both its diagnoses and the identification of an optimal treatment plan. For example, while much of the current research focuses on PTSD diagnoses, many veterans also struggle with depression and anxiety. Studies estimate that $9.6\\%$ of veterans struggle with and receive a diagnosis of depression (Liu et al., 2019) and the prevalence of diagnosed anxiety disorder incidence rates varies widely from 0.01 to 23.7 per 1,000 service members (Russell et al., 2022). Differential diagnoses will highlight different aspects of PTSD symptom presentation and require different treatment modalities to avoid being ineffective or exacerbating the comorbid symptoms. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,664,487,876]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The U.S. Veterans Affairs/Department of Defense (2017) clinical practice guidelines recommend a tiered approach to PTSD treatment. The first recommendation cited to have the strongest evidence is individual, manualized, trauma-focused psychotherapy. These first-line therapies include Prolonged Exposure therapy (PE; Foa et al., 2005, 2018), Cognitive Processing Therapy (CPT; Resick et al., 2002), and Eye Movement Desensitization and Reprocessing therapy (EMDR; Shapiro, 1989; Rothbaum et al., 2005; Valiente-Gomez et al., 2017). Second tier treatment, per the VA/DOD guidelines (2017) are non-trauma, manualized therapies or pharmacotherapy. Non-trauma focused, manualized therapies include stress inoculation training and present-centered therapy. The recommended pharmacotherapies include three selective serotonin reuptake inhibitors (SSRIs; paroxetine, sertraline, and fluoxetine) and one selective norepinephrine reuptake inhibitor (SNRI; venlafaxine). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,878,487,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The current psychotherapeutic treatment modalities have seemed to exhibit particularly high efficacy in their reduction of PTSD symptomatology specifically. Prolonged Exposure therapy has been ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,93,915,505]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"shown to reduce PTSD symptomatology with a pre-post effect size of $d = 0.87$ (Eftekhari et al., 2013). A meta-analysis of Cognitive Processing therapy for PTSD symptom reduction found an effect size of $g = 1.24$ when compared to control conditions (Asmundson et al., 2019). Further evidence with a more broad view is found in a meta-analysis of exposure therapies (not treatment specific), reporting a significant reduction in PTSD symptoms when compared to control conditions with an effect size of $g = 0.86$ (McLean et al., 2022). A meta-analysis examining the use of EMDR for PTSD symptom reduction found an overall effect size of $g = -0.64$ (Chen et al., 2014). The effect sizes found for the reduction of PTSD symptoms through pharmacotherapy are generally much lower, with a meta-analysis finding SSRIs to be statistically superior to placebo administration but with a small effect size ( $d = 0.23$ ; Hoskins et al., 2015). While the evidence indicates that individuals can benefit from trauma-focused, manualized therapies, the consensus on whether they significantly outperform non-trauma-focused therapies has been called into question. Recent studies have exhibited mixed-results as to whether patients are receiving clinically meaningful benefit from first-line therapies such as PE and CPT (Steenkamp et al., 2020). Furthermore, these first-line therapies have been found to be only marginally superior to non-trauma focused therapies and active control groups (Steenkamp et al., 2015). While these first-line therapies provide great benefit for some, they are not without their limitations, namely high nonresponse, underresponse, and dropout rates among participants (Steenkamp et al., 2020). Together these findings indicate that the highly complex nature of PTSD and the management of these symptoms within a military population may not be a good match for a one-size-fits-all treatment approach (Steenkamp et al., 2020). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,507,915,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The framework of clinical work with military veterans has largely been focused on the identification of PTSD symptoms and symptom reduction following trauma exposure. The identification of the individual's struggle and the goal of reducing their suffering are not only admirable, but are essential for providing help to countless veterans. The current model of PTSD and its treatment has proven to be efficacious in the reduction of PTSD specific symptoms but seems to fall short in addressing the existential needs and issues veterans face. The difficulty engaging veterans in long-term treatment across months has led to decreased satisfaction across treatment modalities, even though their completion seems to promise significant symptom reduction (Kehle-Forbes et al., 2016; Smith et al., 2019). Alternatively, intensive treatment programs (one or two weeks) have been examined as a potential way to improve on the high dropout rate and limited engagement among individuals (Hendriks et al., 2018; Watkins et al., 2018). While the evidence indicates that massed, trauma-focused therapies are beneficial (Hendriks et al., 2018), they do not directly address the potential for posttraumatic growth and there is limited research on intensive treatment programs influenced by posttraumatic growth theory. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,791,915,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Posttraumatic growth (PTG) is defined as positive psychological changes that can be experienced as a result of the struggle in the aftermath of traumatic or highly challenging circumstances (Tedeschi et al., 2018). Posttraumatic growth theory, largely influenced by Janoff-Bulman (1989), assumes that trauma involves emotional distress as a result of core beliefs being shattered following traumatic events. The disruption of the core belief system leads to struggle and the potential for transformative outcomes and growth. The concept of struggle refers to the difficulties encountered in the process of reconstructing ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,38,915,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,208,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,948,505,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"02 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[836,948,915,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"1","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[77,93,490,164]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"one's core beliefs. The struggle and distress can often prompt deliberative rumination within the individual. When paired with disclosure to a trusted individual, this deliberative rumination can aid in the process of reconceptualizing one's core belief system (Tedeschi and Moore, 2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,165,489,292]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Posttraumatic growth has been shown to exhibit itself in five domains across individuals (Tedeschi and Calhoun, 1996; Tedeschi et al., 2017). This five-factor model has been established through factor analysis of the posttraumatic growth inventory (PTGI; Tedeschi and Calhoun, 1996; Tedeschi et al., 2017) and several other studies (Linley et al., 2007; Taku et al., 2008; Brunet et al., 2010; Lee et al., 2010). The five domains identified in prior research include: Relating to Others, Personal Strength, Appreciation of Life, New Possibilities, and Spiritual-Existential Change. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,292,489,376]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The domain of Relating to Others in PTG reflects a deeper emotional quality to relationships, often paired with an increased sense of mutual respect, disclosure, openness, and compassion (Moore et al., 2021). As trauma survivors disclose their experiences, an empathic listener can be very important in the process (Tedeschi and Calhoun, 2006). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,378,490,463]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The domain of Personal Strength is often exhibited after the individual has simply managed to survive the trauma and its aftermath. Reflection on the experience can instill a greater sense of personal strength as they recognize the self-reliance and courage it took to reach where they are (Tedeschi and Calhoun, 1996; Moore et al., 2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,464,490,533]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Appreciation of Life includes a new perspective that allows the individual to experience a new sense of gratitude for things previously overlooked. This increased sense of appreciation is often the result of actual loss or having narrowly escaped the loss (Tedeschi and Calhoun, 1996; Moore et al., 2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,535,490,648]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Traumatic experiences involve loss of things such as capabilities, roles, relationships and alter an anticipated future. In the struggle to deal with such significant loss, it is possible that new ways to live are discovered. The recognition of new possibilities for a positive future may be essential to developing PTG (Roepke and Seligman, 2015). The search for fulfillment in areas previously unconsidered, is referred to as the domain of New Possibilities (Tedeschi and Calhoun, 1996; Moore et al., 2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,649,489,776]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The domain of Spiritual-Existential Change may occur when individuals reconsider existential issues and potentially reconfigure their beliefs and belief systems as a result of their experience with trauma (Tedeschi and Calhoun, 1996; Moore et al., 2021). The impact of traumatic events can cause survivors to consider existential questions such as life meaning and purpose (Tedeschi and Riffle, 2016). Also, for many survivors of trauma, considerations of forgiveness, spirituality, and religious beliefs may be an important component of PTG (Schultz et al., 2010). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,778,490,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rather than being a new form of therapy, PTG-based intervention is an integrative approach that utilizes elements and research knowledge drawn from several existing approaches, specifically: cognitive-behavioral, narrative, existential, and interpersonal. PTG-based intervention acknowledges the evolving evidence base for trauma interventions within a philosophy that proposes that trauma survivors can both achieve symptom reduction and experience transformative posttraumatic growth (Tedeschi and Moore, 2021) in the five domains of PTG. It is not simply focused on symptom reduction (although PTG-based intervention may result in reduced ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,93,919,178]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"trauma related symptoms), but promotes and emphasizes the importance of managing emotional distress and moving toward growth that would not have been likely if not for the struggle with the traumatic events. The PTG model of intervention is unique in the emphasis on PTG, but also integrates four primary elements of existing approaches listed below. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,179,919,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Cognitive-behavioral interventions identify change in core beliefs and cognitions as underlying mechanisms of change. Core beliefs may be formulated in early life and people often make assumptions about themselves and the world that may go unexamined until encountering trauma that disrupts one's \"assumptive world\" (Janoff-Bulman, 1989). Therefore, the PTG intervention model is directed toward schema change (Janoff-Bulman, 2006) using a variety of methods. The process of reconstructing one's core belief system is an evidence-based approach that is a foundation for cognitive processing therapy (Resick et al., 2008) as well as PTG-based intervention. Further, many trauma survivors must achieve a sufficient degree of emotional regulation before being able to tolerate the emotional stress associated with schema change. Therefore, psychoeducation about trauma reactions and teaching emotional regulation methods (i.e., relaxation, mindfulness, present-moment awareness, etc.) are an integral component of the PTG integrative intervention approach. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,420,917,563]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PTG-based intervention also integrates the concept of developing a new life narrative into its approach. With the revision of core beliefs, trauma survivors are often tasked with making personal decisions about what kind of life they wish to have in the future and incorporating the past trauma into their personal narrative of their past, present, and future. Narrative therapies, such as those delivered through expressive writing and reflection have been shown to have positive effects on PTG (Hijazi et al., 2014). Interventions that integrate narrative development have been shown to be of benefit with a range of trauma survivors (Neimeyer, 2006; Smyth et al., 2008). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,564,917,690]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Along with core belief and narrative examination, the struggle with the aftermath of trauma often leads to an awareness of existential questions such as meaning and purpose of trauma and their lives. Survivors may struggle with questions about fairness, justice, and finding new meaning and purpose following significant loss (Frankl, 1962). The existential element is drawn from the concepts within logotherapy and existential therapy generally (Tedeschi and Riffle, 2016). Examination of existential issues is deliberately addressed within the PTG-based approach. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,692,917,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Interpersonal and \"common factors\" have been shown to be significant components of most psychotherapeutic interventions (Norcross and Wampold, 2011). In the PTG-based intervention, individuals called \"expert guides\" are individuals trained in providing a supportive environment, non-judgmental listening, unconditional positive regard, and activities toward promoting growth beyond symptom reduction (Calhoun and Tedeschi, 2013). This interpersonal element provides the foundation for trauma survivors to expand their support system, construct new core beliefs, and personal narrative that promotes posttraumatic growth. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,834,917,920]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PTG-based intervention is provided by individuals trained in providing \"expert companionship\" often referred to as \"expert guides.\" PTG-based intervention is conceptualized as a training program that follows the natural process following the aftermath of trauma. The goals are not limited to symptom reduction, but include managing distress, and achieving growth in multiple domains. There are five ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,38,151,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,38,917,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,211,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[489,948,507,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"03 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,948,915,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"2","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,93,485,120]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"general components in the structure of PTG-based intervention (Calhoun and Tedeschi, 2013). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,122,487,277]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Psychoeducation is provided regarding how trauma symptoms develop (Barlow, 2014) and understanding distressing symptoms (Meichenbaum, 2012). Further, psychoeducation is provided regarding the potential of PTG, the domains of PTG, and sharing personal examples. This includes a discussion of how core beliefs have been disrupted and how a reconceptualization and development of new core beliefs can be transformative toward living well and thriving in the aftermath of trauma (Calhoun and Tedeschi, 2013; Tedeschi and Moore, 2021). In addition, assurance about facing and addressing existential questions is provided within a caring and non-judgmental interpersonal relationship. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,279,487,405]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Teaching and practicing methods of emotional regulation is integrated throughout the structure of PTG-based intervention. This includes relaxation, focus on breathing, grounding techniques, mindfulness exercises, meditation, relaxed music listening, and exercise. Experiential practice is demonstrated and emphasized over intellectual understanding of these emotional regulation techniques. It is beneficial to allow survivors to experience a variety of ways to regulate emotions and select personal preferences to apply to their own lives (Cooper et al., 2019). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,407,487,562]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Disclosure is essential within the PTG-based intervention structure. Disclosure is modeled by the \"expert guides\" and a safe and supportive environment is fostered. However, in contrast to exposure-based therapies (Peterson et al., 2019), the disclosure is not focused on the specifics of the traumatic events, but on the impact of these events on the individual's core belief system about self, others, the world, and the future (Williams et al., 2019). Disclosure about one's personal life story broadly defined is encouraged within a non-judgmental context. Openness to sharing key personal life events, influences, successes, perceived failures, and decreasing defensiveness are important aspects of self-reflection and a sense of being accepted. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,564,487,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Development of a personal \"life story\" brings together an understanding of key past experiences, perhaps extending into childhood. It is not simply disclosure about the traumatic event. Rather, the development of the survivor's personal story includes the trauma in the context of entire past and future. It includes looking forward and consideration of new possibilities for the future and new ways of understanding the past. The narrative may bring up past events, regrets, guilt, or unresolved anger. Some aspects may require acceptance and other change in moving toward the future with growth. Development of a new \"life story\" narrative is achieved with the support of the \"expert guide\" and in the process of disclosure. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,721,487,804]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"As posttraumatic growth occurs, survivors may have new insights, goals, sense of meaning and purpose. An awareness of ways they can support the growth of others who may have experienced their own traumas, leads to a stronger connection with family and community. This can be manifested in new goals in life and awareness of service to help others and sharing their experience of PTG. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,806,487,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The Warrior PATHH (Progressive and Alternative Training for Helping Heroes) program is the flagship program of the Boulder Crest Foundation (BCF), a non-profit organization focused on the psychological health of U.S. veterans. The Warrior PATHH program is a 7 days intensive residency program developed to provide PTG-based training and experiences to veterans. The program consists of 48 psychoeducational modules, which are described in a 200-page guide developed for program instructors. Although the program does not offer traditional, evidenced-based psychotherapies, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,93,915,376]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"the program does utilize a variety of complementary and alternative interventions (e.g., mindfulness/meditation, yoga, equine therapy) and traditional psychotherapeutic techniques (e.g., psychoeducation, distress management, relationship building, narrative development, goal setting). A unique aspect of Warrior PATHH is that it is peer-delivered and is not run or managed by mental health professionals. This is an important component of the program as those working within Warrior PATHH are veterans who understand the unique needs and professional culture of those who attend the program. The peers who deliver the bulk of the program are combat veterans who have undergone several months of training from peer leaders with years of experience delivering the program as well as licensed mental health professionals. Peers delivering the program receive ongoing training and consultation from these same peer leaders and professionals. Consequently, Warrior PATHH is considered a training program as opposed to a treatment program. Following the residential portion of the program, a structured 18 months of follow-up is offered through a web-based series of meetings and assignments. A more complete description of the Warrior PATHH program can be found in Moore et al. (2021). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,378,915,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"While the PTG-based intervention approach of Warrior PATHH has been well developed and manualized, to date there has been limited outcome research. A small pilot study of the Warrior PATHH posttraumatic growth-based intervention program found significant, large reductions in symptomatology including PTSD, insomnia, and negative affect (Moore et al., 2021). Additionally, results indicated significant increases in areas of PTG and psychological flexibility. While these results are encouraging, they do not report immediate outcomes of study participants, resulting in the inability to gather a full picture of immediate and long-term effects. Without the report of immediate outcomes, one does not know about the trajectory of benefit to participants and cannot determine any lasting changes. The purpose of the present study was to address this gap in research by conducting a retrospective evaluation of a much larger sample of veterans with PTSD symptoms who completed the Warrior PATHH program. Outcome data were collected at baseline, after the 7 day program was completed, and at 18 months follow-up. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,646,591,661]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Method ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,678,915,833]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Participants were United States combat Veterans completing the Warrior PATHH program. Participants were self-referred and most commonly learned about the program from other veterans and family members familiar with the training program. Participation in the training program was free of cost to all participants and they received no compensation for completing the training. Inclusion criteria for the Warrior PATHH program were individuals who were (1) U.S. military Veterans and (2) had a previous history of trauma. Individuals were excluded from participation if they (1) were diagnosed with any disorder that might require hospitalization, such as psychosis, substance abuse, or active suicidality. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,835,915,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data collection for all participants occurred prior to the initiation of the program (Day 0), which will be referred to as baseline; at the end of the training (Day 7), which will be referred to as endpoint; and 18 months following the completion of training, which will be referred to as follow-up. The formal evaluation at baseline, endpoint, and follow-up was completed through the administration of an electronic questionnaire. A selection of measurements relating to growth and symptomatology ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,39,915,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,210,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,948,507,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"04 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[836,948,915,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"3","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,93,485,120]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"domains are reported in this manuscript. All measurement tools listed were collected at baseline, endpoint, and 18-month follow-up. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,147,169,162]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Measures ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,179,487,334]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Posttraumatic Growth Inventory - Expanded (PTGI-X). The PTGI-X (Tedeschi et al., 2017) is a 25-item self-report measure used to assess the extent to which individuals report positive psychological change following the experience of a traumatic event. Five subscales of this measure assess changes in one's perception of new possibilities, relating to others, personal strength, appreciation of life, and spiritual existential change. Individual items are on a 6-point Likert scale ranging from \"I did not experience this change\" to \"I experienced this change to a very great degree.\" Good internal consistency $(\\alpha = 0.90$ ; Tedeschi et al., 2017) and content validity has been shown in research (Shakespeare-Finch et al., 2013). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,335,487,434]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Positive and Negative Affect Schedule (PANAS). The PANAS (Watson et al., 1988) is a 20-item self-report measure for both positive and negative affect. Individual item responses are on a 5-point frequency scale ranging from \"not at all\" to \"extremely.\" Strong reliability for both the positive $(\\alpha = 0.89)$ and negative subscale $(\\alpha = 0.85)$ and construct validity has been reported in addition to substantial available normative data (Crawford and Henry, 2004). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,435,487,533]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Integration of Stressful Life Experiences Scale (ISLES). The ISLES (Holland et al., 2010) is a 16-item self-report measure used to assess the extent of meaning made following a stressful life experience. Individual items are on a 5-point Likert scale ranging from \"strongly agree\" to \"strongly disagree.\" The ISLES has exhibited strong internal consistency, strong convergent validity, and moderate test-retest reliability (Holland et al., 2010). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,535,487,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Posttraumatic Stress Disorder Checklist DSM 5 (PCL-5). The PCL-5 (Weathers et al., 2013) is a 20-item self-report measure assessing DSM-5 symptoms of PTSD. Individual item responses are on a 5-point frequency scale ranging from \"not at all\" to \"extremely.\" Strong construct validity $(\\alpha = 0.92)$ and test-retest reliability $(r = 0.57)$ has been found in veteran samples (Bovin et al., 2015; Dutra et al., 2019). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,620,487,719]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Depression, Anxiety, and Stress Scale (DASS). The DASS (Antony et al., 1998) is a 21-item self-report measures of the presence and degree of depression, anxiety, and stress-related symptoms. Individual item responses are on a 4-point frequency scale ranging from \"never\" to \"almost always.\" Adequate test-retest reliability ( $\\alpha = 0.86 - 0.90$ ; Gloster et al., 2008) in addition to discriminate and convergent validity has been shown in clinical samples (Brown et al., 1997). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,720,487,819]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Insomnia Severity Index (ISI). The ISI (Bastien et al., 2001) is a 7-item self-report measure, based on DSM-IV and the International Classification of Sleep Disorders criteria, used to assess insomnia over the past 2 weeks. Individual items are assessed on a 5-point Likert scale ranging from \"none\" to \"very severe.\" High reliability and validity have been shown for the ISI in both clinical $(\\alpha = 0.91)$ and community $(\\alpha = 0.90)$ samples (Morin et al., 2011). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,846,196,860]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Intervention ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,877,487,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Framed as an intensive training program for veterans, the evaluated program is the Warrior PATHH (Progressive and Alternative Training for Helping Heroes). The manualized, 7 days training program is based on posttraumatic growth theory and its intervention model (Tedeschi ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,93,915,419]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and McNally, 2011; Calhoun and Tedeschi, 2013; Tedeschi and Moore, 2016, 2018). During this 7 days period, participants are immersed in an all-day intensive regimen combining education and experiential activities. Participants who attend the Warrior PATHH program experienced the following five elements in accordance with the PTG model: psychoeducation about physiological and psychological trauma response and psychological growth; emotion regulation training, including mindfulness and meditative techniques; constructive self-disclosure about trauma and its aftermath that occurs naturally through casual discourse; non-trauma focused narrative development integrating perspectives of past, present, and future; and service goals that are developed to carry out the lessons learned about the value of life, living courageously, and understanding those who have not had the same experiences (Moore et al., 2021). Representing a relational approach to the intervention called Expert Companionship, those providing the intervention are referred to as \"expert guides.\" All expert guides that were responsible for delivering the intervention were U.S. combat veterans who underwent several months of training with established expert guides and mental health professionals trained in the PTG-based intervention. Delivered as a peer-to-peer training program, the Warrior PATHH program took place during a 7 days period at the BCF facility in Bluemont, Virginia, between February 2019 and December 2021. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,445,589,463]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Analyses ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,478,915,646]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Descriptive statistics at baseline, endpoint, and follow-up were calculated for each of the outcome measures. To determine immediate post-intervention effects, paired samples $t$ -tests were conducted for each outcome. Paired samples $t$ -tests are used to determine the statistical significance of the difference in scores on outcome measures from baseline to endpoint. The independent variable in these analyses was study time point which had two levels, baseline (Day 1) and endpoint (Day 7). Dependent variables in these analyses were growth domains, including posttraumatic growth, positive affect, and integration of stressful life experiences; and symptomatology domains, including PTSD symptoms, depression, anxiety, stress, negative affect, and insomnia. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,649,915,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the lasting effects of the Warrior PATHH program on growth and symptomatology domains a series of repeated measures analysis of variance (repeated measures ANOVA) were conducted, which are extensions of the paired-samples $t$ -tests. The independent variable for these repeated measures ANOVAs was \"time\" (baseline, endpoint, and follow-up). The dependent variables for these repeated measures ANOVAs were the specific outcome measures. In the event of a significant main effect of time, pairwise comparisons using a Bonferroni correction were examined to determine differences between specific study time points. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,791,915,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"To determine the moderating effect of gender on immediate and lasting post-intervention effects on growth and symptomatology domains, multiple analyses of covariance (ANCOVA) were conducted. The independent variable for these ANCOVAs examining immediate effects was \"gender,\" the dependent variables were the scores on the specific outcome measures at endpoint, and the covariates were the baseline score of the specific outcome. The independent variable for the ANCOVAs examining lasting effects was \"gender,\" the dependent variables were the scores of the specific outcome measure at follow-up, and the covariates were the endpoint score of the specific outcome. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,38,915,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,208,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,948,505,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"05 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[836,948,914,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"4","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,89,159,107]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,122,490,219]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Participants were 184 United States combat veterans (male = 155, female = 29) who completed the Warrior PATHH training program between February 2019 and December 2021. The most common U.S. military branch of service represented was Army $(n = 110)$ , with the second most frequent being Marine Corps. $(n = 32)$ . Frequencies of all participant demographic variables can be found in Table 1. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,221,489,322]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All participants $(n = 184)$ provided complete data at baseline and endpoint and were included in all analyses examining post-intervention changes. At the optional 18 months follow-up time point, 74 individuals completed outcome measures. Due to the nature of the statistical analyses examining long-term changes, only the 74 individuals who provided data at all three time points were included in the analyses of long-term changes at 18 months. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,347,438,378]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Post-intervention changes in growth domains ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,393,489,577]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A paired samples $t$ -test was used to compare scores on each growth-related outcome variable between baseline and endpoint. Results indicate that immediately following training (Day 7), participants reported a significant increase in scores by $54\\%$ on the posttraumatic growth outcome measure (PTGI-X) from baseline $(\\mathrm{M} = 50.2, \\mathrm{SD} = 31.1)$ to endpoint $(\\mathrm{M} = 77.4, \\mathrm{SD} = 29.6)$ , $t(183) = -8.78$ , $p < 0.001$ . Additionally, there was a significant increase in scores by $45\\%$ on the positive affect subscale of the PANAS from baseline $(\\mathrm{M} = 25.8, \\mathrm{SD} = 8.4)$ to endpoint $(\\mathrm{M} = 37.5, \\mathrm{SD} = 6.9)$ , $t(183) = -14.84$ , $p < 0.001$ . Finally, there was a significant increase in scores by $29\\%$ on the ISLES from baseline $(\\mathrm{M} = 39.2, \\mathrm{SD} = 12.9)$ to endpoint $(\\mathrm{M} = 50.4, \\mathrm{SD} = 10.9)$ , $t(183) = -9.13$ , $p < 0.001$ . Table 2 contains calculated effect sizes for each paired sample comparison. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,577,489,806]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Results from paired samples $t$ -tests for scores on each subscale of the PTGI-X indicate a significant difference between baseline and endpoint for New Possibilities (M = 10.6, SD = 7.3, M = 15.7, SD = 6.3, respectively), $t(183) = -7.13$ , $p < 0.001$ ; Personal Strength (M = 8.9, SD = 5.9, M = 13.8, SD = 4.8, respectively), $t(183) = -9.01$ , $p < 0.001$ ; Appreciation of Life (M = 8.22, SD = 4.2, M = 9.7, SD = 3.9, respectively), $t(183) = -3.71$ , $p < 0.001$ ; Relating to Others (M = 12.6, SD = 9.6, M = 21.5, SD = 9.5, respectively), $t(183) = -9.47$ , $p < 0.001$ ; and Spiritual-Existential Change (M = 10.0, SD = 8.4, M = 16.6, SD = 8.5, respectively), $t(183) = -7.54$ , $p < 0.001$ . Medium effect sizes were found for scores on the subscales of Relating to Others (Cohen's $d = -0.70$ ), Personal Strength (Cohen's $d = -0.66$ ), Spiritual-Existential Change (Cohen's $d = -0.56$ ), and New Possibilities (Cohen's $d = -0.53$ ), and there was a small effect size for scores on Appreciation of Life subscale (Cohen's $d = -0.27$ ). ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,832,354,863]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Post-intervention changes in symptomatology domains ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,877,490,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Next, a paired samples $t$ -test was used to compare scores on each symptomatology-related outcome variable between baseline ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,105,917,511]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0980/ebeb30d7d3a1a74a8fe51f19b3302f218d08cfeff900e1688a4363d1dce3bff1.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td>Demographic variable</td><td>Frequency</td></tr><tr><td>Gender</td><td></td></tr><tr><td>Male</td><td>155</td></tr><tr><td>Female</td><td>29</td></tr><tr><td>Age range</td><td></td></tr><tr><td>23–27</td><td>3</td></tr><tr><td>28–32</td><td>15</td></tr><tr><td>33–37</td><td>46</td></tr><tr><td>38–42</td><td>43</td></tr><tr><td>43–47</td><td>24</td></tr><tr><td>48 or older</td><td>53</td></tr><tr><td>Branch of service</td><td></td></tr><tr><td>Air Force</td><td>18</td></tr><tr><td>Army</td><td>110</td></tr><tr><td>First Responder</td><td>12</td></tr><tr><td>Marine Corps</td><td>32</td></tr><tr><td>Navy</td><td>12</td></tr><tr><td>Military Rank</td><td></td></tr><tr><td>E1-E4</td><td>32</td></tr><tr><td>E5-E6</td><td>69</td></tr><tr><td>E7 or above</td><td>41</td></tr><tr><td>Officer/Warrant Officer</td><td>31</td></tr><tr><td>Not specified</td><td>11</td></tr></table>","table_caption":"[\"TABLE 1 Participant demographics. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[507,545,917,620]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0503/11d8ca2d5a722d246148f514ac56b8ca5f9d8bd6db878412e99417ac88e7f2ab.jpg","list_items":null,"page_idx":"5","sub_type":null,"table_body":"<table><tr><td>Outcome</td><td>Effect Size (d)</td></tr><tr><td>PTG</td><td>-0.65</td></tr><tr><td>Positive affect</td><td>-1.09</td></tr><tr><td>ISLES</td><td>-0.67</td></tr></table>","table_caption":"[\"TABLE 2 Growth domains effect sizes. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[504,649,919,906]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"and endpoint. Results indicate that immediately following training (Day 7), participants reported a significant decrease in scores by $49\\%$ on the PCL-5 from baseline $(M = 39.7, SD = 17.6)$ to endpoint $(M = 20.1, SD = 13.2)$ , $t(183) = 11.75$ , $p < 0.001$ . A significant decrease in scores was reported for all subscales of the DASS. Depression subscale scores decreased by $60\\%$ from baseline $(M = 8.0, SD = 5.2)$ to endpoint $(M = 3.2, SD = 3.0)$ , $t(183) = 10.68$ , $p < 0.001$ ; anxiety subscale scores decreased by $28\\%$ from baseline $(M = 5.8, SD = 4.3)$ to endpoint $(M = 4.2, SD = 3.5)$ , $t(183) = 4.08$ , $p < 0.001$ ; and stress subscale scores decreased by $50\\%$ from baseline $(M = 10.0, SD = 4.4)$ to endpoint $(M = 5.0, SD = 3.3)$ , $t(183) = 12.21$ , $p < 0.001$ . Participant scores on the ISI significantly decreased by $36\\%$ from baseline $(M = 14.3, SD = 6.9)$ to endpoint $(M = 9.1, SD = 5.3)$ , $t(183) = 8.03$ , $p < 0.001$ . Finally, scores on the negative affect subscale of the PANAS significantly decreased by $16\\%$ from baseline $(M = 25.4, SD = 8.2)$ to endpoint $(M = 21.4, SD = 7.4)$ , $t(183) = 4.89$ , $p < 0.001$ . Table 3 contains calculated effect sizes for each paired sample comparison. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,38,151,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[759,38,917,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,211,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[489,948,507,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"06 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,948,917,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"5","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[78,91,445,108]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Long term changes in growth domains ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,121,489,306]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A series of independent samples $t$ -tests were first conducted to determine if the 74 participants who completed follow-up measures were representative of the entire sample. The test variable for each of these analyses was the baseline score of each outcome measure. The grouping variable used was (A = Participants who completed baseline and endpoint data; $n = 110$ ) and (B = participants who completed follow-up measures; $n = 74$ ). Results of these $t$ -tests indicate that there were no significant differences between groups on any outcome measure at baseline, with the exception of baseline depression (Mean Difference $= 1.59$ , $p = 0.041$ ) and baseline ISLES (Mean Difference $= 4.32$ , $p = 0.023$ ) scores. Overall, these findings suggest a follow-up sample representative of the entire sample. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,307,489,450]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A series of repeated measures ANOVAs were then conducted to examine changes in growth-related outcome measures over three time points (baseline, endpoint, and follow-up). The analysis on PTGI-X scores revealed a significant main effect of time, $F(2,146) = 21.26$ , $p < 0.001$ . Pairwise comparisons indicate that PTGI-X scores significantly increased by 27.1 points (52%) from baseline to endpoint ( $p < 0.001$ ) and remained stable until follow-up, exhibited by a further increase of 0.85 points ( $p = 1.00$ ) and a total increase of 54% between baseline and follow-up. The analysis on positive affect subscale scores also revealed a significant main effect ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,492,487,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0338/ab9e7514a52f37a5de033e163b02ea9e90eb5da74aa758677123ea68343001df.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td>Outcome</td><td>Effect Size (d)</td></tr><tr><td>PTSD</td><td>0.87</td></tr><tr><td>Depression</td><td>0.79</td></tr><tr><td>Anxiety</td><td>0.30</td></tr><tr><td>Stress</td><td>0.90</td></tr><tr><td>Insomnia</td><td>0.59</td></tr><tr><td>Negative affect</td><td>0.36</td></tr></table>","table_caption":"[\"TABLE 3 Symptomatology domains effect sizes. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[504,93,917,363]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"of time, $F(2,146) = 56.09$ , $p = < 0.001$ . Pairwise comparisons indicate that scores on the positive affect subscale significantly increased by 11.1 points (41%) from baseline to endpoint ( $p < 0.001$ ). Results indicate that between endpoint and follow-up, positive affect subscale scores significantly decreased by 8.2 points ( $p < 0.001$ ); however, there remained a significant difference between baseline and follow-up scores ( $p = 0.010$ ) exhibited by a total increase of 11% between baseline and follow-up. Regarding the analysis on ISLES scores, Mauchly's test indicated that the assumption of sphericity had been violated, $\\chi^2 (2) = 6.70$ , $p = 0.035$ , therefore the degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity ( $\\varepsilon = 0.918$ ). The results indicate a significant main effect of time, $F(1.84, 134.09) = 23.99$ , $p < 0.001$ . Pairwise comparisons indicate that ISLES scores significantly increased by 9.69 points (23%) from baseline to endpoint ( $p < 0.001$ ) and remained stable until follow-up, exhibited by a non-significant increase of 1.42 points ( $p = 1.00$ ) and a total increase of 27% from baseline to follow-up. Table 4 includes means and standard deviations for each growth-related outcome measure at each time point. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[504,363,917,621]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The analyses on PTGI-X subscale scores revealed a significant main effect of time for Appreciation of Life, $F(2,146) = 3.25$ , $p = 0.041$ ; Personal Strength, $F(2,146) = 24.66$ , $p < 0.001$ ; New Possibilities, $F(2,146) = 13.91$ , $p < 0.001$ ; Relating to Others $F(1.81, 131.96) = 24.21$ , $p < 0.001$ ; and Spiritual-Existential Change, $F(1.75, 127.84) = 17.96$ , $p < 0.001$ . Mauchly's test indicated that the assumption of sphericity had been violated for the scores on subscales Relating to Others, $\\chi^2 (2) = 8.10$ , $p = 0.017$ , and Spiritual-Existential Change, $\\chi^2 (2) = 11.03$ , $p = 0.004$ , therefore the degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity ( $\\varepsilon = 0.904$ , $\\varepsilon = 0.876$ ; respectively). Pairwise comparisons indicate that all subscales with a significant main effect of time, with the exception of the Appreciation of Life subscale, exhibited a significant increase in scores from baseline to endpoint, followed by stability through follow-up. This stability through follow-up was exhibited by a non-significant decrease in scores for Personal Strength and New Possibilities subscales and by a non-significant increase in scores for the Relating to Others and Spiritual-Existential Change subscales. Table 5 includes ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,653,915,747]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0103/084e63b82d570673df2639dd29412d8cd09108aec7a532ac2d5260c130a388f5.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Outcome</td><td colspan=\"2\">Baseline</td><td colspan=\"2\">Endpoint</td><td colspan=\"2\">Follow-up</td></tr><tr><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td></tr><tr><td>PTG</td><td>52.03</td><td>29.20</td><td>79.12</td><td>30.47</td><td>79.97</td><td>31.40</td></tr><tr><td>Positive Affect</td><td>27.20</td><td>7.94</td><td>38.26</td><td>5.74</td><td>30.09</td><td>7.98</td></tr><tr><td>ISLES</td><td>41.66</td><td>11.60</td><td>51.35</td><td>10.49</td><td>52.77</td><td>9.86</td></tr></table>","table_caption":"[\"TABLE 4 Long-term changes in growth domains. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[80,788,915,917]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0110/69d8192bf031b6849dcb3091e8469d550f24e413a674eba6dacc288dae7a18ac.jpg","list_items":null,"page_idx":"6","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Outcome</td><td colspan=\"2\">Baseline</td><td colspan=\"2\">Endpoint</td><td colspan=\"2\">Follow-up</td></tr><tr><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td></tr><tr><td>Appreciation of Life</td><td>8.35</td><td>4.20</td><td>9.89</td><td>3.87</td><td>9.69</td><td>4.04</td></tr><tr><td>Personal Strength</td><td>8.76</td><td>5.49</td><td>13.95</td><td>5.00</td><td>13.65</td><td>5.30</td></tr><tr><td>New Possibilities</td><td>10.73</td><td>7.60</td><td>16.00</td><td>6.46</td><td>15.93</td><td>6.87</td></tr><tr><td>Relating to Others</td><td>13.62</td><td>8.78</td><td>22.34</td><td>9.37</td><td>22.68</td><td>9.28</td></tr><tr><td>Spiritual-Existential Change</td><td>10.57</td><td>8.42</td><td>16.95</td><td>8.89</td><td>18.03</td><td>8.43</td></tr></table>","table_caption":"[\"TABLE 5 Long-term changes in PTGI-X subscales. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[80,38,151,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[759,38,917,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,211,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[489,948,507,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"07 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[835,948,915,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"6","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,93,485,120]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"means and standard deviations for each PTGI-X subscale at each time point. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,147,448,177]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Long term changes in symptomatology domains ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,193,489,734]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"A series of repeated measures ANOVAs were conducted to examine changes in symptomatology-related outcome measures over three time points (baseline, endpoint, and follow-up). Mauchly's Test of Sphericity indicated that the assumption of sphericity had been violated for PCL-5 scores, $\\chi^2 (2) = 15.82$ , $p < 0.001$ , depression scores, $\\chi^2 (2) = 23.17$ , $p < 0.001$ , anxiety scores, $\\chi^2 (2) = 12.80$ , $p = 0.002$ , ISI scores, $\\chi^2 (2) = 12.91$ , $p = 0.002$ , and negative affect scores, $\\chi^2 (2) = 11.52$ , $p = 0.003$ , and therefore a Greenhouse-Geisser correction was used for each of these analyses. The analysis of PCL-5 scores revealed a significant main effect of time, $F(1.67, 146) = 33.87$ , $p < 0.001$ . Pairwise comparisons indicate that PCL-5 scores significantly decreased by 15.66 points $(43\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up, exhibited by a further decrease of 2.43 points $(p = 1.00)$ and a total decrease of $49\\%$ from baseline to follow-up. The analysis of depression subscale scores revealed a significant main effect of time, $F(1.57, 114.49) = 21.05$ , $p < 0.001$ . Pairwise comparisons indicate that depression subscale scores significantly decreased by 3.37 points $(48\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up, exhibited by a further decrease of 0.31 points $(p = 1.00)$ and a total decrease of $53\\%$ from baseline to follow-up. The analysis of anxiety subscale scores revealed a significant main effect of time, $F(1.72, 125.55) = 9.09$ , $p < 0.001$ . Pairwise comparisons indicate that anxiety subscale scores did not significantly decrease from baseline to endpoint $(p = 0.534)$ , but did significantly decrease by 1.55 points from endpoint to follow-up $(p = 0.029)$ resulting in a total decrease of $45\\%$ from baseline to follow-up. The analysis of stress subscale scores revealed a significant main effect of time, $F(2, 146) = 29.30$ , $p < 0.001$ . Pairwise comparisons indicate that stress subscales scores significantly decreased by 4.22 points $(44\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up exhibited by a non-significant further decrease in scores by 0.04 points $(p = 1.00)$ and a total decrease of $44\\%$ from baseline to follow-up. The analysis of ISI scores revealed a significant main effect of time $F(1.72, 125.42) = 15.60$ , $p < 0.001$ . Pairwise comparisons indicate ISI scores significantly decreased by 4.38 points $(32\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up, exhibited by a non-significant further decrease in scores by 0.32 ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,93,915,221]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"points $(p = 1.00)$ and a total decrease of $34\\%$ from baseline to follow-up. The analysis of negative affect subscale scores revealed a significant main effect of time $F(1.74, 127.19) = 20.33$ , $p < 0.001$ . Pairwise comparisons indicate that negative affect subscale scores did not significantly decrease from baseline to endpoint $(p = 0.674)$ , but did significantly decrease by 5.00 points from endpoint to follow-up $(p < 0.001)$ , resulting in a total decrease of $27\\%$ from baseline to follow-up. Table 6 includes means and standard deviations for each symptomatology measure at each time point. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,247,880,277]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gender differences in post-intervention outcomes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,293,915,432]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Multiple one-way ANCOVAs were conducted to determine a statically significant difference between male and female participants on each growth and symptomatology-related outcome measure at endpoint, controlling for participant baseline scores. After adjustment for pre-intervention scores, there was only one outcome measure, DASS anxiety subscale scores, that resulted in a statistically significant difference in post-intervention scores between male and female participants, $F(1, 181) = 4.17$ , $p = 0.043$ , partial $\\eta^2 = 0.023$ . Analysis of covariance results, in addition to adjusted means and standard errors, for all outcome measures can be found in Table 7. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,461,912,476]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Gender differences in long-term outcomes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,492,915,619]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, multiple one-way ANCOVAs were conducted to determine a statistically significant difference between male and female participants on each growth- and symptomatology-related outcome measure at follow-up, controlling for participant endpoint scores. After adjustment for endpoint scores, no outcome measure at follow-up indicated a statistically significant difference between male and female participants. Analysis of covariance results, in addition to adjusted means and standard errors, for all outcome measures at follow-up can be found in Table 8. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,646,621,661]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Discussion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,677,915,734]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present study examined the impact of a manualized, posttraumatic growth-oriented training program on various growth and symptomatology-related outcome variables among U.S. military veterans. The utilized training program, the Warrior PATHH program, ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,771,915,916]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0381/18bd0626043c0056ad75d9cbfac121d25777bcaebac1d46e9e34f1b4596f2a63.jpg","list_items":null,"page_idx":"7","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Outcome</td><td colspan=\"2\">Baseline</td><td colspan=\"2\">Endpoint</td><td colspan=\"2\">Follow-Up</td></tr><tr><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td></tr><tr><td>PTSD</td><td>36.80</td><td>18.20</td><td>21.14</td><td>13.05</td><td>18.70</td><td>14.20</td></tr><tr><td>Depression</td><td>6.99</td><td>5.27</td><td>3.62</td><td>3.25</td><td>3.31</td><td>3.74</td></tr><tr><td>Anxiety</td><td>5.55</td><td>4.47</td><td>4.62</td><td>3.89</td><td>3.07</td><td>3.35</td></tr><tr><td>Stress</td><td>9.68</td><td>4.59</td><td>5.46</td><td>3.33</td><td>5.42</td><td>4.09</td></tr><tr><td>Insomnia</td><td>13.77</td><td>7.29</td><td>9.39</td><td>5.51</td><td>9.07</td><td>5.74</td></tr><tr><td>Negative Affect</td><td>24.00</td><td>7.59</td><td>22.51</td><td>6.48</td><td>17.51</td><td>6.87</td></tr></table>","table_caption":"[\"TABLE 6 Long-term changes in symptomatology domains. \"]","table_footnote":"[]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,38,915,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,210,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,948,505,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"08 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[836,948,915,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"7","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,104,917,303]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0339/58d97f79874badaacce06a140ba51232ffba76469119e3d65996d9e235dcd7d5.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Outcome</td><td colspan=\"2\">Male (n = 155)</td><td colspan=\"2\">Female (n = 29)</td><td rowspan=\"2\">F</td><td rowspan=\"2\">p</td><td rowspan=\"2\">partial η²</td></tr><tr><td>Meana</td><td>SE</td><td>Meana</td><td>SE</td></tr><tr><td>PTG</td><td>77.26</td><td>2.40</td><td>77.89</td><td>5.58</td><td>0.011</td><td>0.918</td><td>0.000</td></tr><tr><td>Positive Affect</td><td>37.47</td><td>0.56</td><td>37.51</td><td>1.29</td><td>0.001</td><td>0.976</td><td>0.000</td></tr><tr><td>ISLES</td><td>50.36</td><td>0.88</td><td>50.82</td><td>2.05</td><td>0.042</td><td>0.838</td><td>0.000</td></tr><tr><td>PTSD</td><td>20.58</td><td>1.06</td><td>17.41</td><td>2.47</td><td>1.38</td><td>0.242</td><td>0.008</td></tr><tr><td>Depression</td><td>3.34</td><td>0.24</td><td>2.39</td><td>0.56</td><td>2.38</td><td>0.125</td><td>0.013</td></tr><tr><td>Anxiety</td><td>4.45</td><td>0.28</td><td>3.00</td><td>0.65</td><td>4.17</td><td>0.043</td><td>0.023</td></tr><tr><td>Stress</td><td>5.19</td><td>0.26</td><td>4.00</td><td>0.61</td><td>3.22</td><td>0.074</td><td>0.017</td></tr><tr><td>Insomnia</td><td>9.21</td><td>0.43</td><td>8.17</td><td>1.00</td><td>0.923</td><td>0.338</td><td>0.005</td></tr><tr><td>Negative Affect</td><td>21.66</td><td>0.60</td><td>19.69</td><td>1.39</td><td>1.70</td><td>0.194</td><td>0.009</td></tr></table>","table_caption":"[\"TABLE 7 Effect of gender on post-intervention outcomes. \"]","table_footnote":"[\"${}^{a}$ Adjusted means after controlling for baseline scores are presented. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[80,355,917,552]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":"images/0305/bde9213fc7adb26cd9068b69baf5a09b688dbd7da18182c5355a796f23c06380.jpg","list_items":null,"page_idx":"8","sub_type":null,"table_body":"<table><tr><td rowspan=\"2\">Outcome</td><td colspan=\"2\">Male (n = 63)</td><td colspan=\"2\">Female (n = 11)</td><td rowspan=\"2\">F</td><td rowspan=\"2\">p</td><td rowspan=\"2\">partial η²</td></tr><tr><td>Meana</td><td>SE</td><td>Meana</td><td>SE</td></tr><tr><td>PTG</td><td>79.77</td><td>3.98</td><td>81.13</td><td>9.52</td><td>0.017</td><td>0.896</td><td>0.000</td></tr><tr><td>Positive Affect</td><td>29.93</td><td>1.02</td><td>31.01</td><td>2.44</td><td>0.167</td><td>0.684</td><td>0.002</td></tr><tr><td>ISLES</td><td>52.05</td><td>1.23</td><td>56.90</td><td>2.94</td><td>2.33</td><td>0.132</td><td>0.032</td></tr><tr><td>PTSD</td><td>19.56</td><td>1.79</td><td>13.80</td><td>4.28</td><td>1.54</td><td>0.219</td><td>0.021</td></tr><tr><td>Depression</td><td>3.51</td><td>0.47</td><td>2.17</td><td>1.14</td><td>1.19</td><td>0.279</td><td>0.017</td></tr><tr><td>Anxiety</td><td>3.28</td><td>0.42</td><td>1.83</td><td>1.02</td><td>1.71</td><td>0.196</td><td>0.023</td></tr><tr><td>Stress</td><td>5.73</td><td>0.51</td><td>3.66</td><td>1.22</td><td>2.44</td><td>0.123</td><td>0.033</td></tr><tr><td>Insomnia</td><td>9.21</td><td>0.73</td><td>8.23</td><td>1.75</td><td>0.267</td><td>0.607</td><td>0.004</td></tr><tr><td>Negative Affect</td><td>17.67</td><td>0.88</td><td>16.62</td><td>2.11</td><td>0.211</td><td>0.647</td><td>0.003</td></tr></table>","table_caption":"[\"TABLE 8 Effect of gender on long-term outcomes. \"]","table_footnote":"[\"${}^{a}$ Adjusted means after controlling for endpoint scores are presented. \"]","text":null,"text_format":null,"text_level":null,"type":"table"},{"bbox":"[80,592,489,749]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"is not conceptualized as a psychotherapeutic intervention. Rather, this manualized training program is peer based and developed to help veterans develop the tools necessary to increase their capacity to regulate thoughts, emotions, and actions in a civilian environment. The primary focus of the Warrior PATHH training is the facilitation of PTG and its five domains. However, the integrated nature of the training means that many elements of empirically based PTSD treatments have been incorporated into the design. The incorporation of these elements implies that completion of the training program should also have an impact on the presentation of PTSD related symptomatology. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,775,346,790]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Post-intervention outcomes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,804,489,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In accordance with our hypotheses regarding immediate post-intervention changes, findings revealed significant improvements on all growth-related outcome measures immediately following the training. Specifically, participants reported a $54\\%$ increase in scores on the posttraumatic growth inventory (PTGI-X) from baseline to endpoint, indicating that participants experienced a noteworthy enhancement in their perception of posttraumatic growth-related domains in the aftermath of the training. Further evidence of this growth is exhibited ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,592,917,834]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"by significant improvements on all five subscales of the PTGI-X. Similarly, a significant increase in scores was observed for the positive affect subscale of the PANAS, exhibited by a $45\\%$ increase in scores from baseline to endpoint. This suggests that participants experienced notable improvement in their overall positive emotional states following the training. Finally, findings revealed a significant increase in scores on the ISLES from baseline to endpoint by $29\\%$ , indicating that participants are able to report an increased sense of meaning following their previous trauma exposure. The observed effect sizes for each paired sample comparison, as presented in Table 2, further support the robustness of this study's findings. The magnitude of change found in each growth-related outcome variable provides additional evidence for the meaningful impact of training program on participants self-reported experiences. Overall, the results provide strong empirical support for the effectiveness of the Warrior PATHH training program in promoting posttraumatic growth, positive affect, and the integration of stressful experiences immediately following training. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,834,917,919]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"While the program was not focused on treatment, it is very noteworthy that participants reported significant reduction of PTSD symptomatology scores by $49\\%$ from baseline to endpoint. This suggests a notable alleviation of PTSD related symptoms among participants. Additional significant reductions were found for depression $(60\\%)$ , anxiety $(28\\%)$ , and stress $(50\\%)$ scores from ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,38,917,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,211,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[489,948,507,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"09 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[836,948,915,960]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"8","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[80,93,487,149]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"baseline to endpoint. Finally, insomnia symptom scores decreased by $36\\%$ and negative affect by $16\\%$ from baseline to endpoint. The degree to which each of these domains changed from baseline to endpoint is demonstrated by paired sample comparisons in Table 3. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,175,485,193]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Long term 18months follow-up outcomes ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,206,487,449]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The observed increase in growth domains and decrease in symptomatology domains across participants immediately following the Warrior PATHH program sheds light on just how powerful an intensive training of this type can be. However, it is important to examine whether the improvements are maintained long-term after the individuals return to their normal environment. For example, each individual who attends the training has removed themselves from many of the daily stressors they experience, is given a strict schedule to adhere to, and is surrounded by individuals with similar experiences who are more likely to understand their struggles. Once the individual returns home, they are again exposed to any routine daily stressors, are responsible for their own schedule, and may not have the same level of empathetic community found during training. Significant results at the 18 months follow-up would indicate a high level of impact from the training, resulting in changes that are maintained for one and a half years post-training. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,450,487,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data from repeated measures ANOVAs indicates that, for those who provided data at all three time points $(n = 74)$ , the significant increase in all growth-related outcome measure scores from baseline was maintained at the 18 months follow-up. Both PTGI-X and ISLES scores did not differ significantly from endpoint to follow-up, indicating stability and lasting benefits from the training program. Although there was a significant decrease in positive affect scores between endpoint and follow-up assessments, the scores remained significantly higher than baseline, indicating a lasting positive impact of the training. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,592,487,705]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Scores on all symptomatology-related outcome measures that exhibited a significant decrease from baseline to endpoint remained stable at the 18 months follow-up, maintaining their significant decrease from the baseline assessment. While both anxiety and negative affect scores experienced a non-significant decrease from baseline to endpoint, scores for both domains experienced a significant decrease from baseline to follow-up assessment. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,732,431,749]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Examination of gender of participants ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[80,763,487,904]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present study also aimed to investigate the potential differences between male and female participants on various growth and symptomatology-related outcome measures at both endpoint and follow-up. The results of multiple one-way ANCOVA's indicate that after adjusting for pre-intervention scores, there was only a single outcome measure, DASS anxiety subscale scores, that showed a small but statistically significant difference in post-intervention scores between male and female participants. The effect size, as indicated by the partial $\\eta^2$ value, was very small, only explaining approximately $2.3\\%$ of the variance in scores on the anxiety subscale. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,906,487,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Interestingly, no significant gender differences were found for any other growth or symptomatology related outcome measure at ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,93,915,149]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"endpoint or follow-up, after controlling for the appropriate covariates. These findings indicate that on almost all outcome variables assessed, male and female participants showed similar levels of improvement at endpoint and maintenance of such improvement at follow-up. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,149,915,249]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The discrepancy in samples size for the analyses examining gender differences at follow-up should be noted, as male participants $(n = 63)$ far outnumbered female participants $(n = 11)$ . This overall small sample of participants may have influenced the statistical power to detect differences between genders. Furthermore, the smaller sample size of female participants may have limited the ability to detect any effects that could have been present. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,250,915,391]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The findings of these analyses are encouraging in that both female and male veterans seem to experience the same level of benefit from the posttraumatic growth-oriented training employed in this study. More specifically, the large increases in PTG and decreases in PTSD symptomatology were exhibited by participants, regardless of gender. These results indicate that the current training protocol seems to adequately address the needs of both male and female veterans, however future studies with larger and more balanced gender samples are needed to further explore the potential influence of gender on the assessed variables. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[510,418,727,434]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"PCL-5 threshold scores ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[509,450,915,833]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The PCL-5 was used to assess prevalence and severity of PTSD symptomatology among participants completing the training program. The high impact of the training on post-intervention and long-term follow up PCL-5 scores warrants further investigation. While the use of the PCL-5 was strictly to assess prevalence and severity of PTSD symptoms, and not a tool used to make a diagnosis, an investigation of the participants who fall above and below the diagnosis threshold score can be informative. For example, a provisional PTSD diagnosis can be made with a score of 33 or greater on the PCL-5. At the baseline assessment $(n = 184)$ , there were 120 individuals with scores greater than 33 and who theoretically would qualify for this provisional diagnosis. Immediately following the training, only 31 individuals had scores greater than 33, indicating that 89 individuals $(74\\%)$ have theoretically reduced symptomatology to a point that would no longer meet the diagnostic threshold. For those who provided data at all three study time points $(n = 74)$ , there were 40 individuals with PCL-5 scores greater than 33, meeting criteria for a provisional PTSD diagnosis at the baseline assessment. At the endpoint assessment, only 12 individuals had scores greater than 33, indicating 28 fewer individuals $(70\\%)$ met the diagnostic criteria regarding PCL-5 scores. One and a half years later at the 18 months follow-up assessment, 15 individuals had PCL5 scores greater than 33 indicating a rise in PTSD symptoms over the course of 18 months for 3 of the individuals. This rise in the number of individuals who exceed the diagnostic threshold is expected over time but highlights the need for continued support beyond the immediate post-intervention period. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[509,834,915,933]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Together, these results underscore the positive impact of the Warrior PATHH training program in reducing PTSD symptomatology among veterans, despite its primary focus of increasing PTG. The substantial impact on reported PTSD symptomatology, exhibited by a $49\\%$ decrease in reported symptoms from baseline to endpoint, warrants further investigation to identify factors associated with increased PTG and symptom improvement. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[761,38,915,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10.3389/fpsyg.2023.1322837 ","text_format":null,"text_level":null,"type":"header"},{"bbox":"[80,948,208,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Frontiers in Psychology ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[490,948,505,958]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"10 ","text_format":null,"text_level":null,"type":"page_number"},{"bbox":"[836,948,915,959]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"9","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"frontiersin.org ","text_format":null,"text_level":null,"type":"footer"},{"bbox":"[78,91,186,105]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Limitations ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,122,489,235]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The present study is not without its limitations, primarily the lack of a control group. While a single-group design is appropriate for the current study, future studies should consider employing randomized controlled trail designs to further investigate the effects of the training and help establish causal relationships. The ethics and complexity of adding a control group to a study of this nature should be carefully examined to account for many of the factors present in the current training protocol. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,236,489,306]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"While demographic variables were collected, certain variables that may be of interest to the field were not collected in this study (i.e., nature of trauma, time since trauma, and age of service). Analysis of the relationship between these and outcome variables may identify certain patterns in training benefit. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,307,490,420]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Finally, the findings of this study were based on a specific manualized intervention within a specific population, U.S. military veterans. While the sample size and analyses allow for the results to be generalizable to U.S. military veteran populations, they may not be generalizable to other study populations. Future studies should consider adapting and employing the utilized training among other populations that are at an increased risk of trauma exposure. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,445,205,463]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conclusion ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,478,489,677]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"In conclusion, the results of this study demonstrated significant improvements in growth-related outcomes, including posttraumatic growth, positive affect, and the integration of stressful life experiences, immediately following the training. These improvements were generally maintained until the follow-up assessment, 18 months later, indicating the potential for enduring positive effects. Additionally, participants showed significant reduction in symptoms related to PTSD, depression, anxiety, stress, insomnia, and negative affect. These reductions in symptom-related measures were also maintained until the follow-up assessment. Together, the evidence indicates that the employed posttraumatic growth-oriented training program provides benefits to veterans extending beyond increases in posttraumatic growth, addressing many of the issues that veterans face following exposure to trauma. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[77,678,490,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"An important implication of the impact of this training program involves the use of peer-based delivery. The substantial impact of this peer-based approach suggests that a properly designed program delivered by peers who have a high degree of cultural competence may provide a unique pathway to addressing mental health needs. There is also the implication that peers may be especially effective at delivering such programs as they optimize the important relational component that is central to success. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[78,816,201,832]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"References ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[77,844,489,908]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":"[\"Antony, M. M., Bieling, P. J., Cox, B. J., Enns, M. W., and Swinson, R. P. (1998). Psychometric properties of the 42-item and 21-item versions of the depression anxiety stress scales in clinical groups and a community sample. *Psychol. Assess.* 10, 176-181. doi: 10.1037/1040-3590.10.2.176 \",\"Asmundson, G. J. G., Thorisdottir, A. S., Roden-Foreman, J. W., Baird, S. O., and Witcraft, S. M. (2019). A meta-analytic review of cognitive processing therapy for adults \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[507,90,789,108]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Data availability statement ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,122,917,165]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The datasets presented in this article are not readily available because of concerns for confidentiality. Requests to access the datasets should be directed to the corresponding author, GE, gary_elkins@baylor.edu. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,189,687,206]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Ethics statement ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,222,917,293]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The studies involving humans were approved by Baylor University's Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,317,732,334]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Author contributions ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,350,917,478]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"JR: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing. RT: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Writing - review & editing. BM: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Writing - review & editing. CA: Conceptualization, Writing - review & editing. GE: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing - original draft, Writing - review & editing. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,502,598,521]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Funding ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,535,917,564]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,574,710,590]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Conflict of interest ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,607,917,634]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"RT, BM, and GE receive payment for consulting services through the Boulder Crest Institute for Posttraumatic Growth. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[505,634,917,677]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ","text_format":null,"text_level":null,"type":"text"},{"bbox":"[507,688,680,705]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Publisher's note ","text_format":null,"text_level":"1","type":"text"},{"bbox":"[505,720,917,791]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 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Available at: http://search.ebscohost.com/login.aspx?direct=true&db=psyh&AN=2014-05860-000&authotype=shib&site=ehost-live&scope=site \"]","page_idx":"10","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,38,151,49]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"10","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. 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PTSD symptoms and suicide risk in veterans: serial indirect effects via depression and anger. J. Affect. Disord. 214, 100-107. doi: 10.1016/j.jad.2017.03.008 \",\"McLean, C. P., Levy, H. C., Miller, M. L., and Tolin, D. F. (2022). Exposure therapy for PTSD: a meta-analysis. Clin. Psychol. Rev. 91:102115. doi: 10.1016/j.cpr.2021.102115 \",\"Meichenbaum, D. (2012). Roadmap to resilience: a guide for military, trauma victims and their families. Waterloo, ON: Institute Press \",\"Moore, B. A., Tedeschi, R. G., and Greene, T. C. (2021). A preliminary examination of a posttraumatic growth-based program for veteran mental health. *Pract. Innov.* 6, 42-54. doi: 10.1037/pri0000136 \",\"Morin, C. M., Belleville, G., Belanger, L., and Ivers, H. (2011). The insomnia severity index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep 34, 601-608. doi: 10.1093/sleep/34.5.601 \",\"Neimeyer, R. A. (2006). Re-storying loss: fostering growth in the posttraumatic narrative. L. G. Calhoun and R. G. Tedeschi (Eds.), Handbook of posttraumatic growth: Research & practice. (68-80). Mahwah, NJ: Lawrence Erlbaum Associates Publishers \",\"Norcross, J. C., and Wampold, B. E. (2011). Evidence-based therapy relationships: research conclusions and clinical practices. Psychotherapy 48, 98-102. doi: 10.1037/a0022161 \",\"Peterson, A. L., Foa, E. B., and Riggs, D. S. (2019). Prolonged exposure therapy. B. A. Moore and W. E. Penk (Eds.), Treating PTSD in military personnel: A clinical handbook (46-62). Guilford Press \",\"Polusny, M. A., Kumpula, M. J., Meis, L. A., Erbes, C. R., Arbisi, P. A., and Murdoch, M. (2014). Gender differences in the effects of deployment-related stressors and predeployment risk factors on the development of PTSD symptoms in National Guard Soldiers deployed to Iraq and Afghanistan. J. Psychiatr. Res. 49, 1-9. doi: 10.1016/j.jpsychires.2013.09.016 \",\"Resick, P. A., Monson, C. M., and Chard, K. M. (2008). Cognitive processing therapy: veteran/military version. Washington, DC: Department of Veterans Affairs \",\"Resick, P. A., Nishith, P., Weaver, T. L., Astin, M. C., and Feuer, C. A. (2002). A comparison of cognitive-processing therapy with prolonged exposure and a waiting condition for the treatment of chronic posttraumatic stress disorder in female rape victims. J. Consult. Clin. Psychol. 70, 867-879. doi:10.1037//0022-006x.70.4.867 \",\"Roepke, A. M., and Seligman, M. E. P. (2015). Doors opening: a mechanism for growth after adversity. J. Posit. Psychol. 10, 107-115. doi: 10.1080/17439760.2014.913669 \",\"Rothbaum, B. O., Astin, M. C., and Marsteller, F. (2005). Prolonged exposure versus eye movement desensitization and reprocessing (EMDR) for PTSD rape victims. J. Trauma. Stress. 18, 607-616. doi: 10.1002/jts.20069 \",\"Russell, P. D., Judkins, J. L., Blessing, A., Moore, B., and Morissette, S. B. (2022). Incidences of anxiety disorders among active duty service members between 1999 and 2018. J. Anxiety Disord. 91:102608. doi: 10.1016/j.janxdis.2022.102608 \",\"Schultz, J. M., Tallman, B. A., and Altmaier, E. M. (2010). Pathways to posttraumatic growth: the contributions of forgiveness and importance of religion and spirituality. Psychol. Relig. Spiritual. 2, 104-114. doi: 10.1037/a0018454 \",\"Shapiro, F. (1989). Eye movement desensitization: a new treatment for post-traumatic stress disorder. J. Behav. Ther. Exp. Psychiatry 20, 211-217. doi: 10.1016/0005-7916(89)90025-6 \",\"Shakespeare-Finch, J., Martinek, E., Tedeschi, R. G., and Calhoun, L. G. (2013). A qualitative approach to assessing the validity of the posttraumatic growth inventory. J Loss Trauma. 18:572-591. doi: 10.1080/15325024.2012.734207 \",\"Smith, N. B., Sippel, L. M., Rozek, D. C., Hoff, R. A., and Harpaz-Rotem, I. (2019). 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Washington, DC \",\"Valiente-Gómez, A., Moreno-Alcazar, A., Treen, D., Cedron, C., Colom, F., and Pérez, V. (2017). EMDR beyond PTSD: A Systematic Literature Review. Frontiers in Psychology, 8, 1668. doi:10.3389/fpsyg.2017.01668 \",\"Watkins, L. E., Sprang, K. R., and Rothbaum, B. O. (2018). Treating PTSD: a review of evidence-based psychotherapy interventions. Front. Behav. Neurosci. 12:258. doi: 10.3389/fnbeh.2018.00258 \",\"Watson, D., Clark, L., A., and Tellegen, A. (1988). Development and validation of brief measures of positive and negative affect: the PANAS scales. J. Pers. Soc. Psychol. 54, 1063-1070. doi: 10.1037/0022-3514.54.6.1063 \",\"Weathers, F. W., Blake, D. D., Scnurr, P. P., Kaloupek, D. G., Marx, B. P., and Keane, T. M. (2013). The clinician-administered PTSD scale for DSM-5 (CAPS-5). National Center for PTSD, Available at: www.ptsd.va.gov \",\"Williams, A. H., Galovski, T. E., and Resick, P. A. (2019). Cognitive processing therapy. B. A. Moore and W. E. Penk (Eds.), Treating PTSD in military personnel: a clinical handbook (63-77). Guilford Press \",\"Wisco, B. E., Marx, B. P., Wolf, E. J., Miller, M. W., and Southwick, S. M. (2014). Posttraumatic stress disorder in the US veteran population: results from the National Health and resilience in veterans study. J. Clin. Psychiatry 75, 1338-1346. doi: 10.4088/JCP.14m09328 \"]","page_idx":"12","sub_type":"ref_text","table_body":null,"table_caption":null,"table_footnote":null,"text":null,"text_format":null,"text_level":null,"type":"list"},{"bbox":"[80,39,149,48]","code_body":null,"code_caption":null,"image_caption":null,"image_footnote":null,"img_path":null,"list_items":null,"page_idx":"12","sub_type":null,"table_body":null,"table_caption":null,"table_footnote":null,"text":"Rhodes et al. 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Elkins \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,325,220,335]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"gary_elkins@baylor.edu \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,340,220,350]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"RECEIVED 16 October 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,351,233,361]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"ACCEPTED 11 December 2023 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,362,226,372]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PUBLISHED 05 January 2024 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,380,126,388]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"CITATION \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,390,273,410]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes JR, Tedeschi RG, Moore BA, Alldredge CT and Elkins GR (2024) \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,411,315,453]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Posttraumatic growth-oriented peer-based training among U.S. veterans: evaluation of post-intervention and long-term follow-up outcomes. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,454,226,464]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Front. Psychol. 14:1322837. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,464,260,475]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"doi: 10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,482,136,491]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"COPYRIGHT\",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,492,319,514]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"© 2024 Rhodes, Tedeschi, Moore, Alldredge and Elkins. This is an open-access article \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,514,314,524]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"distributed under the terms of the Creative \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,524,314,533]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Commons Attribution License (CC BY). The \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,535,305,545]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"use, distribution or reproduction in other \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,546,305,556]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"forums is permitted, provided the original \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,556,312,567]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"author(s) and the copyright owner(s) are \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,568,314,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"credited and that the original publication in \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,579,290,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"this journal is cited, in accordance with \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,590,280,598]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"accepted academic practice. No use, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,599,302,609]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"distribution or reproduction is permitted \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,609,305,620]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"which does not comply with these terms. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[394,143,904,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Posttraumatic growth-oriented peer-based training among U.S. veterans: evaluation of post-intervention and long-term follow-up outcomes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,305,880,338]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Joshua R. Rhodes<sup>1</sup>, Richard G. Tedeschi<sup>2</sup>, Bret A. Moore<sup>2</sup>, Cameron T. Alldredge<sup>3</sup> and Gary R. Elkins<sup>3*</sup> \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,346,892,379]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"$^{1}$ Department of Psychology, Abilene Christian University, Abilene, TX, United States, $^{2}$ Boulder Crest Institute for Posttraumatic Growth, Bluemont, VA, United States, $^{3}$ Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,401,917,486]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Introduction: Exposure to trauma among U.S. military veterans occurs at a high rate, often resulting in continued difficulty with emotional adjustment and a diagnosis of posttraumatic stress disorder (PTSD). The present study provides data from 184 U.S. military veterans who completed a manualized posttraumatic-growth oriented training program during an integrative seven-day retreat. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,491,917,519]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Methods: Data was collected at baseline, after program completion, and at 18-month follow-up. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,523,917,765]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results: Results on primary outcomes indicated significant increases, with medium to large effect sizes, in growth related outcomes. Specifically, there was a significant increase in scores by $54\\\\%$ on the posttraumatic growth outcome measure (PTGI-X) from baseline $(M = 50.2, SD = 31.1)$ to endpoint $(M = 77.4, SD = 29.6)$ , $t(183) = -8.78$ , $p < 0.001$ . Also, results indicate that immediately following training (Day 7), participants reported a significant decrease of $49\\\\%$ on the PCL-5 from baseline $(M = 39.7, SD = 17.6)$ to endpoint $(M = 20.1, SD = 13.2)$ , $t(183) = 11.75$ , $p < 0.001$ . Depression subscale scores decreased by $60\\\\%$ from baseline $(M = 8.0, SD = 5.2)$ to endpoint $(M = 3.2, SD = 3.0)$ , $t(183) = 10.68$ , $p < 0.001$ ; Anxiety scores decreased by $28\\\\%$ from baseline $(M = 5.8, SD = 4.3)$ to endpoint $(M = 4.2, SD = 3.5)$ , $t(183) = 4.08$ , $p < 0.001$ ; and Stress scores decreased by $50\\\\%$ from baseline $(M = 10.0, SD = 4.4)$ to endpoint $(M = 5.0, SD = 3.3)$ , $t(183) = 12.21$ , $p < 0.001$ . Eighteen-month follow-up data was available for 74 participants and indicated that all significant changes in growth-related outcomes were maintained. Further, all significant changes in symptomatology-related outcomes were also maintained at follow-up. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[393,769,917,826]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion: These findings demonstrate both the immediate and the long-lasting impact of an integrative posttraumatic growth-oriented training program on psychological growth and PTSD symptom reduction among U.S. military veterans. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[394,844,450,854]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n 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null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[736,60,917,71]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"DOI 10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,211,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[490,948,507,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"01 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,948,915,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"0\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,90,213,105]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Introduction \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,122,487,306]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Exposure to trauma among military veterans is very prevalent, with approximately $87\\\\%$ of U.S. veterans reporting exposure to at least one potentially traumatic event (Wisco et al., 2014). Whether or not these reported traumatic events are directly or indirectly related to one's military service, evidence shows the effects of trauma are causing veterans to experience serious difficulties with emotional adjustment (McKinney et al., 2017), resulting in 17.2 Veteran suicides per day in 2019, a number that has remained practically unchanged since 2001 (U.S. Department of Veterans Affairs, 2021). Of this population, individuals ages 55-74 were at the highest risk, accounting for approximately $39\\\\%$ of veteran deaths by suicide in 2019. A notable diagnosis aiming to capture much of this struggle with emotional adjustment following trauma is posttraumatic stress disorder (PTSD). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,307,487,662]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Presentation of PTSD related symptoms may vary across individuals from distinct wars, cultures, and genders as they have been exposed to varying specific traumas (Dutra et al., 2019). Exposure to specific traumas results in differing duration of symptoms, perception of treatment, and treatment response. For example, Chard et al. (2010) found that veterans from the Vietnam war exhibited significantly less symptom reduction following cognitive processing therapy (CPT) when compared to veterans from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). The experience of trauma related symptoms is also moderated by gender as men are more likely to report trauma resulting from exposure to combat when compared to women (Macera et al., 2014; Polusny et al., 2014) and women are more likely to experience military sexual trauma (Haskell et al., 2010; Kimerling et al., 2010). The high rate of comorbidity between PTSD and other psychiatric disorders can lead to difficulty in both its diagnoses and the identification of an optimal treatment plan. For example, while much of the current research focuses on PTSD diagnoses, many veterans also struggle with depression and anxiety. Studies estimate that $9.6\\\\%$ of veterans struggle with and receive a diagnosis of depression (Liu et al., 2019) and the prevalence of diagnosed anxiety disorder incidence rates varies widely from 0.01 to 23.7 per 1,000 service members (Russell et al., 2022). Differential diagnoses will highlight different aspects of PTSD symptom presentation and require different treatment modalities to avoid being ineffective or exacerbating the comorbid symptoms. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,664,487,876]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The U.S. Veterans Affairs/Department of Defense (2017) clinical practice guidelines recommend a tiered approach to PTSD treatment. The first recommendation cited to have the strongest evidence is individual, manualized, trauma-focused psychotherapy. These first-line therapies include Prolonged Exposure therapy (PE; Foa et al., 2005, 2018), Cognitive Processing Therapy (CPT; Resick et al., 2002), and Eye Movement Desensitization and Reprocessing therapy (EMDR; Shapiro, 1989; Rothbaum et al., 2005; Valiente-Gomez et al., 2017). Second tier treatment, per the VA/DOD guidelines (2017) are non-trauma, manualized therapies or pharmacotherapy. Non-trauma focused, manualized therapies include stress inoculation training and present-centered therapy. The recommended pharmacotherapies include three selective serotonin reuptake inhibitors (SSRIs; paroxetine, sertraline, and fluoxetine) and one selective norepinephrine reuptake inhibitor (SNRI; venlafaxine). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,878,487,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The current psychotherapeutic treatment modalities have seemed to exhibit particularly high efficacy in their reduction of PTSD symptomatology specifically. Prolonged Exposure therapy has been \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,93,915,505]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"shown to reduce PTSD symptomatology with a pre-post effect size of $d = 0.87$ (Eftekhari et al., 2013). A meta-analysis of Cognitive Processing therapy for PTSD symptom reduction found an effect size of $g = 1.24$ when compared to control conditions (Asmundson et al., 2019). Further evidence with a more broad view is found in a meta-analysis of exposure therapies (not treatment specific), reporting a significant reduction in PTSD symptoms when compared to control conditions with an effect size of $g = 0.86$ (McLean et al., 2022). A meta-analysis examining the use of EMDR for PTSD symptom reduction found an overall effect size of $g = -0.64$ (Chen et al., 2014). The effect sizes found for the reduction of PTSD symptoms through pharmacotherapy are generally much lower, with a meta-analysis finding SSRIs to be statistically superior to placebo administration but with a small effect size ( $d = 0.23$ ; Hoskins et al., 2015). While the evidence indicates that individuals can benefit from trauma-focused, manualized therapies, the consensus on whether they significantly outperform non-trauma-focused therapies has been called into question. Recent studies have exhibited mixed-results as to whether patients are receiving clinically meaningful benefit from first-line therapies such as PE and CPT (Steenkamp et al., 2020). Furthermore, these first-line therapies have been found to be only marginally superior to non-trauma focused therapies and active control groups (Steenkamp et al., 2015). While these first-line therapies provide great benefit for some, they are not without their limitations, namely high nonresponse, underresponse, and dropout rates among participants (Steenkamp et al., 2020). Together these findings indicate that the highly complex nature of PTSD and the management of these symptoms within a military population may not be a good match for a one-size-fits-all treatment approach (Steenkamp et al., 2020). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,507,915,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The framework of clinical work with military veterans has largely been focused on the identification of PTSD symptoms and symptom reduction following trauma exposure. The identification of the individual's struggle and the goal of reducing their suffering are not only admirable, but are essential for providing help to countless veterans. The current model of PTSD and its treatment has proven to be efficacious in the reduction of PTSD specific symptoms but seems to fall short in addressing the existential needs and issues veterans face. The difficulty engaging veterans in long-term treatment across months has led to decreased satisfaction across treatment modalities, even though their completion seems to promise significant symptom reduction (Kehle-Forbes et al., 2016; Smith et al., 2019). Alternatively, intensive treatment programs (one or two weeks) have been examined as a potential way to improve on the high dropout rate and limited engagement among individuals (Hendriks et al., 2018; Watkins et al., 2018). While the evidence indicates that massed, trauma-focused therapies are beneficial (Hendriks et al., 2018), they do not directly address the potential for posttraumatic growth and there is limited research on intensive treatment programs influenced by posttraumatic growth theory. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,791,915,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Posttraumatic growth (PTG) is defined as positive psychological changes that can be experienced as a result of the struggle in the aftermath of traumatic or highly challenging circumstances (Tedeschi et al., 2018). Posttraumatic growth theory, largely influenced by Janoff-Bulman (1989), assumes that trauma involves emotional distress as a result of core beliefs being shattered following traumatic events. The disruption of the core belief system leads to struggle and the potential for transformative outcomes and growth. The concept of struggle refers to the difficulties encountered in the process of reconstructing \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,149,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[761,38,915,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,208,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[490,948,505,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"02 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[836,948,915,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"1\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[77,93,490,164]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"one's core beliefs. The struggle and distress can often prompt deliberative rumination within the individual. When paired with disclosure to a trusted individual, this deliberative rumination can aid in the process of reconceptualizing one's core belief system (Tedeschi and Moore, 2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,165,489,292]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Posttraumatic growth has been shown to exhibit itself in five domains across individuals (Tedeschi and Calhoun, 1996; Tedeschi et al., 2017). This five-factor model has been established through factor analysis of the posttraumatic growth inventory (PTGI; Tedeschi and Calhoun, 1996; Tedeschi et al., 2017) and several other studies (Linley et al., 2007; Taku et al., 2008; Brunet et al., 2010; Lee et al., 2010). The five domains identified in prior research include: Relating to Others, Personal Strength, Appreciation of Life, New Possibilities, and Spiritual-Existential Change. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,292,489,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The domain of Relating to Others in PTG reflects a deeper emotional quality to relationships, often paired with an increased sense of mutual respect, disclosure, openness, and compassion (Moore et al., 2021). As trauma survivors disclose their experiences, an empathic listener can be very important in the process (Tedeschi and Calhoun, 2006). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,378,490,463]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The domain of Personal Strength is often exhibited after the individual has simply managed to survive the trauma and its aftermath. Reflection on the experience can instill a greater sense of personal strength as they recognize the self-reliance and courage it took to reach where they are (Tedeschi and Calhoun, 1996; Moore et al., 2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,464,490,533]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Appreciation of Life includes a new perspective that allows the individual to experience a new sense of gratitude for things previously overlooked. This increased sense of appreciation is often the result of actual loss or having narrowly escaped the loss (Tedeschi and Calhoun, 1996; Moore et al., 2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,535,490,648]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Traumatic experiences involve loss of things such as capabilities, roles, relationships and alter an anticipated future. In the struggle to deal with such significant loss, it is possible that new ways to live are discovered. The recognition of new possibilities for a positive future may be essential to developing PTG (Roepke and Seligman, 2015). The search for fulfillment in areas previously unconsidered, is referred to as the domain of New Possibilities (Tedeschi and Calhoun, 1996; Moore et al., 2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,649,489,776]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The domain of Spiritual-Existential Change may occur when individuals reconsider existential issues and potentially reconfigure their beliefs and belief systems as a result of their experience with trauma (Tedeschi and Calhoun, 1996; Moore et al., 2021). The impact of traumatic events can cause survivors to consider existential questions such as life meaning and purpose (Tedeschi and Riffle, 2016). Also, for many survivors of trauma, considerations of forgiveness, spirituality, and religious beliefs may be an important component of PTG (Schultz et al., 2010). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,778,490,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rather than being a new form of therapy, PTG-based intervention is an integrative approach that utilizes elements and research knowledge drawn from several existing approaches, specifically: cognitive-behavioral, narrative, existential, and interpersonal. PTG-based intervention acknowledges the evolving evidence base for trauma interventions within a philosophy that proposes that trauma survivors can both achieve symptom reduction and experience transformative posttraumatic growth (Tedeschi and Moore, 2021) in the five domains of PTG. It is not simply focused on symptom reduction (although PTG-based intervention may result in reduced \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,93,919,178]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"trauma related symptoms), but promotes and emphasizes the importance of managing emotional distress and moving toward growth that would not have been likely if not for the struggle with the traumatic events. The PTG model of intervention is unique in the emphasis on PTG, but also integrates four primary elements of existing approaches listed below. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,179,919,420]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Cognitive-behavioral interventions identify change in core beliefs and cognitions as underlying mechanisms of change. Core beliefs may be formulated in early life and people often make assumptions about themselves and the world that may go unexamined until encountering trauma that disrupts one's \\\"assumptive world\\\" (Janoff-Bulman, 1989). Therefore, the PTG intervention model is directed toward schema change (Janoff-Bulman, 2006) using a variety of methods. The process of reconstructing one's core belief system is an evidence-based approach that is a foundation for cognitive processing therapy (Resick et al., 2008) as well as PTG-based intervention. Further, many trauma survivors must achieve a sufficient degree of emotional regulation before being able to tolerate the emotional stress associated with schema change. Therefore, psychoeducation about trauma reactions and teaching emotional regulation methods (i.e., relaxation, mindfulness, present-moment awareness, etc.) are an integral component of the PTG integrative intervention approach. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,420,917,563]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PTG-based intervention also integrates the concept of developing a new life narrative into its approach. With the revision of core beliefs, trauma survivors are often tasked with making personal decisions about what kind of life they wish to have in the future and incorporating the past trauma into their personal narrative of their past, present, and future. Narrative therapies, such as those delivered through expressive writing and reflection have been shown to have positive effects on PTG (Hijazi et al., 2014). Interventions that integrate narrative development have been shown to be of benefit with a range of trauma survivors (Neimeyer, 2006; Smyth et al., 2008). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,564,917,690]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Along with core belief and narrative examination, the struggle with the aftermath of trauma often leads to an awareness of existential questions such as meaning and purpose of trauma and their lives. Survivors may struggle with questions about fairness, justice, and finding new meaning and purpose following significant loss (Frankl, 1962). The existential element is drawn from the concepts within logotherapy and existential therapy generally (Tedeschi and Riffle, 2016). Examination of existential issues is deliberately addressed within the PTG-based approach. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,692,917,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Interpersonal and \\\"common factors\\\" have been shown to be significant components of most psychotherapeutic interventions (Norcross and Wampold, 2011). In the PTG-based intervention, individuals called \\\"expert guides\\\" are individuals trained in providing a supportive environment, non-judgmental listening, unconditional positive regard, and activities toward promoting growth beyond symptom reduction (Calhoun and Tedeschi, 2013). This interpersonal element provides the foundation for trauma survivors to expand their support system, construct new core beliefs, and personal narrative that promotes posttraumatic growth. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,834,917,920]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PTG-based intervention is provided by individuals trained in providing \\\"expert companionship\\\" often referred to as \\\"expert guides.\\\" PTG-based intervention is conceptualized as a training program that follows the natural process following the aftermath of trauma. The goals are not limited to symptom reduction, but include managing distress, and achieving growth in multiple domains. There are five \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,38,151,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[761,38,917,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,211,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[489,948,507,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"03 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,948,915,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"2\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,93,485,120]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"general components in the structure of PTG-based intervention (Calhoun and Tedeschi, 2013). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,122,487,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Psychoeducation is provided regarding how trauma symptoms develop (Barlow, 2014) and understanding distressing symptoms (Meichenbaum, 2012). Further, psychoeducation is provided regarding the potential of PTG, the domains of PTG, and sharing personal examples. This includes a discussion of how core beliefs have been disrupted and how a reconceptualization and development of new core beliefs can be transformative toward living well and thriving in the aftermath of trauma (Calhoun and Tedeschi, 2013; Tedeschi and Moore, 2021). In addition, assurance about facing and addressing existential questions is provided within a caring and non-judgmental interpersonal relationship. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,279,487,405]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Teaching and practicing methods of emotional regulation is integrated throughout the structure of PTG-based intervention. This includes relaxation, focus on breathing, grounding techniques, mindfulness exercises, meditation, relaxed music listening, and exercise. Experiential practice is demonstrated and emphasized over intellectual understanding of these emotional regulation techniques. It is beneficial to allow survivors to experience a variety of ways to regulate emotions and select personal preferences to apply to their own lives (Cooper et al., 2019). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,407,487,562]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Disclosure is essential within the PTG-based intervention structure. Disclosure is modeled by the \\\"expert guides\\\" and a safe and supportive environment is fostered. However, in contrast to exposure-based therapies (Peterson et al., 2019), the disclosure is not focused on the specifics of the traumatic events, but on the impact of these events on the individual's core belief system about self, others, the world, and the future (Williams et al., 2019). Disclosure about one's personal life story broadly defined is encouraged within a non-judgmental context. Openness to sharing key personal life events, influences, successes, perceived failures, and decreasing defensiveness are important aspects of self-reflection and a sense of being accepted. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,564,487,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Development of a personal \\\"life story\\\" brings together an understanding of key past experiences, perhaps extending into childhood. It is not simply disclosure about the traumatic event. Rather, the development of the survivor's personal story includes the trauma in the context of entire past and future. It includes looking forward and consideration of new possibilities for the future and new ways of understanding the past. The narrative may bring up past events, regrets, guilt, or unresolved anger. Some aspects may require acceptance and other change in moving toward the future with growth. Development of a new \\\"life story\\\" narrative is achieved with the support of the \\\"expert guide\\\" and in the process of disclosure. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,721,487,804]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"As posttraumatic growth occurs, survivors may have new insights, goals, sense of meaning and purpose. An awareness of ways they can support the growth of others who may have experienced their own traumas, leads to a stronger connection with family and community. This can be manifested in new goals in life and awareness of service to help others and sharing their experience of PTG. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,806,487,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The Warrior PATHH (Progressive and Alternative Training for Helping Heroes) program is the flagship program of the Boulder Crest Foundation (BCF), a non-profit organization focused on the psychological health of U.S. veterans. The Warrior PATHH program is a 7 days intensive residency program developed to provide PTG-based training and experiences to veterans. The program consists of 48 psychoeducational modules, which are described in a 200-page guide developed for program instructors. Although the program does not offer traditional, evidenced-based psychotherapies, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,93,915,376]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"the program does utilize a variety of complementary and alternative interventions (e.g., mindfulness/meditation, yoga, equine therapy) and traditional psychotherapeutic techniques (e.g., psychoeducation, distress management, relationship building, narrative development, goal setting). A unique aspect of Warrior PATHH is that it is peer-delivered and is not run or managed by mental health professionals. This is an important component of the program as those working within Warrior PATHH are veterans who understand the unique needs and professional culture of those who attend the program. The peers who deliver the bulk of the program are combat veterans who have undergone several months of training from peer leaders with years of experience delivering the program as well as licensed mental health professionals. Peers delivering the program receive ongoing training and consultation from these same peer leaders and professionals. Consequently, Warrior PATHH is considered a training program as opposed to a treatment program. Following the residential portion of the program, a structured 18 months of follow-up is offered through a web-based series of meetings and assignments. A more complete description of the Warrior PATHH program can be found in Moore et al. (2021). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,378,915,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"While the PTG-based intervention approach of Warrior PATHH has been well developed and manualized, to date there has been limited outcome research. A small pilot study of the Warrior PATHH posttraumatic growth-based intervention program found significant, large reductions in symptomatology including PTSD, insomnia, and negative affect (Moore et al., 2021). Additionally, results indicated significant increases in areas of PTG and psychological flexibility. While these results are encouraging, they do not report immediate outcomes of study participants, resulting in the inability to gather a full picture of immediate and long-term effects. Without the report of immediate outcomes, one does not know about the trajectory of benefit to participants and cannot determine any lasting changes. The purpose of the present study was to address this gap in research by conducting a retrospective evaluation of a much larger sample of veterans with PTSD symptoms who completed the Warrior PATHH program. Outcome data were collected at baseline, after the 7 day program was completed, and at 18 months follow-up. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,646,591,661]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Method \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,678,915,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Participants were United States combat Veterans completing the Warrior PATHH program. Participants were self-referred and most commonly learned about the program from other veterans and family members familiar with the training program. Participation in the training program was free of cost to all participants and they received no compensation for completing the training. Inclusion criteria for the Warrior PATHH program were individuals who were (1) U.S. military Veterans and (2) had a previous history of trauma. Individuals were excluded from participation if they (1) were diagnosed with any disorder that might require hospitalization, such as psychosis, substance abuse, or active suicidality. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,835,915,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data collection for all participants occurred prior to the initiation of the program (Day 0), which will be referred to as baseline; at the end of the training (Day 7), which will be referred to as endpoint; and 18 months following the completion of training, which will be referred to as follow-up. The formal evaluation at baseline, endpoint, and follow-up was completed through the administration of an electronic questionnaire. A selection of measurements relating to growth and symptomatology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,149,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[761,39,915,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,210,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[490,948,507,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"04 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[836,948,915,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"3\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,93,485,120]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"domains are reported in this manuscript. All measurement tools listed were collected at baseline, endpoint, and 18-month follow-up. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,147,169,162]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Measures \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,179,487,334]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Posttraumatic Growth Inventory - Expanded (PTGI-X). The PTGI-X (Tedeschi et al., 2017) is a 25-item self-report measure used to assess the extent to which individuals report positive psychological change following the experience of a traumatic event. Five subscales of this measure assess changes in one's perception of new possibilities, relating to others, personal strength, appreciation of life, and spiritual existential change. Individual items are on a 6-point Likert scale ranging from \\\"I did not experience this change\\\" to \\\"I experienced this change to a very great degree.\\\" Good internal consistency $(\\\\alpha = 0.90$ ; Tedeschi et al., 2017) and content validity has been shown in research (Shakespeare-Finch et al., 2013). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,335,487,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Positive and Negative Affect Schedule (PANAS). The PANAS (Watson et al., 1988) is a 20-item self-report measure for both positive and negative affect. Individual item responses are on a 5-point frequency scale ranging from \\\"not at all\\\" to \\\"extremely.\\\" Strong reliability for both the positive $(\\\\alpha = 0.89)$ and negative subscale $(\\\\alpha = 0.85)$ and construct validity has been reported in addition to substantial available normative data (Crawford and Henry, 2004). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,435,487,533]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Integration of Stressful Life Experiences Scale (ISLES). The ISLES (Holland et al., 2010) is a 16-item self-report measure used to assess the extent of meaning made following a stressful life experience. Individual items are on a 5-point Likert scale ranging from \\\"strongly agree\\\" to \\\"strongly disagree.\\\" The ISLES has exhibited strong internal consistency, strong convergent validity, and moderate test-retest reliability (Holland et al., 2010). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,535,487,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Posttraumatic Stress Disorder Checklist DSM 5 (PCL-5). The PCL-5 (Weathers et al., 2013) is a 20-item self-report measure assessing DSM-5 symptoms of PTSD. Individual item responses are on a 5-point frequency scale ranging from \\\"not at all\\\" to \\\"extremely.\\\" Strong construct validity $(\\\\alpha = 0.92)$ and test-retest reliability $(r = 0.57)$ has been found in veteran samples (Bovin et al., 2015; Dutra et al., 2019). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,620,487,719]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Depression, Anxiety, and Stress Scale (DASS). The DASS (Antony et al., 1998) is a 21-item self-report measures of the presence and degree of depression, anxiety, and stress-related symptoms. Individual item responses are on a 4-point frequency scale ranging from \\\"never\\\" to \\\"almost always.\\\" Adequate test-retest reliability ( $\\\\alpha = 0.86 - 0.90$ ; Gloster et al., 2008) in addition to discriminate and convergent validity has been shown in clinical samples (Brown et al., 1997). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,720,487,819]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Insomnia Severity Index (ISI). The ISI (Bastien et al., 2001) is a 7-item self-report measure, based on DSM-IV and the International Classification of Sleep Disorders criteria, used to assess insomnia over the past 2 weeks. Individual items are assessed on a 5-point Likert scale ranging from \\\"none\\\" to \\\"very severe.\\\" High reliability and validity have been shown for the ISI in both clinical $(\\\\alpha = 0.91)$ and community $(\\\\alpha = 0.90)$ samples (Morin et al., 2011). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,846,196,860]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Intervention \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,877,487,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Framed as an intensive training program for veterans, the evaluated program is the Warrior PATHH (Progressive and Alternative Training for Helping Heroes). The manualized, 7 days training program is based on posttraumatic growth theory and its intervention model (Tedeschi \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,93,915,419]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and McNally, 2011; Calhoun and Tedeschi, 2013; Tedeschi and Moore, 2016, 2018). During this 7 days period, participants are immersed in an all-day intensive regimen combining education and experiential activities. Participants who attend the Warrior PATHH program experienced the following five elements in accordance with the PTG model: psychoeducation about physiological and psychological trauma response and psychological growth; emotion regulation training, including mindfulness and meditative techniques; constructive self-disclosure about trauma and its aftermath that occurs naturally through casual discourse; non-trauma focused narrative development integrating perspectives of past, present, and future; and service goals that are developed to carry out the lessons learned about the value of life, living courageously, and understanding those who have not had the same experiences (Moore et al., 2021). Representing a relational approach to the intervention called Expert Companionship, those providing the intervention are referred to as \\\"expert guides.\\\" All expert guides that were responsible for delivering the intervention were U.S. combat veterans who underwent several months of training with established expert guides and mental health professionals trained in the PTG-based intervention. Delivered as a peer-to-peer training program, the Warrior PATHH program took place during a 7 days period at the BCF facility in Bluemont, Virginia, between February 2019 and December 2021. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,445,589,463]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Analyses \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,478,915,646]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Descriptive statistics at baseline, endpoint, and follow-up were calculated for each of the outcome measures. To determine immediate post-intervention effects, paired samples $t$ -tests were conducted for each outcome. Paired samples $t$ -tests are used to determine the statistical significance of the difference in scores on outcome measures from baseline to endpoint. The independent variable in these analyses was study time point which had two levels, baseline (Day 1) and endpoint (Day 7). Dependent variables in these analyses were growth domains, including posttraumatic growth, positive affect, and integration of stressful life experiences; and symptomatology domains, including PTSD symptoms, depression, anxiety, stress, negative affect, and insomnia. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,649,915,791]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the lasting effects of the Warrior PATHH program on growth and symptomatology domains a series of repeated measures analysis of variance (repeated measures ANOVA) were conducted, which are extensions of the paired-samples $t$ -tests. The independent variable for these repeated measures ANOVAs was \\\"time\\\" (baseline, endpoint, and follow-up). The dependent variables for these repeated measures ANOVAs were the specific outcome measures. In the event of a significant main effect of time, pairwise comparisons using a Bonferroni correction were examined to determine differences between specific study time points. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,791,915,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"To determine the moderating effect of gender on immediate and lasting post-intervention effects on growth and symptomatology domains, multiple analyses of covariance (ANCOVA) were conducted. The independent variable for these ANCOVAs examining immediate effects was \\\"gender,\\\" the dependent variables were the scores on the specific outcome measures at endpoint, and the covariates were the baseline score of the specific outcome. The independent variable for the ANCOVAs examining lasting effects was \\\"gender,\\\" the dependent variables were the scores of the specific outcome measure at follow-up, and the covariates were the endpoint score of the specific outcome. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,149,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[761,38,915,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,208,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[490,948,505,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"05 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[836,948,914,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"4\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,89,159,107]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,122,490,219]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Participants were 184 United States combat veterans (male = 155, female = 29) who completed the Warrior PATHH training program between February 2019 and December 2021. The most common U.S. military branch of service represented was Army $(n = 110)$ , with the second most frequent being Marine Corps. $(n = 32)$ . Frequencies of all participant demographic variables can be found in Table 1. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,221,489,322]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"All participants $(n = 184)$ provided complete data at baseline and endpoint and were included in all analyses examining post-intervention changes. At the optional 18 months follow-up time point, 74 individuals completed outcome measures. Due to the nature of the statistical analyses examining long-term changes, only the 74 individuals who provided data at all three time points were included in the analyses of long-term changes at 18 months. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,347,438,378]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Post-intervention changes in growth domains \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,393,489,577]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A paired samples $t$ -test was used to compare scores on each growth-related outcome variable between baseline and endpoint. Results indicate that immediately following training (Day 7), participants reported a significant increase in scores by $54\\\\%$ on the posttraumatic growth outcome measure (PTGI-X) from baseline $(\\\\mathrm{M} = 50.2, \\\\mathrm{SD} = 31.1)$ to endpoint $(\\\\mathrm{M} = 77.4, \\\\mathrm{SD} = 29.6)$ , $t(183) = -8.78$ , $p < 0.001$ . Additionally, there was a significant increase in scores by $45\\\\%$ on the positive affect subscale of the PANAS from baseline $(\\\\mathrm{M} = 25.8, \\\\mathrm{SD} = 8.4)$ to endpoint $(\\\\mathrm{M} = 37.5, \\\\mathrm{SD} = 6.9)$ , $t(183) = -14.84$ , $p < 0.001$ . Finally, there was a significant increase in scores by $29\\\\%$ on the ISLES from baseline $(\\\\mathrm{M} = 39.2, \\\\mathrm{SD} = 12.9)$ to endpoint $(\\\\mathrm{M} = 50.4, \\\\mathrm{SD} = 10.9)$ , $t(183) = -9.13$ , $p < 0.001$ . Table 2 contains calculated effect sizes for each paired sample comparison. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,577,489,806]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Results from paired samples $t$ -tests for scores on each subscale of the PTGI-X indicate a significant difference between baseline and endpoint for New Possibilities (M = 10.6, SD = 7.3, M = 15.7, SD = 6.3, respectively), $t(183) = -7.13$ , $p < 0.001$ ; Personal Strength (M = 8.9, SD = 5.9, M = 13.8, SD = 4.8, respectively), $t(183) = -9.01$ , $p < 0.001$ ; Appreciation of Life (M = 8.22, SD = 4.2, M = 9.7, SD = 3.9, respectively), $t(183) = -3.71$ , $p < 0.001$ ; Relating to Others (M = 12.6, SD = 9.6, M = 21.5, SD = 9.5, respectively), $t(183) = -9.47$ , $p < 0.001$ ; and Spiritual-Existential Change (M = 10.0, SD = 8.4, M = 16.6, SD = 8.5, respectively), $t(183) = -7.54$ , $p < 0.001$ . Medium effect sizes were found for scores on the subscales of Relating to Others (Cohen's $d = -0.70$ ), Personal Strength (Cohen's $d = -0.66$ ), Spiritual-Existential Change (Cohen's $d = -0.56$ ), and New Possibilities (Cohen's $d = -0.53$ ), and there was a small effect size for scores on Appreciation of Life subscale (Cohen's $d = -0.27$ ). \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[78,832,354,863]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Post-intervention changes in symptomatology domains \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,877,490,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Next, a paired samples $t$ -test was used to compare scores on each symptomatology-related outcome variable between baseline \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[507,105,917,511]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0980/ebeb30d7d3a1a74a8fe51f19b3302f218d08cfeff900e1688a4363d1dce3bff1.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Demographic variable</td><td>Frequency</td></tr><tr><td>Gender</td><td></td></tr><tr><td>Male</td><td>155</td></tr><tr><td>Female</td><td>29</td></tr><tr><td>Age range</td><td></td></tr><tr><td>23–27</td><td>3</td></tr><tr><td>28–32</td><td>15</td></tr><tr><td>33–37</td><td>46</td></tr><tr><td>38–42</td><td>43</td></tr><tr><td>43–47</td><td>24</td></tr><tr><td>48 or older</td><td>53</td></tr><tr><td>Branch of service</td><td></td></tr><tr><td>Air Force</td><td>18</td></tr><tr><td>Army</td><td>110</td></tr><tr><td>First Responder</td><td>12</td></tr><tr><td>Marine Corps</td><td>32</td></tr><tr><td>Navy</td><td>12</td></tr><tr><td>Military Rank</td><td></td></tr><tr><td>E1-E4</td><td>32</td></tr><tr><td>E5-E6</td><td>69</td></tr><tr><td>E7 or above</td><td>41</td></tr><tr><td>Officer/Warrant Officer</td><td>31</td></tr><tr><td>Not specified</td><td>11</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 1 Participant demographics. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[507,545,917,620]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0503/11d8ca2d5a722d246148f514ac56b8ca5f9d8bd6db878412e99417ac88e7f2ab.jpg\",\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Outcome</td><td>Effect Size (d)</td></tr><tr><td>PTG</td><td>-0.65</td></tr><tr><td>Positive affect</td><td>-1.09</td></tr><tr><td>ISLES</td><td>-0.67</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 2 Growth domains effect sizes. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[504,649,919,906]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"and endpoint. Results indicate that immediately following training (Day 7), participants reported a significant decrease in scores by $49\\\\%$ on the PCL-5 from baseline $(M = 39.7, SD = 17.6)$ to endpoint $(M = 20.1, SD = 13.2)$ , $t(183) = 11.75$ , $p < 0.001$ . A significant decrease in scores was reported for all subscales of the DASS. Depression subscale scores decreased by $60\\\\%$ from baseline $(M = 8.0, SD = 5.2)$ to endpoint $(M = 3.2, SD = 3.0)$ , $t(183) = 10.68$ , $p < 0.001$ ; anxiety subscale scores decreased by $28\\\\%$ from baseline $(M = 5.8, SD = 4.3)$ to endpoint $(M = 4.2, SD = 3.5)$ , $t(183) = 4.08$ , $p < 0.001$ ; and stress subscale scores decreased by $50\\\\%$ from baseline $(M = 10.0, SD = 4.4)$ to endpoint $(M = 5.0, SD = 3.3)$ , $t(183) = 12.21$ , $p < 0.001$ . Participant scores on the ISI significantly decreased by $36\\\\%$ from baseline $(M = 14.3, SD = 6.9)$ to endpoint $(M = 9.1, SD = 5.3)$ , $t(183) = 8.03$ , $p < 0.001$ . Finally, scores on the negative affect subscale of the PANAS significantly decreased by $16\\\\%$ from baseline $(M = 25.4, SD = 8.2)$ to endpoint $(M = 21.4, SD = 7.4)$ , $t(183) = 4.89$ , $p < 0.001$ . Table 3 contains calculated effect sizes for each paired sample comparison. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,38,151,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[759,38,917,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,211,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[489,948,507,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"06 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,948,917,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"5\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[78,91,445,108]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Long term changes in growth domains \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,121,489,306]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A series of independent samples $t$ -tests were first conducted to determine if the 74 participants who completed follow-up measures were representative of the entire sample. The test variable for each of these analyses was the baseline score of each outcome measure. The grouping variable used was (A = Participants who completed baseline and endpoint data; $n = 110$ ) and (B = participants who completed follow-up measures; $n = 74$ ). Results of these $t$ -tests indicate that there were no significant differences between groups on any outcome measure at baseline, with the exception of baseline depression (Mean Difference $= 1.59$ , $p = 0.041$ ) and baseline ISLES (Mean Difference $= 4.32$ , $p = 0.023$ ) scores. Overall, these findings suggest a follow-up sample representative of the entire sample. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[77,307,489,450]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A series of repeated measures ANOVAs were then conducted to examine changes in growth-related outcome measures over three time points (baseline, endpoint, and follow-up). The analysis on PTGI-X scores revealed a significant main effect of time, $F(2,146) = 21.26$ , $p < 0.001$ . Pairwise comparisons indicate that PTGI-X scores significantly increased by 27.1 points (52%) from baseline to endpoint ( $p < 0.001$ ) and remained stable until follow-up, exhibited by a further increase of 0.85 points ( $p = 1.00$ ) and a total increase of 54% between baseline and follow-up. The analysis on positive affect subscale scores also revealed a significant main effect \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,492,487,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0338/ab9e7514a52f37a5de033e163b02ea9e90eb5da74aa758677123ea68343001df.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td>Outcome</td><td>Effect Size (d)</td></tr><tr><td>PTSD</td><td>0.87</td></tr><tr><td>Depression</td><td>0.79</td></tr><tr><td>Anxiety</td><td>0.30</td></tr><tr><td>Stress</td><td>0.90</td></tr><tr><td>Insomnia</td><td>0.59</td></tr><tr><td>Negative affect</td><td>0.36</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 3 Symptomatology domains effect sizes. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[504,93,917,363]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"of time, $F(2,146) = 56.09$ , $p = < 0.001$ . Pairwise comparisons indicate that scores on the positive affect subscale significantly increased by 11.1 points (41%) from baseline to endpoint ( $p < 0.001$ ). Results indicate that between endpoint and follow-up, positive affect subscale scores significantly decreased by 8.2 points ( $p < 0.001$ ); however, there remained a significant difference between baseline and follow-up scores ( $p = 0.010$ ) exhibited by a total increase of 11% between baseline and follow-up. Regarding the analysis on ISLES scores, Mauchly's test indicated that the assumption of sphericity had been violated, $\\\\chi^2 (2) = 6.70$ , $p = 0.035$ , therefore the degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity ( $\\\\varepsilon = 0.918$ ). The results indicate a significant main effect of time, $F(1.84, 134.09) = 23.99$ , $p < 0.001$ . Pairwise comparisons indicate that ISLES scores significantly increased by 9.69 points (23%) from baseline to endpoint ( $p < 0.001$ ) and remained stable until follow-up, exhibited by a non-significant increase of 1.42 points ( $p = 1.00$ ) and a total increase of 27% from baseline to follow-up. Table 4 includes means and standard deviations for each growth-related outcome measure at each time point. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[504,363,917,621]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The analyses on PTGI-X subscale scores revealed a significant main effect of time for Appreciation of Life, $F(2,146) = 3.25$ , $p = 0.041$ ; Personal Strength, $F(2,146) = 24.66$ , $p < 0.001$ ; New Possibilities, $F(2,146) = 13.91$ , $p < 0.001$ ; Relating to Others $F(1.81, 131.96) = 24.21$ , $p < 0.001$ ; and Spiritual-Existential Change, $F(1.75, 127.84) = 17.96$ , $p < 0.001$ . Mauchly's test indicated that the assumption of sphericity had been violated for the scores on subscales Relating to Others, $\\\\chi^2 (2) = 8.10$ , $p = 0.017$ , and Spiritual-Existential Change, $\\\\chi^2 (2) = 11.03$ , $p = 0.004$ , therefore the degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity ( $\\\\varepsilon = 0.904$ , $\\\\varepsilon = 0.876$ ; respectively). Pairwise comparisons indicate that all subscales with a significant main effect of time, with the exception of the Appreciation of Life subscale, exhibited a significant increase in scores from baseline to endpoint, followed by stability through follow-up. This stability through follow-up was exhibited by a non-significant decrease in scores for Personal Strength and New Possibilities subscales and by a non-significant increase in scores for the Relating to Others and Spiritual-Existential Change subscales. Table 5 includes \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,653,915,747]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0103/084e63b82d570673df2639dd29412d8cd09108aec7a532ac2d5260c130a388f5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Outcome</td><td colspan=\\\"2\\\">Baseline</td><td colspan=\\\"2\\\">Endpoint</td><td colspan=\\\"2\\\">Follow-up</td></tr><tr><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td></tr><tr><td>PTG</td><td>52.03</td><td>29.20</td><td>79.12</td><td>30.47</td><td>79.97</td><td>31.40</td></tr><tr><td>Positive Affect</td><td>27.20</td><td>7.94</td><td>38.26</td><td>5.74</td><td>30.09</td><td>7.98</td></tr><tr><td>ISLES</td><td>41.66</td><td>11.60</td><td>51.35</td><td>10.49</td><td>52.77</td><td>9.86</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 4 Long-term changes in growth domains. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[80,788,915,917]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0110/69d8192bf031b6849dcb3091e8469d550f24e413a674eba6dacc288dae7a18ac.jpg\",\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Outcome</td><td colspan=\\\"2\\\">Baseline</td><td colspan=\\\"2\\\">Endpoint</td><td colspan=\\\"2\\\">Follow-up</td></tr><tr><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td></tr><tr><td>Appreciation of Life</td><td>8.35</td><td>4.20</td><td>9.89</td><td>3.87</td><td>9.69</td><td>4.04</td></tr><tr><td>Personal Strength</td><td>8.76</td><td>5.49</td><td>13.95</td><td>5.00</td><td>13.65</td><td>5.30</td></tr><tr><td>New Possibilities</td><td>10.73</td><td>7.60</td><td>16.00</td><td>6.46</td><td>15.93</td><td>6.87</td></tr><tr><td>Relating to Others</td><td>13.62</td><td>8.78</td><td>22.34</td><td>9.37</td><td>22.68</td><td>9.28</td></tr><tr><td>Spiritual-Existential Change</td><td>10.57</td><td>8.42</td><td>16.95</td><td>8.89</td><td>18.03</td><td>8.43</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 5 Long-term changes in PTGI-X subscales. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[80,38,151,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[759,38,917,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,211,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[489,948,507,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"07 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[835,948,915,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"6\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,93,485,120]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"means and standard deviations for each PTGI-X subscale at each time point. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,147,448,177]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Long term changes in symptomatology domains \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,193,489,734]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"A series of repeated measures ANOVAs were conducted to examine changes in symptomatology-related outcome measures over three time points (baseline, endpoint, and follow-up). Mauchly's Test of Sphericity indicated that the assumption of sphericity had been violated for PCL-5 scores, $\\\\chi^2 (2) = 15.82$ , $p < 0.001$ , depression scores, $\\\\chi^2 (2) = 23.17$ , $p < 0.001$ , anxiety scores, $\\\\chi^2 (2) = 12.80$ , $p = 0.002$ , ISI scores, $\\\\chi^2 (2) = 12.91$ , $p = 0.002$ , and negative affect scores, $\\\\chi^2 (2) = 11.52$ , $p = 0.003$ , and therefore a Greenhouse-Geisser correction was used for each of these analyses. The analysis of PCL-5 scores revealed a significant main effect of time, $F(1.67, 146) = 33.87$ , $p < 0.001$ . Pairwise comparisons indicate that PCL-5 scores significantly decreased by 15.66 points $(43\\\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up, exhibited by a further decrease of 2.43 points $(p = 1.00)$ and a total decrease of $49\\\\%$ from baseline to follow-up. The analysis of depression subscale scores revealed a significant main effect of time, $F(1.57, 114.49) = 21.05$ , $p < 0.001$ . Pairwise comparisons indicate that depression subscale scores significantly decreased by 3.37 points $(48\\\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up, exhibited by a further decrease of 0.31 points $(p = 1.00)$ and a total decrease of $53\\\\%$ from baseline to follow-up. The analysis of anxiety subscale scores revealed a significant main effect of time, $F(1.72, 125.55) = 9.09$ , $p < 0.001$ . Pairwise comparisons indicate that anxiety subscale scores did not significantly decrease from baseline to endpoint $(p = 0.534)$ , but did significantly decrease by 1.55 points from endpoint to follow-up $(p = 0.029)$ resulting in a total decrease of $45\\\\%$ from baseline to follow-up. The analysis of stress subscale scores revealed a significant main effect of time, $F(2, 146) = 29.30$ , $p < 0.001$ . Pairwise comparisons indicate that stress subscales scores significantly decreased by 4.22 points $(44\\\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up exhibited by a non-significant further decrease in scores by 0.04 points $(p = 1.00)$ and a total decrease of $44\\\\%$ from baseline to follow-up. The analysis of ISI scores revealed a significant main effect of time $F(1.72, 125.42) = 15.60$ , $p < 0.001$ . Pairwise comparisons indicate ISI scores significantly decreased by 4.38 points $(32\\\\%)$ from baseline to endpoint $(p < 0.001)$ and remained stable until follow-up, exhibited by a non-significant further decrease in scores by 0.32 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,93,915,221]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"points $(p = 1.00)$ and a total decrease of $34\\\\%$ from baseline to follow-up. The analysis of negative affect subscale scores revealed a significant main effect of time $F(1.74, 127.19) = 20.33$ , $p < 0.001$ . Pairwise comparisons indicate that negative affect subscale scores did not significantly decrease from baseline to endpoint $(p = 0.674)$ , but did significantly decrease by 5.00 points from endpoint to follow-up $(p < 0.001)$ , resulting in a total decrease of $27\\\\%$ from baseline to follow-up. Table 6 includes means and standard deviations for each symptomatology measure at each time point. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,247,880,277]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gender differences in post-intervention outcomes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,293,915,432]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Multiple one-way ANCOVAs were conducted to determine a statically significant difference between male and female participants on each growth and symptomatology-related outcome measure at endpoint, controlling for participant baseline scores. After adjustment for pre-intervention scores, there was only one outcome measure, DASS anxiety subscale scores, that resulted in a statistically significant difference in post-intervention scores between male and female participants, $F(1, 181) = 4.17$ , $p = 0.043$ , partial $\\\\eta^2 = 0.023$ . Analysis of covariance results, in addition to adjusted means and standard errors, for all outcome measures can be found in Table 7. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,461,912,476]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Gender differences in long-term outcomes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,492,915,619]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Finally, multiple one-way ANCOVAs were conducted to determine a statistically significant difference between male and female participants on each growth- and symptomatology-related outcome measure at follow-up, controlling for participant endpoint scores. After adjustment for endpoint scores, no outcome measure at follow-up indicated a statistically significant difference between male and female participants. Analysis of covariance results, in addition to adjusted means and standard errors, for all outcome measures at follow-up can be found in Table 8. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,646,621,661]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Discussion \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,677,915,734]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The present study examined the impact of a manualized, posttraumatic growth-oriented training program on various growth and symptomatology-related outcome variables among U.S. military veterans. The utilized training program, the Warrior PATHH program, \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,771,915,916]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0381/18bd0626043c0056ad75d9cbfac121d25777bcaebac1d46e9e34f1b4596f2a63.jpg\",\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Outcome</td><td colspan=\\\"2\\\">Baseline</td><td colspan=\\\"2\\\">Endpoint</td><td colspan=\\\"2\\\">Follow-Up</td></tr><tr><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td><td>Mean</td><td>SD</td></tr><tr><td>PTSD</td><td>36.80</td><td>18.20</td><td>21.14</td><td>13.05</td><td>18.70</td><td>14.20</td></tr><tr><td>Depression</td><td>6.99</td><td>5.27</td><td>3.62</td><td>3.25</td><td>3.31</td><td>3.74</td></tr><tr><td>Anxiety</td><td>5.55</td><td>4.47</td><td>4.62</td><td>3.89</td><td>3.07</td><td>3.35</td></tr><tr><td>Stress</td><td>9.68</td><td>4.59</td><td>5.46</td><td>3.33</td><td>5.42</td><td>4.09</td></tr><tr><td>Insomnia</td><td>13.77</td><td>7.29</td><td>9.39</td><td>5.51</td><td>9.07</td><td>5.74</td></tr><tr><td>Negative Affect</td><td>24.00</td><td>7.59</td><td>22.51</td><td>6.48</td><td>17.51</td><td>6.87</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 6 Long-term changes in symptomatology domains. \\\"]\",\n \"table_footnote\": \"[]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[80,39,149,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[761,38,915,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,210,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[490,948,505,958]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"08 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[836,948,915,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"7\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,104,917,303]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0339/58d97f79874badaacce06a140ba51232ffba76469119e3d65996d9e235dcd7d5.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Outcome</td><td colspan=\\\"2\\\">Male (n = 155)</td><td colspan=\\\"2\\\">Female (n = 29)</td><td rowspan=\\\"2\\\">F</td><td rowspan=\\\"2\\\">p</td><td rowspan=\\\"2\\\">partial η²</td></tr><tr><td>Meana</td><td>SE</td><td>Meana</td><td>SE</td></tr><tr><td>PTG</td><td>77.26</td><td>2.40</td><td>77.89</td><td>5.58</td><td>0.011</td><td>0.918</td><td>0.000</td></tr><tr><td>Positive Affect</td><td>37.47</td><td>0.56</td><td>37.51</td><td>1.29</td><td>0.001</td><td>0.976</td><td>0.000</td></tr><tr><td>ISLES</td><td>50.36</td><td>0.88</td><td>50.82</td><td>2.05</td><td>0.042</td><td>0.838</td><td>0.000</td></tr><tr><td>PTSD</td><td>20.58</td><td>1.06</td><td>17.41</td><td>2.47</td><td>1.38</td><td>0.242</td><td>0.008</td></tr><tr><td>Depression</td><td>3.34</td><td>0.24</td><td>2.39</td><td>0.56</td><td>2.38</td><td>0.125</td><td>0.013</td></tr><tr><td>Anxiety</td><td>4.45</td><td>0.28</td><td>3.00</td><td>0.65</td><td>4.17</td><td>0.043</td><td>0.023</td></tr><tr><td>Stress</td><td>5.19</td><td>0.26</td><td>4.00</td><td>0.61</td><td>3.22</td><td>0.074</td><td>0.017</td></tr><tr><td>Insomnia</td><td>9.21</td><td>0.43</td><td>8.17</td><td>1.00</td><td>0.923</td><td>0.338</td><td>0.005</td></tr><tr><td>Negative Affect</td><td>21.66</td><td>0.60</td><td>19.69</td><td>1.39</td><td>1.70</td><td>0.194</td><td>0.009</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 7 Effect of gender on post-intervention outcomes. \\\"]\",\n \"table_footnote\": \"[\\\"${}^{a}$ Adjusted means after controlling for baseline scores are presented. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[80,355,917,552]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": \"images/0305/bde9213fc7adb26cd9068b69baf5a09b688dbd7da18182c5355a796f23c06380.jpg\",\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": \"<table><tr><td rowspan=\\\"2\\\">Outcome</td><td colspan=\\\"2\\\">Male (n = 63)</td><td colspan=\\\"2\\\">Female (n = 11)</td><td rowspan=\\\"2\\\">F</td><td rowspan=\\\"2\\\">p</td><td rowspan=\\\"2\\\">partial η²</td></tr><tr><td>Meana</td><td>SE</td><td>Meana</td><td>SE</td></tr><tr><td>PTG</td><td>79.77</td><td>3.98</td><td>81.13</td><td>9.52</td><td>0.017</td><td>0.896</td><td>0.000</td></tr><tr><td>Positive Affect</td><td>29.93</td><td>1.02</td><td>31.01</td><td>2.44</td><td>0.167</td><td>0.684</td><td>0.002</td></tr><tr><td>ISLES</td><td>52.05</td><td>1.23</td><td>56.90</td><td>2.94</td><td>2.33</td><td>0.132</td><td>0.032</td></tr><tr><td>PTSD</td><td>19.56</td><td>1.79</td><td>13.80</td><td>4.28</td><td>1.54</td><td>0.219</td><td>0.021</td></tr><tr><td>Depression</td><td>3.51</td><td>0.47</td><td>2.17</td><td>1.14</td><td>1.19</td><td>0.279</td><td>0.017</td></tr><tr><td>Anxiety</td><td>3.28</td><td>0.42</td><td>1.83</td><td>1.02</td><td>1.71</td><td>0.196</td><td>0.023</td></tr><tr><td>Stress</td><td>5.73</td><td>0.51</td><td>3.66</td><td>1.22</td><td>2.44</td><td>0.123</td><td>0.033</td></tr><tr><td>Insomnia</td><td>9.21</td><td>0.73</td><td>8.23</td><td>1.75</td><td>0.267</td><td>0.607</td><td>0.004</td></tr><tr><td>Negative Affect</td><td>17.67</td><td>0.88</td><td>16.62</td><td>2.11</td><td>0.211</td><td>0.647</td><td>0.003</td></tr></table>\",\n \"table_caption\": \"[\\\"TABLE 8 Effect of gender on long-term outcomes. \\\"]\",\n \"table_footnote\": \"[\\\"${}^{a}$ Adjusted means after controlling for endpoint scores are presented. \\\"]\",\n \"text\": null,\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"table\"\n },\n {\n \"bbox\": \"[80,592,489,749]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"is not conceptualized as a psychotherapeutic intervention. Rather, this manualized training program is peer based and developed to help veterans develop the tools necessary to increase their capacity to regulate thoughts, emotions, and actions in a civilian environment. The primary focus of the Warrior PATHH training is the facilitation of PTG and its five domains. However, the integrated nature of the training means that many elements of empirically based PTSD treatments have been incorporated into the design. The incorporation of these elements implies that completion of the training program should also have an impact on the presentation of PTSD related symptomatology. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,775,346,790]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Post-intervention outcomes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,804,489,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"In accordance with our hypotheses regarding immediate post-intervention changes, findings revealed significant improvements on all growth-related outcome measures immediately following the training. Specifically, participants reported a $54\\\\%$ increase in scores on the posttraumatic growth inventory (PTGI-X) from baseline to endpoint, indicating that participants experienced a noteworthy enhancement in their perception of posttraumatic growth-related domains in the aftermath of the training. Further evidence of this growth is exhibited \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,592,917,834]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"by significant improvements on all five subscales of the PTGI-X. Similarly, a significant increase in scores was observed for the positive affect subscale of the PANAS, exhibited by a $45\\\\%$ increase in scores from baseline to endpoint. This suggests that participants experienced notable improvement in their overall positive emotional states following the training. Finally, findings revealed a significant increase in scores on the ISLES from baseline to endpoint by $29\\\\%$ , indicating that participants are able to report an increased sense of meaning following their previous trauma exposure. The observed effect sizes for each paired sample comparison, as presented in Table 2, further support the robustness of this study's findings. The magnitude of change found in each growth-related outcome variable provides additional evidence for the meaningful impact of training program on participants self-reported experiences. Overall, the results provide strong empirical support for the effectiveness of the Warrior PATHH training program in promoting posttraumatic growth, positive affect, and the integration of stressful experiences immediately following training. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,834,917,919]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"While the program was not focused on treatment, it is very noteworthy that participants reported significant reduction of PTSD symptomatology scores by $49\\\\%$ from baseline to endpoint. This suggests a notable alleviation of PTSD related symptoms among participants. Additional significant reductions were found for depression $(60\\\\%)$ , anxiety $(28\\\\%)$ , and stress $(50\\\\%)$ scores from \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,39,149,48]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Rhodes et al. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[761,38,917,49]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"10.3389/fpsyg.2023.1322837 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"header\"\n },\n {\n \"bbox\": \"[80,948,211,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Frontiers in Psychology \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[489,948,507,959]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"09 \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"page_number\"\n },\n {\n \"bbox\": \"[836,948,915,960]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"8\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"frontiersin.org \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"footer\"\n },\n {\n \"bbox\": \"[80,93,487,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"baseline to endpoint. Finally, insomnia symptom scores decreased by $36\\\\%$ and negative affect by $16\\\\%$ from baseline to endpoint. The degree to which each of these domains changed from baseline to endpoint is demonstrated by paired sample comparisons in Table 3. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,175,485,193]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Long term 18months follow-up outcomes \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,206,487,449]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The observed increase in growth domains and decrease in symptomatology domains across participants immediately following the Warrior PATHH program sheds light on just how powerful an intensive training of this type can be. However, it is important to examine whether the improvements are maintained long-term after the individuals return to their normal environment. For example, each individual who attends the training has removed themselves from many of the daily stressors they experience, is given a strict schedule to adhere to, and is surrounded by individuals with similar experiences who are more likely to understand their struggles. Once the individual returns home, they are again exposed to any routine daily stressors, are responsible for their own schedule, and may not have the same level of empathetic community found during training. Significant results at the 18 months follow-up would indicate a high level of impact from the training, resulting in changes that are maintained for one and a half years post-training. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,450,487,590]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Data from repeated measures ANOVAs indicates that, for those who provided data at all three time points $(n = 74)$ , the significant increase in all growth-related outcome measure scores from baseline was maintained at the 18 months follow-up. Both PTGI-X and ISLES scores did not differ significantly from endpoint to follow-up, indicating stability and lasting benefits from the training program. Although there was a significant decrease in positive affect scores between endpoint and follow-up assessments, the scores remained significantly higher than baseline, indicating a lasting positive impact of the training. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,592,487,705]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Scores on all symptomatology-related outcome measures that exhibited a significant decrease from baseline to endpoint remained stable at the 18 months follow-up, maintaining their significant decrease from the baseline assessment. While both anxiety and negative affect scores experienced a non-significant decrease from baseline to endpoint, scores for both domains experienced a significant decrease from baseline to follow-up assessment. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,732,431,749]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Examination of gender of participants \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,763,487,904]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The present study also aimed to investigate the potential differences between male and female participants on various growth and symptomatology-related outcome measures at both endpoint and follow-up. The results of multiple one-way ANCOVA's indicate that after adjusting for pre-intervention scores, there was only a single outcome measure, DASS anxiety subscale scores, that showed a small but statistically significant difference in post-intervention scores between male and female participants. The effect size, as indicated by the partial $\\\\eta^2$ value, was very small, only explaining approximately $2.3\\\\%$ of the variance in scores on the anxiety subscale. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[80,906,487,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Interestingly, no significant gender differences were found for any other growth or symptomatology related outcome measure at \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,93,915,149]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"endpoint or follow-up, after controlling for the appropriate covariates. These findings indicate that on almost all outcome variables assessed, male and female participants showed similar levels of improvement at endpoint and maintenance of such improvement at follow-up. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,149,915,249]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The discrepancy in samples size for the analyses examining gender differences at follow-up should be noted, as male participants $(n = 63)$ far outnumbered female participants $(n = 11)$ . This overall small sample of participants may have influenced the statistical power to detect differences between genders. Furthermore, the smaller sample size of female participants may have limited the ability to detect any effects that could have been present. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,250,915,391]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The findings of these analyses are encouraging in that both female and male veterans seem to experience the same level of benefit from the posttraumatic growth-oriented training employed in this study. More specifically, the large increases in PTG and decreases in PTSD symptomatology were exhibited by participants, regardless of gender. These results indicate that the current training protocol seems to adequately address the needs of both male and female veterans, however future studies with larger and more balanced gender samples are needed to further explore the potential influence of gender on the assessed variables. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[510,418,727,434]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"PCL-5 threshold scores \",\n \"text_format\": null,\n \"text_level\": \"1\",\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,450,915,833]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"The PCL-5 was used to assess prevalence and severity of PTSD symptomatology among participants completing the training program. The high impact of the training on post-intervention and long-term follow up PCL-5 scores warrants further investigation. While the use of the PCL-5 was strictly to assess prevalence and severity of PTSD symptoms, and not a tool used to make a diagnosis, an investigation of the participants who fall above and below the diagnosis threshold score can be informative. For example, a provisional PTSD diagnosis can be made with a score of 33 or greater on the PCL-5. At the baseline assessment $(n = 184)$ , there were 120 individuals with scores greater than 33 and who theoretically would qualify for this provisional diagnosis. Immediately following the training, only 31 individuals had scores greater than 33, indicating that 89 individuals $(74\\\\%)$ have theoretically reduced symptomatology to a point that would no longer meet the diagnostic threshold. For those who provided data at all three study time points $(n = 74)$ , there were 40 individuals with PCL-5 scores greater than 33, meeting criteria for a provisional PTSD diagnosis at the baseline assessment. At the endpoint assessment, only 12 individuals had scores greater than 33, indicating 28 fewer individuals $(70\\\\%)$ met the diagnostic criteria regarding PCL-5 scores. One and a half years later at the 18 months follow-up assessment, 15 individuals had PCL5 scores greater than 33 indicating a rise in PTSD symptoms over the course of 18 months for 3 of the individuals. This rise in the number of individuals who exceed the diagnostic threshold is expected over time but highlights the need for continued support beyond the immediate post-intervention period. \",\n \"text_format\": null,\n \"text_level\": null,\n \"type\": \"text\"\n },\n {\n \"bbox\": \"[509,834,915,933]\",\n \"code_body\": null,\n \"code_caption\": null,\n \"image_caption\": null,\n \"image_footnote\": null,\n \"img_path\": null,\n \"list_items\": null,\n \"page_idx\": \"9\",\n \"sub_type\": null,\n \"table_body\": null,\n \"table_caption\": null,\n \"table_footnote\": null,\n \"text\": \"Together, these results underscore the positive impact of the Warrior PATHH training program in reducing PTSD symptomatology among veterans, despite its primary focus of increasing PTG. 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